tretinoin and Leukemia--Promyelocytic--Acute

The association of glomerulonephritis and malignant hematological disease is uncommon, but well known in chronic leukemias, lymphomas, and monoclonal gammopathies. However, only a few cases of glomerulonephritis and acute myeloid leukemia have been reported in the literature. We describe the first case of a genetically diagnosed acute promyelocytic leukemia presenting with nephrotic range proteinuria that resolved with induction therapy with ATRA and ATO and performed a comprehensive review of the literature.

Topics: Antineoplastic Combined Chemotherapy Protocols; Arsenicals; Glomerulonephritis; Humans; Induction Chemotherapy; Leukemia, Promyelocytic, Acute; Oxides; Tretinoin

to review the current diagnostic and therapeutic landscape of AML in Latin America as a reflection of other low- and middle-income countries and regions of the world. Encompassing both acute promyelocytic and non-promyelocytic disease types.. We reviewed the literature and study registries concerning epidemiological features of patients with AML/APL treated in Latin America, as well as evaluated diagnostic and genetic stratification and patient fitness assessment challenges, the importance of early mortality and supportive care capacity, intensive and non-intensive chemotherapy alternatives, consolidation, and maintenance strategies including novel agents and hematopoietic stem cell transplantation.. Although most of the current technologies and treatment options are available in the region, a significant fraction of patients have only limited access to them. In addition, mortality in the first weeks from diagnosis is higher in the region compared to developed countries.. Disparities in access to technologies, supportive care capacity, and availability of novel agents and HSCT hinder results in our region, reflecting barriers common to other LMICs. Recent developments in the diagnosis and treatment of this disease must be implemented through education, collaborative clinical research, and advocacy to improve outcomes.

Topics: Antineoplastic Combined Chemotherapy Protocols; Hematopoietic Stem Cell Transplantation; Humans; Latin America; Leukemia, Myeloid, Acute; Leukemia, Promyelocytic, Acute; Tretinoin

Acute promyelocytic leukemia patients with PLZF-RARa rearrangement have no obvious differentiation-inducing effect on retinoic acid, have a poor response to traditional chemotherapy, and have poor overall prognosis. A case of acute promyelocytic leukemia with PLZF / RARa rearrangement reported in this article was treated with induction chemotherapy with arsenic trioxide combined with a new anthracycline (idarubicin) cytotoxic chemotherapy. The patient achieved complete response in the bone marrow. After the first induction, and achieved molecular remission after the second consolidation chemotherapy. At present, the patient was followed up for 40 months after hematological and cytogenetic remission, and the PLZF / RARa real-time PCR test was continuously negative.

Topics: Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Humans; Leukemia, Promyelocytic, Acute; Oxides; Tretinoin

Processed from natural minerals, arsenic trioxide (ATO) as an ancient Chinese medicine has been used to treat diseases for over 2000 years. And it was applied to treat acute promyelocytic leukemia (APL) since the 1970s in China. Summarizing the clinical evidence of ATO in cancer is conducive to further understanding, development, and promotion of its pharmacological research.. It is the first time to comprehensively assess and summarize the evidence of ATO in cancer treatment via umbrella review.. 8 databases in English or Chinese from their inception to February 21, 2023 were searched by two reviewers separately and suitable meta-analyses (MAs) were included in this umbrella review. Their methodological quality and risk of bias were evaluated and data of outcomes was extracted and pooled again. The evidence certainty of pooled results was classified.. 17 MAs with 27 outcomes and seven comparisons in three cancers were included in this umbrella review. However, their methodological quality was unsatisfactory with 6 MAs as low quality and 12 MAs as critically low quality. Their shortcomings were mainly focused on protocol, literature selecting, bias risk, small sample study bias, and conflicts of interest or funding. And they were all assessed as high risk in bias. It was suggested that ATO had an advantage in enhancing complete remission rate, event-free survival, and recurrence free survival and decreasing recurrence rate, cutaneous toxicity, hyper leukocyte syndrome, tretinoin syndrome, edema and hepatotoxicity in different comparisons of APL with low or moderate certainty. Besides, compared with transcatheter arterial chemoembolization (TACE) alone, ATO plus TACE also could improve objective response rate, disease control rate, survival rate (0.5, 1, 2, and 3-year) and life quality and reduce the level of alpha fetoprotein in primarily hepatocellular carcinoma with low or moderate certainty. However, no significant results were found in MM. Finally, key findings were as followed. ATO has potential broad-spectrum anticancer effects but the clinical transformation is rarely achieved. Route of administration may affect the antitumor effects of ATO. ATO can act synergistically in combination with a variety of antitumor therapies. The safety and drug resistance of ATO should be paid more attention to.. ATO may be a promising drug in anticancer treatment although earlier RCTs have dragged down the level of evidence. However, high-quality clinical trials are expected to explore its broad-spectrum anticancer effects, wide application, appropriate route of administration, and compound dosage form.

Topics: Arsenic Trioxide; Carcinoma, Hepatocellular; Chemoembolization, Therapeutic; Humans; Leukemia, Promyelocytic, Acute; Liver Neoplasms; Randomized Controlled Trials as Topic; Tretinoin

Topics: Blast Crisis; Humans; Leukemia, Promyelocytic, Acute; Oncogene Proteins, Fusion; Tretinoin

Because there are few evidence-based guidelines and an extremely low incidence rate, managing and treating patients who have transitioned from acute promyelocytic leukemia (APL), which was diagnosed during pregnancy, to acute myeloid leukemia (AML), can be difficult.. In this case, a 34-year-old pregnant patient was diagnosed with APL in medium-risk group in June 2017. After the all-trans retinoic acid and arsenic trioxide-based full-course treatment, the patients achieved complete remission (CR) and were well-tolerated. After 5 years, the patient complained of fatigue for 3 months.. Bone marrow examination revealed hypercellularity with approximately 50% immunophenotypic abnormal myeloblasts with MLL-AF9 fusion gene. Based on the AML diagnosis criteria of the World Health Organization, the patient was eventually diagnosed with a rare transformation from APL to AML.. The patient was treated with two cycles of induction chemotherapy and an allogeneic hematopoietic stem cell transplantation (allo-HSCT).. Until now, the patient is in continuous remission with no signs of APL and AML.. Despite the rarity of APL to AML transformation, it is crucial to track the disease's progress and administer treatment on time. It remains uncertain whether the risk stratification and clinical outcomes of secondary AML with MLL-AF9 are equivalent to those of de novo AML with MLL-AF9. The management and treatment of these patients should be personalized and require further observation.

Topics: Adult; Female; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Leukemia, Promyelocytic, Acute; Myeloid-Lymphoid Leukemia Protein; Oncogene Proteins, Fusion; Pregnancy; Remission Induction; Tretinoin

Differentiation therapy using all-trans retinoic acid (ATRA) is well established for the treatment of acute promyelocytic leukemia (APL). Several attempts have been made to treat non-APL acute myeloid leukemia (AML) patients by employing differentiation inducers, such as hypomethylating agents and low-dose cytarabine, with encouraging results. In the present review, I focus on other possible differentiation inducers: kinase inhibitors and interferons (IFNs). A number of kinase inhibitors have been reported to induce differentiation, including CDK inhibitors, GSK3 inhibitors, Akt inhibitors, p38 MAPK inhibitors, Src family kinase inhibitors, Syk inhibitors, mTOR inhibitors, and HSP90 inhibitors. Other powerful inducers are IFNs, which were reported to enhance differentiation with ATRA. Although clinical trials for these kinase modulators remain scarce, their mechanisms of action have been, at least partly, clarified. The Raf/MEK/ERK MAPK pathway and the RARα downstream are affected by many of the kinase inhibitors and IFNs and seem to play a pivotal role for the induction of myeloid differentiation. Further clarification of the mechanisms, as well as the establishment of efficient combination therapies with the kinase inhibitors or IFNs, may lead to the development of effective therapeutic strategies for AML.

Topics: Antineoplastic Agents; Cell Differentiation; Glycogen Synthase Kinase 3; Humans; Interferons; Leukemia, Myeloid, Acute; Leukemia, Promyelocytic, Acute; Protein Kinase Inhibitors; Tretinoin

Acute myeloid leukemia (AML) is an aggressive and often fatal hematopoietic malignancy. A very attractive way to treat myeloid leukemia, called "differentiation therapy", was proposed when in vitro studies showed that some compounds are capable of inducing differentiation of AML cell lines. One of the differentiation-inducing agents, all-

Topics: Antineoplastic Agents; Cell Differentiation; Humans; Leukemia, Myeloid, Acute; Leukemia, Promyelocytic, Acute; Tretinoin; Vitamin D; Vitamins

The advent of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) has significantly improved the outcomes of acute promyelocytic leukemia (APL); nevertheless, a small fraction of patients still experience relapse. Due to the infrequency of APL relapse coupled with the rapid change in the therapeutic landscape, there are limited available data regarding the treatment of relapsed APL. In this situation, however, ATO-based therapy has been shown to result in high rates of hematological and molecular complete remission (CR). Autologous hematopoietic cell transplantation (HCT) is considered the postremission therapy of choice when patients achieve molecular CR, whereas recent studies have suggested that molecular CR is not prerequisite for the success of autologous HCT. Allogeneic HCT can be reserved for selected patients, i.e., those who cannot achieve CR and those who relapse after autologous HCT, because of high toxicities and the expectation of highly favorable outcomes with autologous HCT during CR. For patients who are ineligible for HCT, prolonged administration of ATRA + ATO would be a viable option. To further refine the therapy for patients with relapsed APL, it is imperative to aggregate clinical data of patients who relapse after the ATRA + ATO frontline therapy within the framework of national and international collaboration.

Topics: Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Humans; Leukemia, Promyelocytic, Acute; Oxides; Recurrence; Treatment Outcome; Tretinoin

Acute promyelocytic leukemia (APL) is associated with severe coagulopathy leading to rapid morbidity and mortality if left untreated. The definitive diagnosis of APL is made by identifying a balanced reciprocal translocation between chromosomes 15 and 17. This t(15;17) results in a fusion transcript of promyelocytic leukemia (PML) and retinoic acid receptor alpha (RARA) genes and the expression of a functional PML/RARA protein. Detection of a fused PML/RARA genomic DNA sequence using fluorescence in situ hybridization (FISH) or by detection of the PML/RARA fusion transcript via reverse transcriptase polymerase chain reaction (RT-PCR) has revolutionized the diagnosis and monitoring of APL. Once confirmed, APL is cured in over 90% of cases, making it the most curable subtype of acute leukemia today. Patients with low-risk APL are successfully treated using a chemotherapy-free combination of all-trans retinoic acid and arsenic trioxide (ATO). In this review, we explore the work that has gone into the modern-day diagnosis and highly successful treatment of this once devastating leukemia.

Topics: Arsenic; Arsenic Trioxide; Humans; In Situ Hybridization, Fluorescence; Leukemia, Promyelocytic, Acute; Nuclear Proteins; Promyelocytic Leukemia Protein; Receptors, Retinoic Acid; Retinoic Acid Receptor alpha; Transcription Factors; Translocation, Genetic; Tretinoin; Tumor Suppressor Proteins

Despite enormous global investment, translational medical research faces considerable challenges and patients, and their doctors are frequently frustrated by the apparent lack of research activity or progress. Understanding the factors that prevent innovative research discoveries from making it to clinical trials is a multifaceted problem. However, one question that must be addressed is whether the nature of current research activity and the factors that influence the conduct of pre-clinical research, permit, or hamper the timely progression of laboratory-based observations to proof of concept (PoC) clinical trials. Inherent in this question is to what extent a deep mechanistic understanding of a potential new therapy is required before commencing PoC studies, and whether patients are better served when mechanistic and clinical studies progress side by side rather than in a more linear fashion. Here we address these questions by revisiting the historical development of hugely impactful and paradigm-changing innovations in the treatment of hematological cancers. First, we compare the history and route to clinical PoC, of two molecularly-targeted therapies that are BCR:ABL inhibitors in chronic myeloid leukaemia and all-trans retinoic acid (ATRA) in acute promyelocytic leukaemia (APL). We then discuss the history of arsenic trioxide as additional APL therapy, and the repurposing of thalidomide as effective multiple myeloma therapy. These stories have surprising elements of commonality that demand debate about the modern-day hard and soft governance of medical research and whether these processes appropriately align the priorities of advancing scientific knowledge and the need of patients.

Topics: Arsenic Trioxide; Arsenicals; Hematologic Neoplasms; Humans; Leukemia, Promyelocytic, Acute; Oxides; Thalidomide; Translational Research, Biomedical; Tretinoin

Myeloid malignancies have always been at the forefront of an improved understanding of the molecular pathogenesis of cancer. In accordance, over the last years, basic research focusing on the aberrations underlying malignant transformation of myeloid cells has provided the basis for precision medicine approaches and subsequently has led to the development of powerful therapeutic strategies. In this review article, we will recapitulate what has happened since in the 1980s the use of all-trans retinoic acid (ATRA), as a first targeted cancer therapy, has changed one of the deadliest leukemia subtypes, acute promyelocytic leukemia (APL), into one that can be cured without classical chemotherapy today. Similarly, imatinib, the first molecularly designed cancer therapy, has revolutionized the management of chronic myeloid leukemia (CML). Thus, targeted treatment approaches have become the paradigm for myeloid malignancy, but many questions still remain unanswered, especially how identical mutations can be associated with different phenotypes. This might be linked to the impact of the cell of origin, gene-gene interactions, or the tumor microenvironment including the immune system. Continuous research in the field of myeloid neoplasia has started to unravel the molecular pathways that are not only crucial for initial treatment response, but also resistance of leukemia cells under therapy. Ongoing studies focusing on leukemia cell vulnerabilities do already point to novel (targetable) "Achilles heels" that can further improve myeloid cancer therapy.

Topics: Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid; Leukemia, Promyelocytic, Acute; Precision Medicine; Tretinoin; Tumor Microenvironment

Sphingolipid-mediated regulation in cancer development and treatment is largely ceramide-centered with the complex sphingolipid metabolic pathways unfolding as attractive targets for anticancer drug discovery. The dynamic interconversion of sphingolipids is tightly controlled at the level of enzymes and cellular compartments in response to endogenous or exogenous stimuli, such as anticancer drugs, including retinoids. Over the past two decades, evidence emerged that retinoids owe part of their potency in cancer therapy to modulation of sphingolipid metabolism and ceramide generation. Ceramide has been proposed as a 'tumor-suppressor lipid' that orchestrates cell growth, cell cycle arrest, cell death, senescence, autophagy, and metastasis. There is accumulating evidence that cancer development is promoted by the dysregulation of tumor-promoting sphingolipids whereas cancer treatments can kill tumor cells by inducing the accumulation of endogenous ceramide levels. Resistance to cancer therapy may develop due to a disrupted equilibrium between the opposing roles of tumor-suppressor and tumor-promoter sphingolipids. Despite the undulating effect and complexity of sphingolipid pathways, there are emerging opportunities for a plethora of enzyme-targeted therapeutic interventions that overcome resistance resulting from perturbed sphingolipid pathways. Here, we have revisited the interconnectivity of sphingolipid metabolism and the instrumental role of ceramide-biosynthetic and degradative enzymes, including bioactive sphingolipid products, how they closely relate to cancer treatment and pathogenesis, and the interplay with retinoid signaling in cancer. We focused on retinoid targeting, alone or in combination, of sphingolipid metabolism nodes in cancer to enhance ceramide-based therapeutics. Retinoid and ceramide-based cancer therapy using novel strategies such as combination treatments, synthetic retinoids, ceramide modulators, and delivery formulations hold promise in the battle against cancer.

Topics: Animals; Antineoplastic Agents; Apoptosis; Autophagy; Cell Cycle Checkpoints; Ceramides; Drug Delivery Systems; Drug Discovery; Drug Therapy, Combination; Humans; Leukemia, Promyelocytic, Acute; Liposomes; Signal Transduction; Tretinoin

Most acute promyelocytic leukemia (APL) are characterized by reciprocal translocations t(15;17)(q22;21), which results in the fusion of PML gene at 15q22 with RARα gene at 17q21. However, several complex variant translocations also have been reported. Here we report a 62-year-old man with typical morphology and clinical features of APL with a complex karyotype including add(11)(p15) and t(13,20)(q12;q11.2) without typical t(15;17) assayed by the G-banding analysis. FISH with a PML/RARα dual-color DNA probe showed an atypical fusion signal, RT-qPCR analysis showed PML/RARα fusion transcripts, and NGS detected FLT3, WT1, and KRAS mutations. The patient achieved complete remission after treatment with conventional chemotherapy combined ATRA and ATO. Although the mechanism of this kind of cryptic variant remains unknown, we conclude that the cryptic PML/RARα fusion with add(11)(p15), t(13,20)(q12;q11.2) seems not to alter the effectiveness of chemotherapy combined with ATRA and ATO.

Topics: Antineoplastic Agents; Arsenic Trioxide; Humans; Karyotype; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Oncogene Proteins, Fusion; Tretinoin

Acute myeloid leukemia is characterized by arrested differentiation, and agents that overcome this block are therapeutically useful, as shown by the efficacy of all-trans retinoic acid in acute promyelocytic leukemia. However, the early promise of differentiation therapy did not translate into clinical benefit for other subtypes of acute myeloid leukemia, in which cytotoxic chemotherapeutic regimens remained the standard of care. Recent advances, including insights from sequencing of acute myeloid leukemia genomes, have led to the development of targeted therapies, comprising agents that induce differentiation of leukemic cells in preclinical models and clinical trials, thus rejuvenating interest in differentiation therapy. These agents act on various cellular processes including dysregulated metabolic programs, signaling pathways, epigenetic machinery and the cell cycle. In particular, inhibitors of mutant IDH1/2 and FLT3 have shown clinical benefit, leading to approval by regulatory bodies of their use. Besides the focus on recently approved differentiation therapies, this review also provides an overview of differentiation- inducing agents being tested in clinical trials or investigated in preclinical research. Combinatorial strategies are currently being tested for several agents (inhibitors of KDM1A, DOT1L, BET proteins, histone deacetylases), which were not effective in clinical studies as single agents, despite encouraging anti-leukemic activity observed in preclinical models. Overall, recently approved drugs and new investigational agents being developed highlight the merits of differentiation therapy; and ongoing studies promise further advances in the treatment of acute myeloid leukemia in the near future.

Topics: Antineoplastic Agents; Cell Differentiation; Histone Demethylases; Humans; Leukemia, Myeloid, Acute; Leukemia, Promyelocytic, Acute; Tretinoin

The unraveling of the pathophysiology of acute myeloid leukemia (AML) has resulted in rapid translation of the information into clinical practice. After more than 40 years of slow progress in AML research, the US Food and Drug Administration has approved nine agents for different AML treatment indications since 2017. In this review, we detail the progress that has been made in the research and treatment of AML, citing key publications related to AML research and therapy in the English literature since 2000. The notable subsets of AML include acute promyelocytic leukemia (APL), core-binding factor AML (CBF-AML), AML in younger patients fit for intensive chemotherapy, and AML in older/unfit patients (usually at the age cutoff of 60-70 years). We also consider within each subset whether the AML is primary or secondary (therapy-related, evolving from untreated or treated myelodysplastic syndrome or myeloproliferative neoplasm). In APL, therapy with all-trans retinoic acid and arsenic trioxide results in estimated 10-year survival rates of ≥80%. Treatment of CBF-AML with fludarabine, high-dose cytarabine, and gemtuzumab ozogamicin (GO) results in estimated 10-year survival rates of ≥75%. In younger/fit patients, the "3+7" regimen (3 days of daunorubicin + 7 days of cytarabine) produces less favorable results (estimated 5-year survival rates of 35%; worse in real-world experience); regimens that incorporate high-dose cytarabine, adenosine nucleoside analogs, and GO are producing better results. Adding venetoclax, FLT3, and IDH inhibitors into these regimens has resulted in encouraging preliminary data. In older/unfit patients, low-intensity therapy with hypomethylating agents (HMAs) and venetoclax is now the new standard of care. Better low-intensity regimens incorporating cladribine, low-dose cytarabine, and other targeted therapies (FLT3 and IDH inhibitors) are emerging. Maintenance therapy now has a definite role in the treatment of AML, and oral HMAs with potential treatment benefits are also available. In conclusion, AML therapy is evolving rapidly and treatment results are improving in all AML subsets as novel agents and strategies are incorporated into traditional AML chemotherapy. LAY SUMMARY: Ongoing research in acute myeloid leukemia (AML) is progressing rapidly. Since 2017, the US Food and Drug Administration has approved 10 drugs for different AML indications. This review updates the research and treatment pathways for AML.

Topics: Age Factors; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Bridged Bicyclo Compounds, Heterocyclic; Cladribine; Core Binding Factors; Cytarabine; Daunorubicin; Gemtuzumab; Humans; Leukemia, Myeloid, Acute; Leukemia, Promyelocytic, Acute; Maintenance Chemotherapy; Mutation; Myelodysplastic Syndromes; Myeloproliferative Disorders; Neoplasm, Residual; Sulfonamides; Survival Rate; Translational Research, Biomedical; Tretinoin; Vidarabine

Acute promyelocytic leukemia (APL) with myelofibrosis (MF) is rare, and only 14 cases have been reported in the literature to date.. A 42-year-old woman was admitted to the hospital with easy bruising and excessive bleeding. With the remission of the primary disease during treatment, the degree of fibrosis did not decrease, but worsened progressively.. The woman was diagnosed with acute promyelocytic leukemia with secondary myelofibrosis.. All-trans retinoic acid (ATRA) was discontinued after 6 months of complete remission of APL. Arsenic trioxide (ATO) was discontinued because of supraventricular tachycardia 9 months after complete remission of APL.. After withdrawal of ATRA for 2 months, the degree of fibrosis was significantly alleviated, and after withdrawal of ATRA for 8 months and ATO for 5 months, bone marrow biopsy showed no reticular fiber deposition.. In this case report and review of an additional 14 cases of APL with MF, we highlighted the importance of the degree of MF to be evaluated by bone marrow biopsy at the time of bone marrow aspiration when APL is suspected. If MF is present, the type of MF should be determined in a timely manner, and appropriate intervention measures should be taken accordingly.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Female; Humans; Induction Chemotherapy; Leukemia, Promyelocytic, Acute; Primary Myelofibrosis; Treatment Outcome; Tretinoin

All-trans-retinoic acid (ATRA) is effective for preventing cancer and treating skin diseases and acute promyelocytic leukaemia (APL). These pharmacological effects of ATRA are mainly mediated by retinoid X receptors (RXRs) and retinoic acid receptors (RARs). This article provides a comprehensive overview of the clinical progress on and the molecular mechanisms of ATRA in the treatment of APL. ATRA can promote the transcriptional activation of differentiation-related genes and regulate autophagy by inhibiting mTOR, which results in anti-APL effects. In detail, the structures, pharmacological effects, and clinical studies of 68 types of ATRA analogues are described. These compounds have excellent antitumour therapeutic potential and could be used as lead compounds for further development and research.

Topics: Antineoplastic Agents; Cell Proliferation; Humans; Leukemia, Promyelocytic, Acute; TOR Serine-Threonine Kinases; Tretinoin

Topics: Cell Differentiation; Humans; Leukemia, Promyelocytic, Acute; Nanotechnology; Tretinoin

Although life-threatening hemorrhage is a usual manifestation of acute promyelocytic leukemia (APL), thrombotic events seem to be more common in APL compared to other subtypes of acute leukemia. The treatment and prophylaxis of thrombosis are controversial due to the high risk of bleeding caused by disseminated intravascular coagulation (DIC) and thrombocytopenia. To the best of our knowledge we report the first case of APL in a patient with prosthetic heart valves successfully treated with a combination of all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO). We hope this case report helps clinicians to manage different spectra of coagulopathy in APL successfully.. A 38-year-old Asian man presented with diagnosis of APL confirmed by bone marrow biopsy. He was on warfarin due to prosthetic mitral and aortic valves. He was at risk of both hemorrhagic events due to DIC and life-threatening valve thrombosis. Our management regimen included unfractionated heparin adjusted according to the platelet count to prevent both valve thrombosis and bleeding events. The patient tolerated treatment well without any hemorrhagic or thrombotic events, and complete molecular remission was achieved by ATRA and ATO without the need for chemotherapeutic agents.. Although this case is exceptional, a precise evaluation may be needed to select the appropriate dose and type of anticoagulant to treat a patient with APL.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Heart Valves; Heparin; Humans; Leukemia, Promyelocytic, Acute; Male; Tretinoin

Topics: Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Humans; Leukemia, Promyelocytic, Acute; Quality of Life; Treatment Outcome; Tretinoin

In 1957, Hillestad et al. defined acute promyelocytic leukemia (APL) for the first time in the literature as a distinct type of acute myeloid leukemia (AML) with a "rapid downhill course" characterized with a severe bleeding tendency. APL, accounting for 10-15% of the newly diagnosed AML cases, results from a balanced translocation, t(15;17) (q22;q12-21), which leads to the fusion of the promyelocytic leukemia (PML) gene with the retinoic acid receptor alpha (RARA) gene. The PML-RARA fusion oncoprotein induces leukemia by blocking normal myeloid differentiation. Before using anthracyclines in APL therapy in 1973, no effective treatment was available. In the mid-1980s, all-trans retinoic acid (ATRA) monotherapy was used with high response rates, but response durations were short. Later, the development of ATRA, chemotherapy, and arsenic trioxide combinations turned APL into a highly curable malignancy. In this review, we summarize the evolution of APL therapy, focusing on key milestones that led to the standard-of-care APL therapy available today and discuss treatment algorithms and management tips to minimize induction mortality.

Topics: Algorithms; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Humans; Leukemia, Promyelocytic, Acute; Oncogene Proteins, Fusion; Tretinoin

Approximately one third of patients diagnosed with acute promyelocytic leukemia (APL) are above the age of sixty. It is important to ensure older adults receive optimal diagnosis and management since this subtype of acute myeloid leukemia - given appropriate treatment - is highly curable with lower risk of adverse events compared to other types of leukemia. Historically, older age has been a risk factor for early death and poorer overall survival. However, prospects have changed with the introduction of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). APL is curable in the majority of patients regardless of age, and the threshold of fitness that makes ATRA/ATO therapy possible is likely to be lower than for cytotoxic chemotherapy. APL frequently presents as a medical emergency and rapid diagnosis and intervention - typically involving referral to a specialist centre - is a major determinant of outcome. After diagnosis, management of APL in older adults presents particular challenges. Geriatric assessment, including evaluation of frailty, comorbidities and polypharmacy can assist in providing optimal supportive care for older adults during remission induction and may help individualize therapy in the post-remission phase. Here, we review the available evidence, highlighting areas of consensus, gaps in evidence and opportunities for research to enhance diagnosis, management and survivorship for older patients.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Humans; Leukemia, Promyelocytic, Acute; Remission Induction; Treatment Outcome; Tretinoin

Hemorrhagic death is the leading cause of treatment failure in acute promyelocytic leukemia (APL). Our ability to identify patients at greatest risk of hemorrhage, and to actively prevent hemorrhage, remains limited. Nevertheless, some data is available to guide contemporary clinical practice and future investigation. Circulating disease burden, best represented by the peripheral WBC / blast count, is the most consistent predictor of major and fatal bleeding risk. In contrast, laboratory markers of disseminated intravascular coagulation (DIC) appear to be poor predictors. A number of interventions have been posited to reduce bleeding risk. Prompt initiation of all-trans retinoic acid (ATRA), avoidance of invasive procedures, transfusion support, and cytoreduction all have theoretical merit. Though they lack strong evidence to support their benefit with respect to bleeding, they are associated with limited risks, and are therefore advisable. Low-dose therapeutic heparin and antifibrinolytics have not shown the ability to positively modify bleeding risk, and heparin has been associated with harm. Thrombomodulin has shown promise in limited retrospective studies however further prospective data are needed. rFVIIa may have a role in cases of life-threatening bleeding however evidence is largely anecdotal. Additional studies evaluating the above interventions, and investigating other potential interventions are needed.

Topics: Blast Crisis; Factor VIII; Hemorrhage; Heparin; Humans; Leukemia, Promyelocytic, Acute; Thrombomodulin; Tretinoin

The use of all trans-retinoic acid and arsenic trioxide combination as the induction regimen for acute promyelocytic leukemia (APL) has revolutionized the management and outcomes of this disease. Modern risk-adapted frontline therapy has provided excellent therapeutic results. However, significant numbers of APL patients relapse after frontline therapy, and the optimal management strategy for relapsed APL, specifically the role and type of hematopoietic cell transplantation (HCT) are still to be defined. Both autologous and allogeneic HCTs are associated with durable remission and prolonged survival when utilized in appropriate disease settings. Once remission has been achieved, consolidation with autologous HCT for APL patients with negative minimal residual disease (MRD) status, and with allogeneic HCT for APL patients with positive MRD status appear to offer the best long-term outcomes. In this article, we provide a comprehensive review of existing literature on the efficacy of HCT in treatment of relapse/refractory APL and we discuss the appropriate use of this modality.

Topics: Arsenic Trioxide; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Promyelocytic, Acute; Transplantation, Autologous; Treatment Outcome; Tretinoin

Acute myeloid leukemia (AML) is an aggressive, often fatal hematopoietic malignancy.

Topics: Animals; Apoptosis; Hematopoiesis; Humans; Leukemia, Myeloid, Acute; Leukemia, Promyelocytic, Acute; Neoplastic Stem Cells; Tretinoin

After being in the therapeutic wilderness for several decades, acute myeloid leukemia has been recently thrust into the limelight with a series of drug approvals. Technical refinements in production, genetic manipulation and chemical modification of monoclonal antibodies led to growing interest in antibodies-based treatment strategies. Much of the focus of these efforts in acute myeloid leukemia has been on CD33 as a target. On September 2, 2017, the U.S. Food and Drug Administration approved gemtuzumab ozogamicin for treatment of relapsed or refractory CD33

Topics: Aged; Animals; Antineoplastic Agents; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Arsenicals; Calicheamicins; Chlorides; Clinical Trials as Topic; Cytarabine; Daunorubicin; Drug Approval; Drug Evaluation, Preclinical; Drug Resistance, Neoplasm; Gemtuzumab; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Leukemia, Promyelocytic, Acute; Mice; Middle Aged; Multicenter Studies as Topic; Recurrence; Sialic Acid Binding Ig-like Lectin 3; Tretinoin

Most acute promyelocytic leukemia (APL) patients respond to all-trans-retinoic acid (ATRA)and have a good prognosis. However, variants APL who carry PLZF/RARа, STAT5B/RARа, and STAT3/RARа are insensitive to ATRA and have poor prognoses. The standard treatment for variants APL is still unclear due to the small sample size.. Here we reported a Chinese male who was admitted to our hospital with the complaint of rib pain, dyspnea, and fever (37.5°C). Blood tests showed leukopenia (1.83 × 10/L), anemia (hemoglobin 73 g/L), and thrombocytopenia (54 × 10/L). Prothrombin time and activated partial thromboplastin time were normal.. The patient was diagnosed as STAT5b-RARa-positive APL based on the clinical and laboratory findings.. ATRA was used immediately for induction treatment, then he was treated with ATRA + arsenic trioxide and got the severe cardiac insufficiency. Subsequently, consolidation chemotherapy was added with ATRA + Huangdai tablets + idarubicin and decitabine, cytarabine, aclamycin (DCAG).. The patient relapsed soon after his first molecular complete remission (CRm), fortunately, he got a second CRm with DCAG. He has survived for more than 9 months and remains CRm, now he is looking for a suitable donor to prepare for hematopoietic stem cell transplantation (HSCT).. APL patients with STAT5B-RARa is not only resistant to ATRA, but also to conventional combination chemotherapy such as daunorubicin and cytarabine/idarubicin and cytarabine or other regimens. Relapse and extramedullary infiltration is common, HSCT is a effective treatment, and the best time for HSCT is after the first CR. It should be noted that this patient got CRm with DCAG after relapse, so the role of decitabine in APL with STAT5B-RARa needs to be considered.

Topics: Adolescent; Adult; Aged; Antimetabolites, Antineoplastic; Antineoplastic Agents; Arsenic Trioxide; Asian People; Consolidation Chemotherapy; Cytarabine; Decitabine; Drug Therapy, Combination; Female; Hospitalization; Humans; Idarubicin; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Recurrence; Retinoic Acid Receptor alpha; STAT5 Transcription Factor; Treatment Outcome; Tretinoin

The retinoids are a group of compounds including vitamin A and its active metabolite all-trans-retinoic acid (ATRA). Retinoids regulate a variety of physiological functions in multiple organ systems, are essential for normal immune competence, and are involved in the regulation of cell growth and differentiation. Vitamin A derivatives have held promise in cancer treatment and ATRA is used in differentiation therapy of acute promyelocytic leukemia (APL). ATRA and other retinoids have also been successfully applied in a variety of dermatological conditions such as skin cancer, psoriasis, acne, and ichthyosis. Moreover, modulation of retinoic acid receptors and retinoid X (or rexinoid) receptors function may affect dermal cells. The studies using complex genetic models with various combinations of retinoic acid receptors (RARs) and retinoid X (or rexinoid) receptors (RXRs) indicate that retinoic acid and its derivatives have therapeutic potential for a variety of serious dermatological disorders including some malignant conditions. Here, we provide a synopsis of the main advances in understanding the role of ATRA and its receptors in dermatology.

Topics: Cell Differentiation; Humans; Leukemia, Promyelocytic, Acute; Receptors, Retinoic Acid; Retinoid X Receptors; Signal Transduction; Skin; Skin Neoplasms; Tretinoin

Acute promyelocytic leukaemia differentiation syndrome (APL DS) is seen when patients with APL are treated with all-trans retinoic acid (ATRA) and/or arsenic trioxide (ATO). Presenting symptoms are varied but frequently include dyspnoea, unexplained fever, weight gain >5 kg, unexplained hypotension, acute renal failure and a chest radiograph demonstrating pulmonary infiltrates or pleural or pericardial effusion. Immediate treatment with steroids at the first clinical suspicion is recommended and ATRA/ATO should be stopped in severe cases or if there is no response to treatment. The utility of steroid prophylaxis in order to prevent APL DS is less certain. Here we provide a detailed review of the pathogenesis, clinical signs and symptoms as well as management and prophylaxis strategies of APL DS.

Topics: Acute Kidney Injury; Arsenic Trioxide; Cell Differentiation; Humans; Hypotension; Leukemia, Promyelocytic, Acute; Pulmonary Edema; Steroids; Syndrome; Tretinoin

Abstract　　Among myeloid leukemias, the acute promyelocytic leukemia (APL) was found to be specifically sensitive to all-trans retinoic acid (ATRA), almost all APL patients respond to ATRA therapy. The ATRA induces remission of APL patients by stimulating the differentiation of the leukemia cells. However, with the long-term application of ATRA alone, ATRA resistance has become one of the main causes of chemotherapy failure in the patients with acute promyelocytic leukemia. At present, the mechanism of ATRA-resistance is not completely clear, this review discusses the mechanism of drug-resistance in terms of signal pathways, genes, proteins and enzyme.. 急性早幼粒细胞白血病对全反式维甲酸耐药机制的研究进展.. 在髓系白血病中，急性早幼粒细胞白血病（acute promyelocytic leukemia，APL）对全反式维甲酸（all-trans retinoic acid，ATRA）特别敏感。几乎所有APL患者对ATRA治疗都有反应，ATRA通过刺激白血病细胞分化，诱导APL患者缓解。然而，随着长期单用ATRA，ATRA耐药已成为APL患者化疗失败的主要原因之一。目前，对ATRA耐药机制尚不完全清楚，本文将从信号通路、基因、蛋白和酶问题来阐述其耐药机制.

Topics: Antineoplastic Agents; Cell Differentiation; Humans; Leukemia, Promyelocytic, Acute; Tretinoin

The application of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) has revolutionized the treatment of acute promyelocytic leukemia (APL). More than 80-90% of patients are expected to be cured with a combination of ATRA, ATO and/or chemotherapy. In this review, we focus on the remaining obstacles to a cure for all patients with APL. We review the issue of early death and coagulopathy and discuss the particular challenges in the care of patients with high-risk APL and patients with relapsed APL. We also give recommendations and highlight ongoing efforts to improve the persistently high early death rate and the outcomes of high risk and relapsed APL patients.

Topics: Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Disease-Free Survival; Hemorrhage; Humans; Incidence; Leukemia, Promyelocytic, Acute; Mortality; Neoplasm Recurrence, Local; Practice Guidelines as Topic; Randomized Controlled Trials as Topic; Remission Induction; Standard of Care; Time Factors; Tretinoin

All-trans retinoic acid (ATRA), an active metabolite of vitamin A, plays important roles in cell proliferation, cell differentiation, apoptosis, and embryonic development. The effects of ATRA are mediated by nuclear retinoid receptors as well as non-genomic signal pathway, such as MAPK and PKA. The great success of differentiation therapy with ATRA in acute promyelocytic leukemia (APL) not only improved the prognosis of APL but also spurred the studies of ATRA in the treatment of other tumors. Since the genetic and physiopathological simplicity of APL is not common in human malignancies, the combination of ATRA with other agents (chemotherapy, epigenetic modifiers, and arsenic trioxide, etc) had been extensively investigated in a variety of tumors. In this review, we will discuss in details about ATRA and its role in cancer treatment.

Topics: Antineoplastic Agents; Apoptosis; Arsenic Trioxide; Cell Differentiation; Cell Proliferation; Drug Therapy; Humans; Leukemia, Promyelocytic, Acute; Neoplasms; Receptors, Retinoic Acid; Signal Transduction; Tretinoin

The outcome of acute promyelocytic leukemia (APL) has drastically improved following the identification of the PML-RARA oncogene as a key player in the pathogenesis of APL, and the subsequent introduction of all-trans retinoic acid (ATRA) as a therapeutic agent. Areas covered: Randomized trials have recently demonstrated the efficacy of arsenic trioxide (ATO) in combination with ATRA for the front-line treatment of standard and medium risk APL patients. This chemotherapy-free combination is associated with a decreased cumulative rate of relapse, prolonged overall survival, and reduced early death rate. Expert commentary: The most challenging issue in the management of APL remains the significant rate of early deaths in high-risk patients. The ongoing studies will clarify the possible role of ATO in this setting in combination with ATRA and other agents. The aim of this review is to report data of efficacy and safety of intravenous ATO in newly diagnosed patients and discuss on its potential role as a new standard of care for APL patients.

Topics: Administration, Intravenous; Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Humans; Leukemia, Promyelocytic, Acute; Treatment Outcome; Tretinoin

Since the comprehensive recommendations for the management of acute promyelocytic leukemia (APL) reported in 2009, several studies have provided important insights, particularly regarding the role of arsenic trioxide (ATO) in frontline therapy. Ten years later, a European LeukemiaNet expert panel has reviewed the recent advances in the management of APL in both frontline and relapse settings in order to develop updated evidence- and expert opinion-based recommendations on the management of this disease. Together with providing current indications on genetic diagnosis, modern risk-adapted frontline therapy, and salvage treatment, the review contains specific recommendations for the identification and management of the most important complications such as the bleeding disorder APL differentiation syndrome, QT prolongation, and other all-

Topics: Aged; Arsenic Trioxide; Disease Management; Female; Hemorrhagic Disorders; Humans; Leukemia, Promyelocytic, Acute; Practice Guidelines as Topic; Pregnancy; Recurrence; Tretinoin

Acute promyelocytic leukemia (APL) in human immunodeficiency virus (HIV)-infected individuals is very rare. There is currently no consensus regarding the use of anti-cancer drugs with highly active anti-retroviral therapy (ART) in these patients due to their small number. We herein report two cases of APL with HIV-infected patients. Both cases received all-trans-retinoic acid-containing chemotherapies and achieved complete remission. ART was continued throughout the treatment course. The clinical course of these cases suggests that it is preferable to perform standard chemotherapy for APL with ART if patients have an adequate performance status.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Antiretroviral Therapy, Highly Active; HIV Infections; Humans; Leukemia, Promyelocytic, Acute; Male; Remission Induction; Treatment Outcome; Tretinoin

Classical acute promyelocytic leukemia (APL) cases are associated with the promyelocytic leukemia-retinoic acid receptor α (PML-RARα) chimeric fusion protein. Almost all the variant chimeric proteins share the same RARα component. Currently, more than 11 fusion partners of RARα have been identified, of which PML accounts for 95%, promyelocytic leukemia zinc finger (PLZF) take up2%, and the remaining are other variants. Although all-trans retinoic acid and arsenic trioxide have shown remarkable induction of molecular remission in classical APL, they have no appreciable effects on APL associated with other variant gene fusions (eg, PLZF-RARα and STAT5b-RARα). Here, we summarize all variant translocations, their key features, their leukemogenic potential as well as recent advances in studies of PLZF-RARα-associated APL. Basic pathogenic differences between classical APL and PLZF-RARα-associated APL are further discussed. We also highlight the critical leukemogenic events that are the backbone of these variant translocations so as to gain new insights into refractory APL.

Topics: Humans; Leukemia, Promyelocytic, Acute; Oncogene Proteins, Fusion; STAT5 Transcription Factor; Tretinoin

The family of retinoic acid receptors (RARs: RARα, -β, and -γ) has remarkable pleiotropy characteristics, since the retinoic acid/RARs pathway is involved in numerous biological processes not only during embryonic development, but also in the postnatal phase and during adulthood. In this review, we trace the roles of RA/RARs signaling in the immune system (where this pathway has both an immunosuppressive role or is involved in the inflammatory response), in hematopoiesis (enhancing hematopoietic stem cell self-renewal, progenitor cells differentiation or maintaining the bone marrow microenvironment homeostasis), and in bone remodeling (where this pathway seems to have controversial effects on bone formation or osteoclast activation). Moreover, in this review is shown the involvement of

Topics: Animals; Gene Rearrangement; Genetic Pleiotropy; Humans; Leukemia, Promyelocytic, Acute; Receptors, Retinoic Acid; Signal Transduction; Tretinoin

Topics: Aged; Antineoplastic Agents; Arsenic Poisoning; Arsenic Trioxide; Drug Therapy, Combination; Female; Humans; Idarubicin; Leukemia, Promyelocytic, Acute; Myoclonus; Remission Induction; Steroids; Topoisomerase II Inhibitors; Treatment Outcome; Tretinoin; Withholding Treatment

The diagnosis of acute promyelocytic leukemia (APL) in pregnancy is an uncommon, life-threatening emergency. Choice of treatment and management of complications are challenging.. We report the case of a patient with diagnosis of APL at gestational age (GA) 24 + 4. We describe the interdisciplinary management during pregnancy and delivery and provide a 2-year follow-up. Existing reports on APL in pregnancy are summarized.. Single-agent induction therapy with all-trans retinoic acid (ATRA) was started and resulted in normalization of blood cell counts after 32 days. Vaginal delivery of a healthy baby occurred at GA 34 + 4. Consolidation therapy consisted of four courses of ATRA and arsenic trioxide (ATO). Less than 100 cases of APL in pregnancy are published. Misdiagnosis as HELLP syndrome with fatal outcome may occur. Combination therapies (ATRA-plus anthracyclines) were used in the majority of reports.. Diagnosis and treatment of APL during pregnancy continues to be a challenge requiring interdisciplinary team work. Single-agent ATRA therapy may evolve as a safe and less-toxic treatment modality.

Topics: Adult; Antineoplastic Agents; Arsenic Trioxide; Arsenicals; Female; Gestational Age; Humans; Leukemia, Promyelocytic, Acute; Neoadjuvant Therapy; Pregnancy; Pregnancy Complications, Neoplastic; Treatment Outcome; Tretinoin

The concept of differentiation therapy emerged from the fact that hormones or cytokines may promote differentiation ex vivo, thereby irreversibly changing the phenotype of cancer cells. Its hallmark success has been the treatment of acute promyelocytic leukaemia (APL), a condition that is now highly curable by the combination of retinoic acid (RA) and arsenic. Recently, drugs that trigger differentiation in a variety of primary tumour cells have been identified, suggesting that they are clinically useful. This Opinion article analyses the basis for the clinical successes of RA or arsenic in APL by assessing the respective roles of terminal maturation and loss of self-renewal. By reviewing other successful examples of drug-induced tumour cell differentiation, novel approaches to transform differentiating drugs into more efficient therapies are proposed.

Topics: Animals; Antineoplastic Agents; Arsenic Trioxide; Cell Differentiation; Humans; Leukemia, Promyelocytic, Acute; Tretinoin

Acute promyelocytic leukaemia has changed from being a highly fatal to a highly curable disease. Over time, key discoveries have identified the genetic and molecular abnormalities, which cause the disease. First choice of treatment has now changed from all-trans retinoic acid (ATRA) and chemotherapy to a chemo-free combination of arsenic trixoide and ATRA. This new regimen has shown equal responses and overall cure rates compared with the previous standard of care containing conventional chemotherapy, but with much lower toxicity. This will pave the way for better and easier treatment for elderly and frail patients.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Disseminated Intravascular Coagulation; History, 20th Century; Humans; In Situ Hybridization, Fluorescence; Leukemia, Promyelocytic, Acute; Tretinoin

We present a rather uncommon side effect observed in a 20-year-old man with acute promyelocytic leukemia during treatment with ATRA. He developed a high platelet counts reaching up to 1655×10⁹/L on day 29 of ATRA treatment, and started to recover spontaneously on day 33 of treatment, without any change in ATRA, or adding any cytoreduction therapy. No complications associated with thrombocytosis were observed. IL-6 seems to play an important role in the pathogenesis of the thrombocytosis induced by ATRA. However, it is unclear what are the precipitating factors for this rare phenomenon and whether it is caused by certain predisposing factors that might be related to patient's, disease pathogenesis or other unknown factors.

Topics: Bone Marrow; Ecchymosis; Humans; Interleukin-6; Leukemia, Promyelocytic, Acute; Male; Thrombocytosis; Tretinoin; Young Adult

With the introduction of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) acute promyelocytic leukemia (APL) has become from a detrimental to one of the most curable malignant diseases in humans. In particular, the chemotherapy-free regimen with ATO/ATRA has been proven to be highly effective in de novo APL and has become standard first-line therapy in younger adult, non-high-risk patients. Nevertheless, early death is still a major issue in APL, particularly in older patients, emphasizing the need of rapid diagnostics and supportive care together with immediate access to ATRA-based therapy. Despite the dramatic progress achieved in therapy of APL challenging situations occur, particularly in patients excluded from controlled studies with clinical knowledge mainly based on case reports and registries. Rapid identification and treatment of newly diagnosed patients as well as the management of toxicities and complications remain challenging. We offer up-to-date information and guidance regarding treatment of APL. Based on a literature review of existing scientific evidence we also discuss the approach to high-risk, elderly, pregnant and pediatric patients, treatment in patients with renal failure as well as of therapy-related or relapsed/refractory APL.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Electrocardiography; Female; Fetus; Humans; Induction Chemotherapy; Leukemia, Promyelocytic, Acute; Leukocytosis; Neoplasms, Second Primary; Pregnancy; Recurrence; Renal Dialysis; Renal Insufficiency; Tretinoin

The treatment of acute promyelocytic leukemia (APL) has changed significantly in recent years. Today, APL patients with standard risk (also known as low risk) can be treated chemotherapy-free only with all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO). For high-risk patients, induction chemotherapy should be added. The curative results are good and comparable to those achieved in the past with chemotherapy plus ATRA. However, toxicities, especially infectious complications, are reduced. The main risk remains early lethal bleeding. Timely diagnosis and early ATRA treatment can reduce this risk. This review presents and discusses current treatment strategies and recommendations for APL in children.. Die Behandlung der Akuten Promyelozyten-Leukämie (APL) hat sich in den letzten Jahren deutlich geändert. Heute können APL Patienten mit Standardrisiko – (auch als Niedrigrisiko bezeichnet) ohne Chemotherapie nur mit all-trans-Retinsäure (ATRA) und Arsentrioxid (ATO) behandelt werden. Bei Hochrisikopatienten sollte eine Induktions-Chemotherapie hinzugefügt werden. Die kurativen Ergebnisse sind gut und vergleichbar mit jenen, die in der Vergangenheit mit Chemotherapie plus ATRA erzielt wurden. Toxizitäten, insbesondere infektiöse Komplikationen sind jedoch deutlich seltener. Das Hauptrisiko bleiben frühe letale Blutungen. Durch rechtzeitige Diagnose und frühe ATRA-Behandlung kann dieses Risiko reduziert werden. In der vorliegenden Übersicht werden die aktuellen Behandlungsstrategien und Empfehlungen für APL bei Kindern dargestellt und diskutiert.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Child; Humans; Leukemia, Promyelocytic, Acute; Treatment Outcome; Tretinoin

The treatment of acute promyelocytic leukemia (APL) has evolved rapidly in the past two decades after the introduction of highly active drugs, including tretinoin (all- trans-retinoic acid) and arsenic trioxide. It is now possible to treat this disease without the use of traditional cytotoxic chemotherapy. Today's clinical guidelines include multiple regimens, some of which continue to use cytotoxic chemotherapy. This leaves the practicing oncologist with multiple treatment options when faced with a new case of APL. In an effort to standardize our approach to the treatment of newly diagnosed APL, we sought to develop a set of treatment recommendations at our institution. We identified eight major controversial issues in the treatment of APL. These controversial issues include the optimal dose and schedule of both all- trans-retinoic acid and arsenic trioxide, the optimal regimen for high-risk APL, the need for intrathecal prophylaxis, the use of prophylactic corticosteroids, and the need for maintenance therapy after consolidation. We reviewed the relevant literature and used the Delphi method among the coauthors to reach consensus for recommendations on the basis of the best available data and our own clinical experience. In this clinical review, we present our consensus recommendations, the reasoning behind them, and the grading of the evidence that supports them.

Topics: Adult; Age Factors; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Central Nervous System Neoplasms; Clinical Trials as Topic; Consolidation Chemotherapy; Disease Management; Drug Administration Schedule; Expert Testimony; Humans; Induction Chemotherapy; Leukemia, Promyelocytic, Acute; Maintenance Chemotherapy; Neoplasm Grading; Neoplasm Staging; Tretinoin

Recent clinical trials have demonstrated that the immense majority of acute promyelocytic leukemia (APL) patients can be definitively cured by the combination of two targeted therapies: retinoic acid (RA) and arsenic. Mouse models have provided unexpected insights into the mechanisms involved. Restoration of PML nuclear bodies upon RA- and/or arsenic-initiated PML/RARA degradation is essential, while RA-triggered transcriptional activation is dispensable for APL eradication. Mutations of the arsenic-binding site of PML/RARA, but also PML, have been detected in therapy-resistant patients, demonstrating the key role of PML in APL cure. PML nuclear bodies are druggable and could be harnessed in other conditions.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Arsenicals; Humans; Leukemia, Promyelocytic, Acute; Oncogene Proteins; Oncogene Proteins, Fusion; Tretinoin; Tumor Suppressor Proteins

Vitamin A is an essential micronutrient throughout life. Its physiologically active metabolite retinoic acid (RA), acting through nuclear retinoic acid receptors (RARs), is a potent regulator of patterning during embryonic development, as well as being necessary for adult tissue homeostasis. Vitamin A deficiency during pregnancy increases risk of maternal night blindness and anemia and may be a cause of congenital malformations. Childhood Vitamin A deficiency can cause xerophthalmia, lower resistance to infection and increased risk of mortality. RA signaling appears to be essential for expression of genes involved in developmental hematopoiesis, regulating the endothelial/blood cells balance in the yolk sac, promoting the hemogenic program in the aorta-gonad-mesonephros area and stimulating eryrthropoiesis in fetal liver by activating the expression of erythropoietin. In adults, RA signaling regulates differentiation of granulocytes and enhances erythropoiesis. Vitamin A may facilitate iron absorption and metabolism to prevent anemia and plays a key role in mucosal immune responses, modulating the function of regulatory T cells. Furthermore, defective RA/RARα signaling is involved in the pathogenesis of acute promyelocytic leukemia due to a failure in differentiation of promyelocytes. This review focuses on the different roles played by vitamin A/RA signaling in physiological and pathological mouse hematopoiesis duddurring both, embryonic and adult life, and the consequences of vitamin A deficiency for the blood system.

Topics: Anemia, Iron-Deficiency; Animals; Cell Differentiation; Disease Models, Animal; Embryonic Development; Epigenesis, Genetic; Erythropoiesis; Erythropoietin; Female; Granulocytes; Hematopoiesis; Humans; Leukemia, Promyelocytic, Acute; Pregnancy; Receptors, Retinoic Acid; Signal Transduction; Tretinoin; Vitamin A; Vitamin A Deficiency

The outcomes of acute promyelocytic leukemia (APL) in pregnancy are largely unknown. The MEDLINE database was systematically searched to obtain 43 articles with 71 patients with new-onset APL during pregnancy. Induction therapy included various regimens of all-trans retinoic acid (ATRA), cytarabine, and anthracycline and resulted in a complete remission rate of 93%. Obstetric and fetal complications included pre-term deliveries (46%), spontaneous/therapeutic abortion/intrauterine death (33.3%) and other neonatal complications (25.9%). Mothers diagnosed in the first trimester were more likely to experience obstetric (p < 0.01) and fetal (p < 0.01) complications. To our knowledge, this is the largest systematic review of APL in pregnancy. The vast majority of APL patients in pregnancy may achieve remission with initial induction therapy. APL or its therapy in pregnancy, however, is associated with a high risk of fetal and obstetrical complications. The results of our study may help in patient counseling and informed decision-making.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Consolidation Chemotherapy; Female; Humans; Leukemia, Promyelocytic, Acute; Pregnancy; Pregnancy Complications, Neoplastic; Pregnancy Outcome; Remission Induction; Treatment Outcome; Tretinoin; Young Adult

The outcome of patients with acute promyelocytic leukaemia (APL) has dramatically improved over the last two decades, due to the introduction of combined all-trans retinoic acid (ATRA) and chemotherapy regimens and, more recently, to the advent of arsenic trioxide (ATO). ATRA and anthracycline-based chemotherapy remains a widely used strategy, providing cure rates above 80%, but it is associated with risk of severe infections and occurrence of secondary leukaemias. ATO is the most effective single agent in APL and, used alone or in combination with ATRA or ATRA and reduced-intensity chemotherapy, results in greater efficacy with considerably less haematological toxicity. The toxic profile of ATO includes frequent, but manageable, QTc prolongation and increase of liver enzymes. Two large randomized studies have shown that ATRA + ATO is superior to ATRA + chemotherapy for newly diagnosed low-risk APL resulting in 2-4 year event-free survival rates above 90% and very few relapses. According to real world data, the spectacular progress in APL outcomes reported in clinical trials has not been paralleled by a significant improvement in early death rates, this remains the most challenging issue for the final cure of the disease.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Early Diagnosis; Humans; Leukemia, Promyelocytic, Acute; Oxides; Recurrence; Stem Cell Transplantation; Tretinoin

Acute promyelocytic leukemia (APL) is associated with a complex coagulopathy. In spite of substantial recent improvements in treatment regimens, hemorrhagic death remains the main cause of induction failure. In this review, we delineate recent understanding of the pathophysiology and management of the hemorrhagic diathesis of APL.. Laboratory and clinical data suggest that the malignant leukocytes mediate the hemorrhagic diathesis associated with APL through multiple mechanisms which lead to a combination of consumptive coagulopathy and primary hyperfibrinolysis. Exposure of tissue factor and Annexin II by the leukemic blasts is the main determinants of these processes. Promyelocyte-derived microparticles have recently been implicated in the coagulopathy as well. Total white cell count and platelet count have emerged as good general predictors of hemorrhagic death, along with the different routine hemostatic parameters. Prompt treatment with all-trans retinoic acid, with or without arsenic trioxide, is the most important step in preventing bleeding complications. Repletion of coagulation factors and platelets with blood products remains the mainstay of supportive treatment, whereas the role of recombinant soluble thrombomodulin is currently being investigated.. The coagulopathy of APL is multifactorial, with both disseminated intravascular coagulation and primary hyperfibrinolysis mediated largely by the malignant leukocytes.

Topics: Antineoplastic Combined Chemotherapy Protocols; Blood Coagulation; Blood Coagulation Disorders; Humans; Leukemia, Promyelocytic, Acute; Prognosis; Remission Induction; Thrombomodulin; Treatment Outcome; Tretinoin

Despite major advances in the treatment of acute promyelocytic leukemia (APL), high-risk APL still poses unique challenges. The purpose of this review is to outline current evidence for evaluation and management of high-risk APL and discuss areas of ongoing and future investigation.. With the changing treatment paradigm in APL and increasing use of arsenic trioxide (ATO), reports have questioned the relevance of classic prognostic factors. Despite advancements in therapy, early death remains a primary reason for treatment failure. A randomized, phase III trial demonstrated that all-trans retinoic acid + ATO is at least noninferior and may be superior to all-trans retinoic acid + chemotherapy in low/intermediate-risk APL. One phase III and multiple phase II trials have suggested a benefit of adding ATO to therapy of high-risk patients. Attempts at minimizing chemotherapy in high-risk disease have proven feasible with the use of gemtuzumab ozogamicin, but it is unlikely that cytotoxic chemotherapy will be completely eliminated in this patient population.. Treatment of high-risk APL has evolved significantly over the past 10 years and current scoring systems, management, and treatment regimens have been reviewed. There are as yet unresolved questions, including how to minimize early deaths and optimal therapy in an ATO era.

Topics: Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Blood Coagulation Disorders; Disease Management; Humans; Leukemia, Promyelocytic, Acute; Oxides; Recurrence; Remission Induction; Treatment Outcome; Tretinoin

All trans retinoic acid (ATRA) has revolutionized the therapy of acute promyelocytic leukemia (APL). Treatment of this leukemia with ATRA in combination with chemotherapy has resulted in complete remission rates >90 % and long-term remission rates above 80 %. Furthermore, the combination of ATRA and arsenic trioxide (ATO) was shown to be safe and effective in frontline treatment and, for patients with low and intermediate risk disease, possibly superior to the standard ATRA and anthracycline-based regimen. However, in spite of this tremendous progress, APL still remains associated with a high incidence of early death due to the frequent occurrence of an abrupt bleeding diathesis. This hemorrhagic syndrome more frequently develops in high-risk APL patients, currently defined as those exhibiting >10 × 10(9)/L WBC at presentation. In addition to high WBC count, other molecular and immunophenotypic features have been associated with high-risk APL. Among them, the expression in APL blasts of the stem/progenitor cell antigen CD34, the neural adhesion molecule (CD56), and the T cell antigen CD2 help to identify a subset of patients at higher risk of relapse and often the expression of these markers is associated with high WBC count. At the molecular level, the short PML/RARA isoform and FLT3-internal tandem duplication (ITD) mutations have been associated with increased relapse risk. These observations indicate that extended immunophenotypic and molecular characterization of APL at diagnosis including evaluation of CD2, CD56, and CD34 antigens and of FLT3 mutations may help to better design risk-adapted treatment in this disease.

Topics: Antigens, CD; Antigens, Neoplasm; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Biomarkers, Tumor; Chromosome Aberrations; Disseminated Intravascular Coagulation; DNA-Binding Proteins; fms-Like Tyrosine Kinase 3; Hemorrhagic Disorders; Humans; Immunophenotyping; Leukemia, Promyelocytic, Acute; Leukocyte Count; Nuclear Proteins; Oncogene Proteins, Fusion; Oxides; Prognosis; Risk Factors; Tandem Repeat Sequences; Treatment Outcome; Tretinoin; Tumor Protein p73; Tumor Suppressor Proteins

The management of acute promyelocytic leukemia (APL) has considerably evolved during the past two decades. The advent of all-trans retinoic acid (ATRA) and its inclusion in combinatorial regimens with anthracycline chemotherapy has provided cure rates exceeding 80%; however, this widely adopted approach also conveys significant toxicity including severe myelosuppression and rare occurrence of secondary leukemias. More recently, the advent of arsenic trioxide (ATO) and its use in association with ATRA with or without chemotherapy has further improved patient outcome by allowing to minimize the intensity of chemotherapy, thus reducing serious toxicity while maintaining high anti-leukemic efficacy. The advantage of ATRA-ATO over ATRA chemotherapy has been recently demonstrated in two large randomized trials and this option has now become the new standard of care in low-risk (i.e. non-hyperleukocytic) patients. In light of its rarity, abrupt onset and high risk of early death and due to specific treatment requirements, APL remains a challenging condition that needs to be managed in highly experienced centers. We review here the results of large clinical studies conducted in newly diagnosed APL as well as the recommendations for appropriate diagnosis, prevention and management of the main complications associated with modern treatment of the disease.

Topics: Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Drug-Related Side Effects and Adverse Reactions; Humans; Leukemia, Promyelocytic, Acute; Oxides; Randomized Controlled Trials as Topic; Tretinoin

A 34-year-old man who had been referred to our hospital was diagnosed with acute promyelocytic leukemia (APL). All-trans retinoic acid (ATRA), oral administration, was initiated. On day 25, he developed fever and respiratory distress with bilateral pulmonary infiltrates, suggesting differentiation syndrome (DS) caused by ATRA. These symptoms showed amelioration after discontinuing ATRA and initiating methylprednisolone. ATRA was re-started on day 29 at half the original dose because of residual APL blasts. The patient subsequently developed fever, severe stomatitis, and oropharyngeal ulcers, which persisted even after discontinuing ATRA. On day 48, he suddenly developed severe abdominal pain with free air, observable on an abdominal X-ray, and underwent emergency ileocecal resection. Pathological examination of the resected ileocecal intestines revealed multiple ulcers and perforations. No leukemic cell infiltration was observed. In this case, only ATRA was administered for APL treatment. These findings suggest that ileocecal ulcerations and perforations, as well as oropharyngeal ulcers, might have been caused by DS or ATRA. Furthermore, DNA typing of the HLA-B locus revealed that the patient had HLA-B51 associated with Behçet's disease. Therefore, hypercytokinemia with DS might have induced Behçet's disease-like symptoms, including stomatitis and ileocecal perforation, complications that are particularly observed in patients with HLA-B51.

Topics: Adult; Antineoplastic Agents; Cecal Diseases; HLA-B51 Antigen; Humans; Ileum; Intestinal Perforation; Leukemia, Promyelocytic, Acute; Male; Stomatitis; Tretinoin

Recently, the all-trans retinoic acid (ATRA) plus arsenic trioxide (ATO) protocol has become a promising first-line therapeutic approach in patients with newly diagnosed acute promyelocytic leukemia (APL), but its benefits compared with standard ATRA plus chemotherapy regimen needs to be proven. Herein, we conducted a meta-analysis comparing the efficacy of ATRA plus ATO with ATRA plus chemotherapy for adult patients with newly diagnosed APL.. We systematically searched biomedical electronic databases and conference proceedings through February 2016. Two reviewers independently assessed all studies for relevance and validity.. Overall, three studies were eligible for inclusion in this meta-analysis, which included a total of 585 patients, with 317 in ATRA plus ATO group and 268 in ATRA plus chemotherapy group. Compared with patients who received ATRA and chemotherapy, patients who received ATRA plus ATO had a significantly better event-free survival (hazard ratio [HR] = 0.38, 95% confidence interval [CI]: 0.22-0.67, p = 0.009), overall survival (HR = 0.44, 95% CI: 0.24-0.82, p = 0.009), complete remission rate (relative risk [RR] = 1.05; 95% CI: 1.01-1.10; p = 0.03). There were no significant differences in early mortality (RR = 0.48; 95% CI: 0.22-1.05; p = 0.07).. Thus, this analysis indicated that ATRA plus ATO protocol may be preferred to standard ATRA plus chemotherapy protocol, particularly in low-to-intermediate risk APL patients. Further larger trials were needed to provide more evidence in high-risk APL patients.

Topics: Antineoplastic Agents; Arsenic Trioxide; Arsenicals; Humans; Leukemia, Promyelocytic, Acute; Oxides; Treatment Outcome; Tretinoin

Transcriptional deregulation plays a key role in a large array of cancers, and successful targeting of oncogenic transcription factors that sustain diseases has been a holy grail in the field. Acute promyelocytic leukaemia (APL) driven by chimeric transcription factors encoding retinoic acid receptor alpha fusions is the paradigm of targeted cancer therapy, in which the application of all-trans retinoic acid (ATRA) treatments have markedly transformed this highly fatal cancer to a highly manageable disease. The extremely high complete remission rate resulted from targeted therapies using ATRA in combination with arsenic trioxide will likely be able to minimise or even totally eliminate the use of highly toxic chemotherapeutic agents in APL. In this article, we will review the molecular basis and the upcoming challenges of these targeted therapies in APL, and discuss the recent advance in our understanding of epigenetics underlying ATRA response and their potential use to further improve treatment response and overcome resistance.

Topics: Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; DNA Methylation; Epigenesis, Genetic; Humans; Leukemia, Promyelocytic, Acute; Molecular Targeted Therapy; Oxides; Receptors, Retinoic Acid; Retinoic Acid Receptor alpha; Treatment Outcome; Tretinoin

Historically, acute promyelocytic leukemia (APL) was considered to be one of the most fatal forms of acute leukemia with poor outcomes before the introduction of the vitamin A derivative all-trans retinoic acid (ATRA). With considerable advances in therapy, including the introduction of ATRA initially as a single agent and then in combination with anthracyclines, and more recently by development of arsenic trioxide (ATO)-containing regimens, APL is now characterized by complete remission rates of 90% and cure rates of ∼80%, even higher among low-risk patients. Furthermore, with ATRA-ATO combinations, chemotherapy may safely be omitted in low-risk patients. The disease is now considered to be the most curable subtype of acute myeloid leukemia (AML) in adults. Nevertheless, APL remains associated with a significant incidence of early death related to the characteristic bleeding diathesis. Early death, rather than resistant disease so common in all other subtypes of AML, has emerged as the major cause of treatment failure.

Topics: Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Drug-Related Side Effects and Adverse Reactions; Humans; Leukemia, Promyelocytic, Acute; Oxides; Treatment Failure; Tretinoin

This study aimed to compare the curative effects of the combination therapy of all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO, As₂O₃) with ATRA monotherapy on newly diagnosed acute promyelocytic leukemia (APL).. The studies were retrieved from PubMed, EMBASE, Cochrane Library, ChinaInfo and China National Knowledge Infrastructure (CNKI) databases from the inception to June 20, 2014. Thereafter, the eligible studies were selected based on the predefined criteria, and the literature quality was assessed. The meta-analysis was conducted using Review Manager 5.2 software. The pooled effect size was relative risk (RR) and its 95% confidence interval (CI).. A total of 8 studies containing 480 cases were included, among which 264 were assigned to the ATRA + ATO group and the other 216 to the ATRA group. The meta-analysis showed that ATRA + ATO combination therapy significantly improved the complete remission (CR) rate (RR = 1.09, 95% CI = 1.03-1.16, p = 0.004), decreased the early mortality rate (RR = 0.42, 95% CI = 0.20-0.9, p = 0.03) and relapse rate (RR = 0.17, 95% CI = 0.07-0.42, p < 0.0001), but increased the high risk of liver dysfunction (RR = 2.43, 95% CI = 1.72-3.41, p < 0.00001), comparing with ATRA monotherapy.. The ATRA + ATO combination therapy may be more effective for newly diagnosed APL with a higher CR rate but lower early mortality rate and relapse rate. However, the risks of liver damage should be of concern.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Chemical and Drug Induced Liver Injury; Controlled Clinical Trials as Topic; Humans; Leukemia, Promyelocytic, Acute; Oxides; Randomized Controlled Trials as Topic; Remission Induction; Risk; Tretinoin

Acute promyelocytic leukaemia (APL), the M3 subtype of acute myeloid leukaemia, was once a lethal disease, yet nowadays the majority of patients with APL can be successfully cured by molecularly targeted therapy. This dramatic improvement in the survival rate is an example of the advantage of modern medicine. APL is characterized by a balanced reciprocal chromosomal translocation fusing the promyelocytic leukaemia (PML) gene on chromosome 15 with the retinoic acid receptor α (RARα) gene on chromosome 17. It has been found that all-trans-retinoic acid (ATRA) or arsenic trioxide (ATO) alone exerts therapeutic effect on APL patients with the PML-RARα fusion gene, and the combination of both drugs can act synergistically to further enhance the cure rate of the patients. Here, we provide an insight into the pathogenesis of APL and the mechanisms underlying the respective roles of ATRA and ATO. In addition, treatments that lead to more effective differentiation and apoptosis of APL cells, including leukaemia-initiating cells, and more thorough eradication of the disease will be discussed. Moreover, as a model of translational research, the development of a cure for APL has followed a bidirectional approach of 'bench to bedside' and 'bedside to bench', which can serve as a valuable example for the diagnosis and treatment of other malignancies.

Topics: Antineoplastic Agents; Arsenic Trioxide; Arsenicals; Humans; Leukemia, Promyelocytic, Acute; Molecular Targeted Therapy; Oncogene Proteins, Fusion; Oxides; Translational Research, Biomedical; Tretinoin

We report here the first case of NPM1/RARA-positive acute promyelocytic leukemia (APL) preceded by myeloid sarcoma (MS) in the vertebra. A 52-year-old man was diagnosed with MS, as the tumor cells were positive for myeloperoxidase and CD68 but negative for CD163. After treatment with steroids and radiation, the size of the tumor was markedly reduced and peripheral blood count was normal. Bone marrow examination showed 89.2% consisted of unclassified promyelocytes characterized by round nuclei and abundant small azurophilic granules but no Auer rods. The results of chromosome analysis showed 46,XY,t(5;17)(q35;q12). Reverse-transcription polymerase chain reaction amplified the NPM1/RARA fusion transcripts derived from a combination of NPM1 exon 4 and RARA exon 5, or of NPM1 exon 1 and RARA exon 5; the latter of these has not been reported previously. Electron microscopic examination of the promyelocyte nuclei showed they were oval with mild nuclear chromatin condensation and small- to medium-sized nucleoli. Hematological and molecular complete remission was attained after induction therapy including all-trans retinoic acid. As MS was also diagnosed in two of the seven other reported cases of APL with NPM1/RARA, MS may occur more frequently in APL with NPM1/RARA than APL with PML/RARA.

Topics: Cell Nucleolus; Cell Nucleus; Chromatin; Exons; Gene Fusion; Granulocyte Precursor Cells; Humans; Induction Chemotherapy; Leukemia, Promyelocytic, Acute; Magnetic Resonance Imaging; Male; Microscopy, Electron; Middle Aged; Nuclear Proteins; Nucleophosmin; Receptors, Retinoic Acid; Retinoic Acid Receptor alpha; Reverse Transcriptase Polymerase Chain Reaction; Sarcoma, Myeloid; Tretinoin

Acute promyelocytic leukemia (APL) is one of the well-characterized subtypes of acute myeloid leukemia (AML). The essential drugs used in the treatment strategy for APL include all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), which are both pioneer molecular-targeting agents. They were initially administered to patients based on the therapeutic experience of traditional Chinese medicine, and their marked effectiveness has been demonstrated. Subsequently, the molecular mechanisms of these drugs, as well as the molecular pathogenesis of APL, have been elucidated, whereby the chimeric gene product PML-RARα induces epigenetic changes and transcription repression. This review summarizes the findings of previous studies related to the in vitro and in vivo function of PML-RARα and the effects of ATRA and ATO on PML-RARα and APL cells. These findings are very important, because the concept of epigenetic modulation in oncogenesis and their application as molecular targets in APL therapy have now been accepted in other types of leukemia, as well as for other malignancies.

Topics: Animals; Antineoplastic Agents; Arsenic Trioxide; Arsenicals; Disease Models, Animal; Epigenomics; Humans; Leukemia, Promyelocytic, Acute; Medicine, Chinese Traditional; Mice; Molecular Targeted Therapy; Oncogene Proteins, Fusion; Oxides; Transcription, Genetic; Tretinoin

Although integrity of the p53 signaling pathway in a given tumor was expected to be a critical determinant of response to therapies, most clinical studies failed to link p53 status and treatment outcome. Here, we present two opposite situations: one in which p53 is an essential effector of cure by targeted leukemia therapies and another one in advanced breast cancers in which p53 inactivation is required for the clinical efficacy of dose-dense chemotherapy. If p53 promotes or blocks therapy response, therapies must be tailored on its status in individual tumors.

Topics: Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Breast Neoplasms; Female; Humans; Leukemia, Promyelocytic, Acute; Molecular Targeted Therapy; Oncogene Proteins, Fusion; Oxides; Treatment Outcome; Tretinoin; Tumor Suppressor Protein p53

Recent reports of recurrent mutations in childhood acute myeloid leukemia (AML) have identified potential targets for new therapeutic strategies. Acute promyelocytic leukemia (APL) is characterized commonly by a fusion between the PML gene and the RARA gene, genes targetable by arsenic (ATO) and retinoic acid (ATRA), respectively. A mutation in GATA1, common in AML of Down syndrome (ML-DS), renders cells more susceptible to cytarabine and anthracyclines, thus permitting targeted dose reductions to preserve high survival rates while reducing toxicity. In all other patients, Ras pathway mutations, KMT2A and other methyltransferase mutations, FLT3 mutations, and KIT mutations are all relatively common in childhood AML and all are potentially "druggable". The focus of this review is on those therapies likely to be clinically available in the near future. The preclinical and clinical data providing a rationale for testing in children of specific agents in children is discussed. Whether the expression of a potential target is sufficient to predict response to a targeted therapy is an open question in childhood AML. Development of clinical trials to evaluate targeted therapies in small molecularly defined subsets of AML will be the next great challenge for all cooperative groups in North America and Europe.

Topics: Adolescent; Adult; Arsenic Trioxide; Arsenicals; Child; Child, Preschool; Clinical Trials as Topic; Down Syndrome; Epigenesis, Genetic; GATA1 Transcription Factor; Humans; Leukemia, Myeloid, Acute; Leukemia, Promyelocytic, Acute; Medical Oncology; Molecular Medicine; Mutation; Oxides; ras Proteins; Receptor Protein-Tyrosine Kinases; Treatment Outcome; Tretinoin

Acute Promyelocytic Leukemia (APL) is one of the most curable leukemia which shows great sensitivity to all-trans retinoic acid (ATRA) although a small number of the patients present poor prognosis and short survival. Isochromosome 17 in APL which usually bears an additional copy of RARA/PML fusion gene is considered to be a negative factor on its prognosis. Cryptic t(15;17) on i(17q) leads to an extra copy of PML/RARA rather than RARA/PML which may confer a worse prognosis. We describe here a rare APL case with complex chromosomal abnormality including isochromosome 17 bearing cryptic t(15;17) showing poor outcome. The patient lacks a classic t(15;17) and fluorescence in situ hybridization (FISH) presents 2 PML/RARA fusion signals on both long arms of the isochromosome. The patient also acquired a secondary mutation at relapse when the initial karyotype was already a complex karyotype involving chromosome 13, 17 and 22 at the same time. The poor response of this patient to traditional chemotherapy like ATRA and novel therapy like arsenic trioxide (ATO) suggests that early auto-hematological stem cell transplantation may be the choice of APL with isochromosome 17 especially with cryptic t(15;17) on i(17q). We are the first to show a clear history and evidence of FISH of these kind of cases. A small summary of cases with cryptic t(15;17) on isochromosome 17 is also made.

Topics: Antineoplastic Agents; Arsenic Trioxide; Arsenicals; Bone Marrow Examination; Chromosomes, Human, Pair 15; Chromosomes, Human, Pair 17; Disease Progression; Fatal Outcome; Genetic Predisposition to Disease; Humans; In Situ Hybridization, Fluorescence; Isochromosomes; Karyotype; Leukemia, Promyelocytic, Acute; Male; Molecular Diagnostic Techniques; Mutation; Oncogene Proteins, Fusion; Oxides; Phenotype; Predictive Value of Tests; Time Factors; Translocation, Genetic; Treatment Outcome; Tretinoin; Young Adult

To explore the combination therapy of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO, As2O3) on acute promyelocytic leukemia (APL).. A meta-analysis of six studies was performed. Among 415 included cases, 165 cases were in the ATRA + ATO group, 129 cases in the ATRA-alone group, and 121 cases in the ATO-alone group. The complete remission (CR) rate and incidences of three groups were compared, respectively, between the therapies of ATRA + ATO with ATRA-alone, ATRA + ATO with ATO-alone, and ATRA with ATO.. The assessment results showed that ATRA + ATO therapy significantly improved the CR rate and decreased the incidences of cutaneous reaction compared with ATRA-alone (P < 0.05). However, incidence of liver injury was higher in the ATRA + ATO and ATO-alone groups than that in ATRA-alone group (P < 0.05). Difference in the complications between ATRA + ATO therapy and ATO-alone was not significant (P > 0.05).. In conclusion, we suggest low-dose ATRA and ATO combination therapy may be more effective for the treatment of APL.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Humans; Leukemia, Promyelocytic, Acute; Oxides; Remission Induction; Treatment Outcome; Tretinoin

Arsenic trioxide (ATO) has been shown to be the most effective single agent in acute promyelocytic leukaemia (APL) and has been approved for the treatment of relapsed patients both in the US and Europe. The role of ATO in front-line therapy of APL is under investigation.. Pilot studies using ATO with or without all-trans retinoic acid (ATRA) have been carried out in newly diagnosed APL patients with the aim to reduce the short and long-term toxic effects of chemotherapy and to improve clinical outcome. Especially in patients with non-high-risk APL, the ATRA + ATO approach allowed significant increase in event-free survival and overall survival rates compared to standard ATRA and chemotherapy. This has been demonstrated by pilot studies and, more recently, by a randomized comparative multi-centre study conducted in Italy and Germany.. The ATO + ATRA strategy for APL may provide the first paradigm of acute leukaemia curability by targeted agents and without chemotherapy. However, longer follow-up of available studies and independent confirmation of the Italian-German findings are awaited to firmly establish this paradigm. Finally, extension of this approach to other patient categories such as high-risk, elderly and children will need to be explored in the near future.

Topics: Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Humans; Leukemia, Promyelocytic, Acute; Oxides; Randomized Controlled Trials as Topic; Standard of Care; Treatment Outcome; Tretinoin

Topics: Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Consolidation Chemotherapy; Cytarabine; Daunorubicin; Drug Discovery; Etoposide; Hematopoietic Stem Cell Transplantation; Humans; Idarubicin; Induction Chemotherapy; Leukemia, Myeloid, Acute; Leukemia, Promyelocytic, Acute; Maintenance Chemotherapy; Mercaptopurine; Methotrexate; Molecular Targeted Therapy; Mutation; Recurrence; Tretinoin; Vincristine

Differentiation syndrome (DS), formerly known as retinoic acid syndrome, is a relatively common and potentially severe complication seen in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and/or arsenic trioxide. The full-blown syndrome consists of unexplained fever, weight gain, dyspnea with pulmonary infiltrates, pleuropericardial effusion, hypotension, and renal failure. Most measures currently used for management of DS have very little evidence-based support, and therefore, many remain controversial. Despite the lack of evidence supporting DS prophylaxis, several groups have adopted a preventive strategy with corticosteroids, especially for patients with leukocyte levels higher than from 5 to 10 × 10(9)/L. DS diagnosis should be suspected in the presence of any of the above-mentioned signs and symptoms, and preemptive treatment with dexamethasone should be started immediately. Other supportive measures can also be crucial for the correct management of DS, especially in those patients with life-threatening complications. Temporary discontinuation of all-trans retinoic acid or arsenic trioxide is indicated only for patients in very poor clinical condition or with severe renal or pulmonary dysfunction, sometimes requiring admission to the intensive care unit. Recognition of specific biomarkers and a better understanding of DS pathogenesis can be helpful for the development of specific therapies to counteract DS in a timely manner.

Topics: Adult; Arsenic Trioxide; Arsenicals; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Leukemia, Promyelocytic, Acute; Male; Oxides; Premedication; Syndrome; Tretinoin

Acute promyelocytic leukemia (APL) is characterized by coagulopathy, leukopenic presentation and sensitivity to anthracyclines, all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). For the last 25 years, APL has been treated with a combination of ATRA and chemotherapy for induction followed by consolidation and maintenance therapy. This general treatment approach has resulted in cure rates of 80-90 %. ATO, originally approved in relapsed APL, has been incorporated into contemporary upfront treatment regimens with excellent response rates. Recent studies show that most patients with APL can be cured with ATRA and ATO alone, eliminating cytotoxic chemotherapy and resulting in superior outcomes compared to standard treatment. We will herein review historical treatment of APL, treatment considerations in specific patient populations, and therapeutic updates.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Clinical Trials as Topic; Humans; Leukemia, Promyelocytic, Acute; Oxides; Recurrence; Tretinoin

Modern guidelines based on a large international consensus indicate that treatment of newly diagnosed acute promyelocytic leukemia (APL) requires distinguishing at presentation low-intermediate (<10 × 10(9)/L WBC) from high-risk (>10 × 10(9)/L WBC) disease. The concomitant use of all-trans retinoic acid (ATRA) and anthracycline based chemotherapy, with inclusion of AraC in consolidation for hyperleucocytic patients, has remained the standard of care for the past two decades. The advent of arsenic trioxide (ATO) and results from a large randomized trial, have recently challenged the standard ATRA-chemotherapy approach suggesting that at least patients in the low-intermediate category may be cured without chemotherapy using the ATRA-ATO combination.

Topics: Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Clinical Trials as Topic; Humans; Leukemia, Promyelocytic, Acute; Maintenance Chemotherapy; Oxides; Practice Guidelines as Topic; Tretinoin

Retinoic acid (RA) is an active derivative of vitamin A, and it has different isomers, including ATRA (all-trans-retinoic acid), 13-cRA (13-cis-retinoic acid) and 9-cRA (9-cis-retinoic acid), etc. Combining with RARs and RXRs, RA plays important roles not only in embryonic development but also in cellular growth and differentiation through transcriptional regulation of its target genes. Following the successful application in the differentiation therapy of acute promyelocytic leukemia (APL) in clinical, recent studies have found that the disturbance of RA signal transduction was also related to differentiation, proliferation or apoptosis of tumor cells. To develop novel mechanisms-based differentiation therapy for other tumors, the relationship between RA or its receptors and tumors will be summarized in this review.

Topics: Apoptosis; Arsenic Trioxide; Arsenicals; Cell Differentiation; Cell Proliferation; Drug Resistance, Neoplasm; Drug Therapy, Combination; Gene Expression Regulation, Leukemic; Humans; Leukemia, Promyelocytic, Acute; Neoplastic Cells, Circulating; Oxides; Receptors, Retinoic Acid; Signal Transduction; Tretinoin

Acute promyelocytic leukaemia (APL) is a subtype of acute myeloid leukaemia (AML) with unique biological and clinical features and unique therapeutic requirements. The article provides a brief description of the development, pathophysiology, diagnosis and treatment of APL.. The article is based on the authors' own experience and reviews of key articles and national and international guidelines.. The disease is caused by a single genetic event, namely the translocation t(15;17), which gives rise to the oncoprotein PML-RARA. Clinical and morphological characteristics arouse suspicion of the disease, and the diagnosis is verified by detecting the translocation. At the time of diagnosis most patients have severe coagulopathy and the predominant clinical manifestation is bleeding. Early mortality is due to severe haemorrhage, usually intracranial. Early treatment start with all-trans retinoic acid (ATRA) on suspicion of APL is essential to reduce this early mortality. ATRA is also an important part of continued treatment, in combination with anthracycline-based chemotherapy and possibly arsenic. After this treatment, the prognosis for disease-free long-term survival is > 90%. There are also safe and effective treatment options for elderly patients with complex comorbidities.. With APL it is particularly important to start disease-targeting therapy in the form of ATRA quickly because of the high risk of serious haemorrhages and high early mortality. If serious haemorrhages are avoided, the prognosis is very good.

Topics: Antineoplastic Agents; Chromosomes, Human, Pair 15; Chromosomes, Human, Pair 17; Humans; Leukemia, Promyelocytic, Acute; Oncogene Proteins, Fusion; Translocation, Genetic; Tretinoin

Acute promyelocytic leukemia (APL) is a distinct subset of acute myeloid leukemia (AML) associated with peculiar biologic and clinical features and requiring specific management. At the genetic level, APL is featured by a unique chromosome translocation t(15;17) which results in the PML-RARα gene fusion and chimeric protein. APL is the first example of differentiation therapy targeted to a defined genetic target i.e. PML-RARα. PML-RARα behaves as an altered retinoic acid receptor with an ability of transmitting oncogenic signaling leading to accumulation of undifferentiated promyelocytes. All-trans-retinoic acid (ATRA) induces disease remission in APL patients by triggering terminal differentiation of leukemic promyelocytes. More recently, arsenic trioxide (ATO) has been shown to contribute degradation of the PML-RARα oncoprotein through bonding the PML moiety and has shown excellent synergism with ATRA in clinical trials. Elucidating the oncogenic signaling of PML-RARα through various transcription factors and the study of APL mouse models have greatly helped to understand the molecular pathogenesis of APL. However, the precise molecular mechanism by which t(15;17) is formed and initiates leukemia remains unknown. While transforming oncogenic potential of PML-RARα has been described extensively, the mechanistic events important for the formation of t(15;17) have been taken from the model of Therapy-related APL (t-APL).

Topics: Animals; Antineoplastic Agents; Arsenic Trioxide; Arsenicals; Cell Differentiation; Cell Transformation, Neoplastic; Chromosomes, Human, Pair 15; Chromosomes, Human, Pair 17; Clinical Trials as Topic; Disease Models, Animal; DNA End-Joining Repair; Drug Synergism; Granulocyte Precursor Cells; Humans; Leukemia, Promyelocytic, Acute; Mice; Molecular Targeted Therapy; Neoplasm Proteins; Neoplasms, Second Primary; Neoplastic Stem Cells; Oncogene Proteins, Fusion; Oxides; Signal Transduction; Topoisomerase II Inhibitors; Translocation, Genetic; Tretinoin

Coagulopathy is a unique component of the pathology of acute promyelocytic leukaemia (APL). Though many causative factors have been elucidated, therapies to rectify the coagulopathy are far from being realised. Thrombotic and bleeding complications remain the major causes of early deaths. In this chapter, the known causes of abnormalities in haemostatic function, namely the coagulopathy and changes in the fibrinolytic system, will be reviewed. Major risk factors for these complications are identified. Current available measures for correction of the coagulopathy and their effectiveness are critically examined. Unless the coagulopathy can be effectively controlled, bleeding complications will remain an obstacle to achieving a cure for this disease. The issues that need to be addressed in next phase of investigations are also discussed.

Topics: Annexin A2; Anticoagulants; Antineoplastic Agents; Arsenic Trioxide; Arsenicals; Blood Coagulation Disorders; Blood Coagulation Tests; Carboxypeptidase B2; Disseminated Intravascular Coagulation; Fibrinolysis; Forecasting; Granulocyte Precursor Cells; Hemorrhagic Disorders; Humans; Leukemia, Promyelocytic, Acute; Oxides; Recombinant Proteins; Risk Factors; S100 Proteins; Thrombomodulin; Thrombophilia; Thromboplastin; Tretinoin; Urokinase-Type Plasminogen Activator

If looking for a mnemonic to remember the relevant facts about acute promyelocytic leukemia (APL), one just has to remember that APL is a disease of A's. It is acute and it is highly sensitive to treatment with anthracyclines, all-trans-retinoic acid (RA) and arsenic trioxide (ATO). The presence of fusions involving the retinoic acid receptor alpha (RARA) is without question the central player driving APL and dictating the response of this disease to these therapeutic agents. However, beyond this knowledge, the molecular mechanisms that contribute to the complicated pathogenesis and the response to treatment of APL are not completely defined. As more is understood about this hematological malignancy, there are more opportunities to refine and improve treatment based on this knowledge. In this review article, we discuss the response of APL to these "A" therapies.

Topics: Anthracyclines; Antibiotics, Antineoplastic; Arsenic Trioxide; Arsenicals; Cell Differentiation; Cell Line, Tumor; Drug Resistance, Neoplasm; Gene Expression Regulation, Leukemic; Granulocyte Precursor Cells; Humans; Leukemia, Promyelocytic, Acute; Molecular Targeted Therapy; Neoplasm Proteins; Oncogene Proteins, Fusion; Oxides; Topoisomerase II Inhibitors; Transcription, Genetic; Tretinoin

Since the introduction of all-trans-retinoic acid, the use of this molecularly targeted treatment in combination with anthracycline-based chemotherapy has completely changed the prognosis of acute promyelocytic leukemia (APL) turning it into the most curable acute myeloid leukemia. Also, the use of risk-adapted protocols has optimized the drug combination and the most appropriate dose intensity for each subset of patients classified according to both risk of relapse and vulnerability to drug toxicity. Recent developments have included the investigation of the role of arsenic trioxide (ATO) as front-line treatment after its success in relapsed APL, both to minimize or even omit the use of cytotoxic agents and to reinforce the conventional chemotherapy-based approach. In the present chapter we will address the achievements of conventional treatment with ATRA and chemotherapy, as well as the opportunity to cure more patients with modifications of this therapeutic backbone with the addition of ATO in any phase of treatment.

Topics: Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Clinical Trials as Topic; Consolidation Chemotherapy; Daunorubicin; Harringtonines; Homoharringtonine; Humans; Idarubicin; Leukemia, Promyelocytic, Acute; Maintenance Chemotherapy; Mercaptopurine; Methotrexate; Mitoxantrone; Multicenter Studies as Topic; Oxides; Remission Induction; Tretinoin

Until recently, the standard of care in the treatment of APL has involved the combination of all-trans retinoic acid with anthracycline-based chemotherapy during both induction and consolidation. Additionally, the intensity of consolidation chemotherapy has evolved according to a universally accepted relapse-risk stratification algorithm based on the white cell and platelet counts at presentation. That standard of care is being challenged by the increasing incorporation of arsenic trioxide into front-line treatment protocols, based on two complementary observations. The first is the undoubted anti-leukaemic activity of arsenic trioxide as shown in the relapsed and refractory setting, and in the initial management of low- and intermediate-risk patients. The second is an improved understanding of the action of both all-trans retinoic acid and arsenic trioxide in mediating APL cell eradication, with increasing recognition that PML-RARA fusion protein degradation rather than direct induction of terminal differentiation is the primary mechanism for their ability to eliminate leukaemia initiating cells. As a result, we believe the standard of care for initial therapy in APL is shifting towards an all-trans retinoic acid plus arsenic trioxide-based approach, with additional chemotherapy reserved for patients with high-risk disease.

Topics: Adult; Age Factors; Aged; Anthracyclines; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Blood Coagulation Factors; Clinical Trials as Topic; Combined Modality Therapy; Cytarabine; Etoposide; Humans; Hydroxyurea; Idarubicin; Leukemia, Promyelocytic, Acute; Maintenance Chemotherapy; Middle Aged; Mitoxantrone; Multicenter Studies as Topic; Oxides; Platelet Transfusion; Practice Guidelines as Topic; Remission Induction; Risk Assessment; Thioguanine; Treatment Outcome; Tretinoin

Molecularly targeted therapies have transformed the management of PML-RARA+ acute promyelocytic leukaemia (APL), with survival rates now exceeding 80% in clinical trials. This raises questions about the relevance of post-remission monitoring for PML-RARA transcripts, which has been widely used to predict relapse, guiding early intervention to prevent disease progression and the inherent risk of fatal bleeding. Given the treatability of haematological relapse, survival benefits would only be seen if monitoring could identify patients who could be salvaged if treated early but not later on, although it could be argued that early deployment of arsenic trioxide (ATO) can avoid inducing hyperleucocytosis and the associated differentiation syndrome, which frequently complicate treatment of frank relapse. However, given the low rates of relapse now observed in patients presenting with standard risk disease (i.e. presenting WBC<10×10(9)/l) who achieve early molecular remission, subsequent sequential minimal residual disease (MRD) monitoring confers only a marginal benefit, so could be avoided in this group. However, sequential MRD monitoring may still be of value in patients with high risk APL, although evidence tends to come from historically controlled studies. Therefore, there may remain a role for MRD monitoring in the most clinically challenging subsets of APL, but the continuing debate highlights the need for robust evidence in developing a more individualized approach to management of other subtypes of acute leukaemia.

Topics: Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Biomarkers, Tumor; Cell Differentiation; Clinical Trials as Topic; Disease Management; Drug Monitoring; Drug Resistance, Neoplasm; Historically Controlled Study; Humans; Kaplan-Meier Estimate; Leukemia, Promyelocytic, Acute; Leukocytosis; Neoplasm, Residual; Oncogene Proteins, Fusion; Oxides; Real-Time Polymerase Chain Reaction; Remission Induction; Salvage Therapy; Tretinoin

In the last 2 decades an increasing number of patients reported with extramedullary involvement among relapsed acute promyelocytic leukemia (APL) patients. Several investigators related this phenomenon to the relatively new treatment of all-trans-retinoic-acid (ATRA). In this review article we will examine what has been reported in the medical literature on extramedullary disease in APL: the common sites to be involved, the clinical risk factors to its development, the role of ATRA and arsenic tri-oxide and the recommended treatment.

Topics: Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Benzoates; Cerebral Hemorrhage; Humans; Incidence; Leukemia, Promyelocytic, Acute; Leukemic Infiltration; Models, Biological; Multicenter Studies as Topic; Organ Specificity; Oxides; Prognosis; Randomized Controlled Trials as Topic; Remission Induction; Risk Factors; Tetrahydronaphthalenes; Tretinoin

Acute promyelocytic leukaemia (APL) in children and adolescents shares many features with APL in adults. There are important distinctions, however, between these age groups in the presentation, complications and treatment outcomes. Paediatric patients are more likely to present with high risk features including elevated WBC count or microgranular variant (M3v). Yet the early death rate is lower in paediatric patients compared to adult patients. Overall outcomes such as CR, OS and EFS appear similar in paediatric and adult patients treated on similar regimens except that very young children may have a higher risk of relapse. While contemporary studies have clearly demonstrated improved survival in adults receiving ATO therapy, currently there is more limited data on the role of ATO in paediatric patients. Here we highlight the similarities and important distinctions between paediatric and adult APL while reviewing available data on treatment of paediatric APL.

Topics: Adolescent; Adrenal Cortex Hormones; Adult; Age Factors; Age of Onset; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Biomarkers, Tumor; Blood Coagulation Disorders; Bone Marrow Examination; Cell Differentiation; Child; Child, Preschool; Heart Diseases; Humans; Infant; Leukemia, Promyelocytic, Acute; Multicenter Studies as Topic; Neoplasm, Residual; Neoplasms, Second Primary; Oncogene Proteins, Fusion; Oxides; Prognosis; Pseudotumor Cerebri; Randomized Controlled Trials as Topic; Remission Induction; Risk Factors; Salvage Therapy; Tretinoin

The past three decades have witnessed a great progress in the treatment of acute promyelocytic leukemia (APL). The current application of all-trans retinoic acid, arsenic trioxide (ATO), and anthracycline-based chemotherapies has been proved to be highly effective. Based on the risk factors of APL, optimization of the treatment emphasizes the role of ATO in induction, consolidation and maintenance therapy as a substitute to chemotherapy in low- and intermediate-risk patients, and in potential reduction of chemotherapy in high-risk group without impact on the outcome. However, early death and relapse remain obstacles to further improvement of the rates of remission and long-term survival, and the acute and chronic adverse effects of ATO should be considered for more appropriate management. Efforts should be made to more rationally obtain improved outcomes through the use of less toxic regimens.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Drug Synergism; Humans; Leukemia, Promyelocytic, Acute; Neoplasm Recurrence, Local; Oxides; Salvage Therapy; Tretinoin

Inevitably fatal some 40 years, acute promyelocytic leukemia (APL) can now be cured in more than 95% of cases. This clinical success story is tightly linked to tremendous progress in our understanding of retinoic acid (RA) signaling. The discovery of retinoic acid receptor alpha (RARA) was followed by the cloning of the chromosomal translocations driving APL, all of which involve RARA. Since then, new findings on the biology of nuclear receptors have progressively enlightened the basis for the clinical efficacy of RA in APL. Reciprocally, the disease offered a range of angles to approach the cellular and molecular mechanisms of RA action. This virtuous circle contributed to make APL one of the best-understood cancers from both clinical and biological standpoints. Yet, some important questions remain unanswered including how lessons learnt from RA-triggered APL cure can help design new therapies for other malignancies.

Topics: Humans; Leukemia, Promyelocytic, Acute; Signal Transduction; Tretinoin

Acute promyelocytic leukemia (APL) with tetraploidy chromosome harboring t(15;17)(q23;a21) is extremely rare. To date, there are 14 such cases reports that describe this entity, mostly found in Eastern hemisphere. Herein we described a 51-year-old man with a diagnosis of tetraploid acute promyelocytic leukemia with double (15;17) translocations and compare the prototypically clinicopathologic, genetic and molecular findings with those reported in the literature.

Topics: Antineoplastic Combined Chemotherapy Protocols; Flow Cytometry; Humans; Idarubicin; In Situ Hybridization, Fluorescence; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Oncogene Proteins, Fusion; Tetraploidy; Translocation, Genetic; Tretinoin

Acute promyelocytic leukemia (APL) is a rare subtype of AML characterized by a reciprocal balanced translocation between chromosomes 15 and 17 that fuses the PML gene with the RARα gene and leads to the leukemic phenotype. Although best described in large clinical trials of adults, APL, like other forms of AML, also occurs in children. The positive outcome of children with APL mirrors the dramatic increase in survival seen in adults since the introduction of all-trans retinoic acid (ATRA). In this paper, we review the diagnosis of APL in children as well as large, retrospective, clinical trial data collected on pediatric APL. We also raise management issues and toxicities that are unique to children.

Topics: Antineoplastic Agents; Arsenic; Clinical Trials as Topic; Drug Therapy, Combination; Humans; Leukemia, Promyelocytic, Acute; Survival Rate; Translocation, Genetic; Tretinoin

Incorporation of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) into the management paradigms of acute promyelocytic leukemia (APL) has markedly improved outcomes. Significant progress occurred in understanding the molecular pathogenesis of APL. ATO, in contrast with ATRA, is capable of eradicating the APL-initiating cells and can result in cure. Preclinical and clinical data confirmed the synergy of ATO and ATRA, and the ATRA-ATO combination was proved noninferior to a standard ATRA-chemotherapy regimen in patients with non-high-risk APL. Oral formulations of arsenic exhibited excellent activity in advanced clinical testing and their combinations with ATRA offer an opportunity for a completely oral, chemotherapy-free regimen for curing APL. Nonetheless, significant challenges remain. Reducing early death due to bleeding complications is an important area of unmet need. Data suggest that delays in initiation of ATRA upon suspecting APL continue to occur in the community and contribute to early mortality. Questions remain about the optimal place and schedule of arsenic in the therapeutic sequence and the role of the oral formulations. Refining the role of minimal residual disease in directing treatment decisions is important. Development of novel targeted agents to treat relapsed disease requires deeper understanding of the secondary resistance mechanisms to ATRA and ATO.

Topics: Administration, Oral; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Disease Management; Drug Resistance, Neoplasm; Humans; Leukemia, Promyelocytic, Acute; Neoplasm, Residual; Oxides; Tretinoin

Topics: Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Benzoates; Clinical Trials, Phase III as Topic; Consolidation Chemotherapy; Disseminated Intravascular Coagulation; Gene Fusion; Humans; Induction Chemotherapy; Leukemia, Promyelocytic, Acute; Maintenance Chemotherapy; Molecular Targeted Therapy; Nuclear Proteins; Oxides; Promyelocytic Leukemia Protein; Receptors, Retinoic Acid; Recurrence; Remission Induction; Retinoic Acid Receptor alpha; Tetrahydronaphthalenes; Transcription Factors; Tretinoin; Tumor Suppressor Proteins

Topics: Annexin A2; Antineoplastic Agents; Asparaginase; Cytokines; Disseminated Intravascular Coagulation; Drug Interactions; Hematologic Neoplasms; Humans; Leukemia, Promyelocytic, Acute; Thalidomide; Thrombomodulin; Tretinoin; Venous Thromboembolism

Acute promyelocytic leukemia (APL) is characterized by the occurrence of translocations between chromosomes 15 and 17, resulting in generation of a fusion protein of promyelocytic leukemia (PML) and retinoid A receptor (RAR) α. APL cells are unable to differentiate into mature granulocytes since PML-RARα functions as a strong transcriptional repressor for a gene involved in granulocyte differentiation. All-trans retinoic acid (ATRA) is the first agent that has been developed to target specific disease-causing molecules, i.e., ATRA suppresses abnormal functions of oncogenic proteins. Moreover, ATRA facilitates the differentiation of APL cells toward mature granulocytes by changing epigenetic modifiers from corepressor complexes to co-activator complexes on target genes after binding to the ligand-binding domain at the RARα moiety of the PML-RARα oncoprotein. On the other hand, arsenic trioxide (ATO), another promising agent used to treat APL, directly binds to the PML moiety of the PML-RARα protein, causing oxidation and multimerization. ATO enhances the conjugation of small ubiquitin-like modifiers to PML-RARα, followed by ubiquitination and degradation, relieving the genes associated with granulocytic differentiation from suppressive restraint by the oncoprotein. Recent clinical studies have demonstrated that combination therapy with both ATRA and ATO is useful to achieve remission.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Biomarkers, Tumor; Drug Synergism; Epigenesis, Genetic; Gene Expression Regulation, Leukemic; Humans; Leukemia, Promyelocytic, Acute; Oncogene Proteins, Fusion; Oxides; Treatment Outcome; Tretinoin

All-trans-retinoic acid (ATRA) is a physiologically active metabolite of vitamin A. Its antitumour activities have been extensively studied in a variety of model systems and clinical trials; however, to date the only malignancy responsive to ATRA treatment is acute promyelocytic leukaemia (APL) where it induces complete remission in the majority of cases when administered in combination with light chemotherapy and/or arsenic trioxide. After decades of studies, the efficacy of ATRA to treat other acute myeloid leukaemia (AML) subtypes and solid tumours remains poor. Recent studies directed to improve ATRA responsiveness in non-APL AML seem to indicate that the lack of effective ATRA response in these tumours may be primarily due to aberrant epigenetics, which negatively affect ATRA-regulated gene expression and its antileukaemic activity. Epigenetic reprogramming could potentially restore therapeutic effects of ATRA in all AML subtypes. This review discusses the current progresses in the understanding how ATRA can be utilised in the therapy of non-APL AML and other cancers.

Topics: Animals; Antineoplastic Agents; Humans; Leukemia, Myeloid, Acute; Leukemia, Promyelocytic, Acute; Receptors, Retinoic Acid; Tretinoin

Acute promyelocytic leukemia (APL) is the most curable type of leukemia. A consensus exists regarding the need for administration of both induction and consolidation treatments, albeit using different approaches. However, there is conflicting evidence for the role of maintenance treatment in APL patients.. To examine the efficacy and safety of maintenance therapy in APL patients and to establish the optimal regimen for maintenance.. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 6), MEDLINE (January 1966 to July 2012), LILACS (1982 to July 2012), relevant conference proceedings (2000 to 2012) and databases of ongoing and unpublished trials.. Randomized controlled trials assessing maintenance treatment in patients with newly diagnosed APL in first complete remission (CR) following induction or induction and consolidation therapy.. Two review authors assessed the quality of trials and extracted data. We estimated and pooled hazard ratios (HR) and risk ratios (RR) with 95% confidence intervals (CI) using the fixed-effect model. If significant heterogeneity was present we explored potential causes for such heterogeneity and if not found we used also the random-effects model.. We included 10 randomized controlled trials enrolling 2072 patients in the systematic review, and conducted meta-analysis on nine of them. There was no statistically significant effect on overall survival (OS) in the three main comparisons (HR for any maintenance treatment versus observation 0.79, 95% CI 0.49 to 1.27; HR for all-trans retinoic acid (ATRA)-based maintenance versus non-ATRA based maintenance 1.21, 95% CI 0.73 to 1.98; HR for ATRA alone maintenance versus ATRA and chemotherapy 0.99, 95% CI 0.69 to 1.43). However, disease free survival (DFS) was improved with any maintenance therapy compared to observation (HR 0.59, 95% CI 0.48 to 0.74; 5 trials, 1209 patients) and with ATRA and chemotherapy compared to ATRA alone maintenance (HR for ATRA alone compared to ATRA and chemotherapy 1.38, 95% CI 1.09 to 1.76; 4 trials, 1028 patients). DFS was not improved with ATRA-based regimens compared to non-ATRA based regimens (HR 0.72, 95% CI 0.51 to 1.01; 4 trials, 670 patients). Analysis of clinically relevant adverse events could not be conducted due to paucity of data. Yet, increased reports of grade 3/4 adverse events were noted for any maintenance versus observation and for combined ATRA and chemotherapy versus ATRA alone treatment. The major limitation of this review lies in the variability between the included trials in both maintenance and pre-maintenance parameters. We tried to address this variability and to reduce its potential biases by conducting three separate main comparisons, as outlined above, leaving less statistical power to the presented results.. Maintenance therapy compared to observation in APL patients improved DFS but not OS. Similarly, ATRA and chemotherapy compared to ATRA improved DFS but not OS. In contrast, ATRA based regimens compared to non-ATRA based regimens did not demonstrate a survival benefit. The significance of these findings is limited due to clinical heterogeneity between studies.

Topics: Anthracyclines; Antineoplastic Agents; Disease-Free Survival; Humans; Leukemia, Promyelocytic, Acute; Maintenance Chemotherapy; Randomized Controlled Trials as Topic; Tretinoin; Watchful Waiting

Since the introduction of all-trans retinoic acid (ATRA) and arsenic trioxide (As2O3) for the treatment of acute promyelocytic leukemia (APL), the overall survival rate has improved dramatically. However, relapse/refractory patients showing resistance to ATRA and/or As2O3 are recognized as a clinically significant problem. Genetic mutations resulting in amino acid substitution in the retinoic acid receptor alpha (RARα) ligand binding domain (LBD) and the PML-B2 domain of PML-RARα, respectively, have been reported as molecular mechanisms underlying resistance to ATRA and As2O3. In the LBD mutation, ATRA binding with LBD is generally impaired, and ligand-dependent co-repressor dissociation and degradation of PML-RARα by the proteasome pathway, leading to cell differentiation, are inhibited. The PML-B2 mutation interferes with the direct binding of As2O3 with PML-B2, and PML-RARα SUMOylation with As2O3 followed by multimerization and degradation is impaired. To overcome ATRA resistance, utilization of As2O3 provides a preferable outcome, and recently, a synthetic retinoid Am80, which has a higher binding affinity with PML-RARα than ATRA, has been tested in the clinical setting. However, no strategy attempted to date has been successful in overcoming As2O3 resistance. Detailed genomic analyses using patient samples harvested repeatedly may help in predicting the prognosis, selecting the effective targeting drugs, and designing new sophisticated strategies for the treatment of APL.

Topics: Antineoplastic Agents; Arsenic Trioxide; Arsenicals; Drug Resistance, Neoplasm; Humans; Leukemia, Promyelocytic, Acute; Molecular Targeted Therapy; Oxides; Tretinoin

Despite substantial progress in the management and outcome of acute promyelocytic leukemia (APL) during the last decades, older age remains a prominent negative prognostic factor. The improvement of long-term stabilization and cure of older APL patients is therefore a particular challenge. Data of unselected population-based studies suggest a high rate of exclusion from clinical trials in older age. The comparison of registry and study data indicates that study patients represent a positive selection. Older APL patients seem as sensitive to therapy as younger patients. With conventional therapy, based on all-trans retinoic acid (ATRA) and chemotherapy, over 50 % of older APL patients can probably be cured. Special problems of advanced age are the high rate of early death before or during induction therapy and the high frequency of death in remission with negative influence on the outcome. Both may be related in part to a higher vulnerability against the common treatment with ATRA and chemotherapy. Alternative less toxic approaches including arsenic trioxide (ATO) with or without ATRA and combinations with gemtuzumab ozogamicin or with reduced chemotherapy can induce long-lasting remission in all stages of APL. Considering the high curative potential and the excellent tolerance of ATO in newly diagnosed and relapsed APL, older patients are probably a particular target group for a chemotherapy-free approach with ATO.

Topics: Aged; Aged, 80 and over; Arsenic Trioxide; Arsenicals; Clinical Trials as Topic; Disease Management; Humans; Leukemia, Promyelocytic, Acute; Oxides; Treatment Outcome; Tretinoin

We describe a rare case of acute promyelocytic leukemia (APL) presenting with central nervous system (CNS) involvement at the time of initial diagnosis. A 58-year-old male was hospitalized with palpitations, dyspnea, high grade fever, photophobia, and disturbance of consciousness in March 2010. APL was diagnosed by bone marrow (BM) examination. The cytogenetic analysis of BM cells demonstrated t(15;17)(q22;q11), and PML-RARA chimeric gene was detected by reverse transcriptase-polymerase chain reaction assay. Magnetic resonance imaging of the brain revealed several high intensity regions in the cerebrum and cerebellum. CNS involvement was diagnosed based on the appearance of APL blasts in cerebrospinal fluid (CSF). The patient was treated with all-trans retinoic acid (ATRA), and systemic chemotherapy consisting of idarubicin and cytarabine according to the Japan Adult Leukemia Study Group (JALSG) APL 204 protocol. He was then treated with continuous intrathecal administration of cytotoxic drugs (methotrexate, cytarabine, prednisolone) after systemic chemotherapy, achieving complete remission (CR) in both BM and the CNS. To date, he has been maintained in complete molecular remission in both BM and the CSF for 28 months, to date.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Cells; Central Nervous System Neoplasms; Cytarabine; Humans; Idarubicin; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Neoplasm Invasiveness; Treatment Outcome; Tretinoin

Since the introduction of all-trans retinoic acid, the use of this molecularly targeted treatment in combination with anthracycline-based chemotherapy has completely changed the prognosis of acute promyelocytic leukemia, turning it into the most curable myeloid leukemia. Also, the use of risk-adapted protocols has contributed to optimizing the drug combination and the most appropriate dose intensity for each subset of patients classified according to both the risk of relapse and vulnerability to drug toxicity. Recent developments have included the investigation of the role of arsenic trioxide as front-line treatment after its success in treating relapsed APL, both to minimize or even omit the use of cytotoxic agents and to improve the outcome of the conventional chemotherapy-based approach. In this review, we discuss the current treatment approach for acute promyelocytic leukemia in newly diagnosed patients, particularly taking into account the latest developments with the use of the arsenic trioxide based regimen as targeted first-line treatment without chemotherapy.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Consolidation Chemotherapy; Humans; Leukemia, Promyelocytic, Acute; Molecular Targeted Therapy; Oxides; Remission Induction; Tretinoin

Therapy-related acute promyelocytic leukemia (t-APL) has been increasingly reported after exposure to cytotoxic and/or immunosuppressive agents given for prior malignancies or autoimmune diseases. t-APL represents both a model for better understanding human leukemogenesis and an interesting therapeutic subset which requires specific adaptations for optimal management.. We discuss here potential risk factors for t-APL development and the main biologic and clinical characteristics of t-APL as compared to de-novo APL.In addition, we review therapeutic results obtained in patients with t-APL receiving conventional retinoic acid and chemotherapy and discuss new treatment opportunities with minimal or no exposure to conventional cytotoxic agents.. Genomic studies in patients at risk of t-APL are relevant to better adapt treatment for the primary disease and to implement monitoring during follow-up and early diagnosis of t-APL. Improved molecular characterization of t-APL may include next generation sequencing approaches to better identify distinguishing features as compared to de-novo APL. Early diagnosis of t-APL through careful monitoring of patients at higher risk, coupled to incorporation in the therapeutic armamentarium of novel effective agents such as arsenic trioxide could result in improved clinical outcome for these patients.

Topics: Adult; Antineoplastic Agents; Arsenic Trioxide; Arsenicals; Early Diagnosis; Female; Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Neoplasms, Second Primary; Oxides; Retrospective Studies; Risk Factors; Tretinoin

Acute promyelocytic leukemia (APL) is a unique subtype of acute myeloid leukemia (AML). Its exclusivity is reflected by both the clinical course and the management of patients. This article discusses 2 aspects of the unique management of patients with APL: the role of maintenance therapy and polymerase chain reaction (PCR) monitoring. Despite common practice, the efficacy of maintenance therapy in APL is still debated, and the introduction of arsenic trioxide into frontline protocols makes this debate even more challenging. This article also attempts to clarify details regarding the type and duration of maintenance treatment. The presence of residual leukemic cells, seen using PCR analysis of the PML/RARα fusion gene product, in patients who have experienced a complete response has been shown to have a high correlation with subsequent relapse. This fact led to the broad use of PCR monitoring techniques in patients with APL. Practicing clinicians face several questions with regard to monitoring, such as what is the best technique for monitoring patients with APL, who can benefit the most from these tests, what are the best time points, and for how long is monitoring recommended. These questions are addressed in this article.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Clinical Trials as Topic; Consolidation Chemotherapy; Humans; In Situ Hybridization, Fluorescence; Leukemia, Promyelocytic, Acute; Maintenance Chemotherapy; Monitoring, Physiologic; Oncogene Proteins, Fusion; Oxides; Polymerase Chain Reaction; Tretinoin

Acute promyelocytic leukemia (APL) is a hematological malignancy driven by a chimeric oncoprotein containing the C terminus of the retinoic acid receptor-a (RARa) fused to an N-terminal partner, most commonly promyelocytic leukemia protein (PML). Mechanistically, PML-RARa acts as a transcriptional repressor of RARa and non-RARa target genes and antagonizes the formation and function of PML nuclear bodies that regulate numerous signaling pathways. The empirical discoveries that PML-RARa-associated APL is sensitive to both all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO), and the subsequent understanding of the mechanisms of action of these drugs, have led to efforts to understand the contribution of molecular events to APL cell differentiation, leukemia-initiating cell (LIC) clearance, and disease eradication in vitro and in vivo. Critically, the mechanistic insights gleaned from these studies have resulted not only in a better understanding of APL itself, but also carry valuable lessons for other malignancies.

Topics: Animals; Arsenic Trioxide; Arsenicals; Cell Differentiation; Cell Line, Tumor; Cell Transformation, Neoplastic; Gene Expression Regulation, Leukemic; Humans; Leukemia, Promyelocytic, Acute; Mice; Oncogene Proteins, Fusion; Oxides; Remission Induction; Signal Transduction; Transcriptional Activation; Tretinoin

During last decades acute promyelocytic leukemia, once considered the deadly disease, has evolved to the most treatable of all subtypes of acute myeloid leukemias. The intense clinical and basic research has led to a rational approach to treatment in which the use of the differentiating agent all-trans-retinoic acid has proven to be effective first-line therapy. Arsenic trioxide, used for relapsed disease, further improved the survival rate of patients. The classical model presented the therapeutic success as a result of over-coming of the differentiation block characteristic of neoplastic cells. However, the resent in vivo and ex vivo studies, seem to show that the induction of differentiation process is not required to cure acute promyelocytic leukemia. Rather than inducing differentiation, targeting clonogenic leukemia initiating cells or destroying PML-RARa fusion protein may represent a more effective therapeutic goal in this type of leukemia.

Topics: Antineoplastic Agents; Arsenic Trioxide; Arsenicals; Humans; Leukemia, Promyelocytic, Acute; Oncogene Proteins, Fusion; Oxides; Secondary Prevention; Survival Rate; Tretinoin

To explore the characteristics and risk of etoposide-related leukemia in the treatment of hemophagocytic lymphohistiocytosis (HLH).. Clinical characteristics of a case with secondary acute promyelocytic leukemia (APL) were summarized and 10 cases of secondary leukemia after treatment for HLH from literature were analyzed.. The child was diagnosed with Epstein-Barr virus associated HLH and received HLH-2004 protocol. The cumulative dose of etoposide (VP16) was 3520 mg/m(2). The patient was diagnosed with APL after 28 months of HLH.He achieved complete remission after induction chemotherapy of all-trans-retinoic acid and darubicin. Consolidated chemotherapy was continued. There were 10 reports of etoposide-related leukemia after treatment for HLH in the literature.Review of 11 cases treated with VP16, of which cumulative doses were 900-20 500 mg/m(2). The interval period between HLH and secondary leukemia was 24 months. The types of secondary leukemia included 1 case with acute lymphoblastic leukemia, 1 case with myelodysplastic syndrome and 9 cases of acute myeloid leukemia. The abnormalities of chromosome included 3 patients with 11q23, 3 APL patients with t (15, 17).Seven patients survived and 4 died.. The latency period of etoposide-related leukemia is short. Acute myeloid leukemia and balanced chromosomal abnormality are common in etoposide-related leukemia. The risk factors for development of secondary leukemia are related to cumulative drug doses of etoposide, treatment schedules and co-administration of other antineoplastic agents.It is appropriate to keep suitable range of the cumulative dose of etoposide in HLH therapy in order to reduce the risk of therapy related leukemia.

Topics: Acute Disease; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Child, Preschool; Daunorubicin; Epstein-Barr Virus Infections; Etoposide; Humans; Leukemia, Promyelocytic, Acute; Lymphohistiocytosis, Hemophagocytic; Male; Neoplasms, Second Primary; Risk Assessment; Treatment Outcome; Tretinoin

Despite its dual role in determining cell fate in a wide array of solid cancer cell lines, autophagy has been robustly shown to suppress or kill acute myeloid leukemia cells via degradation of the oncogenic fusion protein that drives leukemogenesis. However, autophagy also induces the demise of acute leukemia cells that do not express the known fusion protein, though the molecular mechanism remains elusive. Nevertheless, since it can induce cooperation with apoptosis and differentiation in response to autophagic signals, autophagy can be manipulated for a better therapy on acute myeloid leukemia.

Topics: Antineoplastic Agents; Apoptosis; Apoptosis Regulatory Proteins; Autophagy; Humans; Leukemia, Myeloid, Acute; Leukemia, Promyelocytic, Acute; Molecular Targeted Therapy; Oncogene Proteins, Fusion; Tretinoin

To review the pathophysiology, risk factors, and management of differentiation syndrome (DS) associated with acute promyelocytic leukemia (APL).. A MEDLINE search was conducted (1977-November 2010) using the terms APL, DS, all-trans retinoic acid (ATRA), retinoic acid syndrome, and arsenic trioxide (ATO).. English articles identified from the MEDLINE search were evaluated.. With ATRA, ATO, and chemotherapy, a complete remission is achievable for most newly diagnosed APL patients. However, treatment with the differentiating agents, ATRA and ATO, can lead to the development of DS. Signs and symptoms of this syndrome include hyperleukocytosis and cardiorespiratory compromise. Severe complications can develop, if DS is not recognized early and treated promptly with corticosteroids. In addition, patients with a high white blood cell count at diagnosis may benefit from prophylactic steroids.. Early recognition and prompt initiation of corticosteroids are key factors in the management of DS. Healthcare professionals need to be familiar with this complication which can arise from differentiation agents.

Topics: Antineoplastic Agents; Arsenic Trioxide; Arsenicals; Glucocorticoids; Humans; Leukemia, Promyelocytic, Acute; Leukocyte Count; Oxides; Risk Factors; Syndrome; Time Factors; Tretinoin

The promyelocytic leukaemia gene PML was originally identified at the t(15;17) translocation of acute promyelocytic leukaemia, which generates the oncogene PML-retinoic acid receptor α. PML epitomises a subnuclear structure called PML nuclear body. Current models propose that PML through its scaffold properties is able to control cell growth and survival at many different levels. Here we discuss the current literature and propose new avenues for investigation.

Topics: Animals; Cell Cycle; Cell Death; Cell Differentiation; Cell Nucleus; Gene Expression Regulation, Neoplastic; Humans; Leukemia, Promyelocytic, Acute; Mice; Neoplastic Stem Cells; Nuclear Proteins; Oncogene Proteins, Fusion; Promyelocytic Leukemia Protein; Receptors, Retinoic Acid; Retinoic Acid Receptor alpha; Signal Transduction; Transcription Factors; Transcription, Genetic; Translocation, Genetic; Tretinoin; Tumor Suppressor Proteins

Leukemias occur worldwide, but there are important geographic differences in incidences.. Three leukemias with special Asian perspectives, acute promyelocytic leukemia (APL), T-cell large granular lymphocyte (T-LGL) leukemia and NK-cell leukemia.. In APL, China has made contributions in discovering the efficacy of all-trans retinoic acid (ATRA) and arsenic trioxide. Some APL patients are potentially curable after treatment with ATRA or arsenic trioxide as a single agent. Combined treatment of APL with ATRA and arsenic trioxide induces remission with deeper molecular response. An oral formulation of arsenic trioxide is available, making outpatient treatment feasible. Future regimens for APL should examine how ATRA and arsenic trioxide can be optimally combined with other synergistic drugs. Asian patients with T-LGL leukemia present more frequently with pure red cell aplasia, but less frequently with neutropenia, recurrent infection, splenomegaly and rheumatoid arthritis as compared with Western patients. These differences have potential effects on treatment and disease pathogenesis. NK-cell leukemia is rapidly fatal and occurs almost exclusively in Asian and South American patients. Conventional anthracycline-based chemotherapy designed for B-cell lymphomas do not work in NK-cell leukemias. Novel therapeutic approaches targeting cellular signaling pathways or preferentially upregulated genes are needed to improve outcome.

Topics: Arsenic Trioxide; Arsenicals; Asian People; Cell Proliferation; Humans; Leukemia; Leukemia, Large Granular Lymphocytic; Leukemia, Promyelocytic, Acute; Oxides; Recurrence; Tretinoin

Acute promyelocytic leukemia (APL) is a unique subtype of acute myeloid leukemia (AML). The prognosis of APL is changing, from the worst among AML as it used to be, to currently the best. The application of all-trans-retinoic acid (ATRA) to the induction therapy of APL decreases the mortality of newly diagnosed patients, thereby significantly improving the response rate. Therefore, ATRA combined with anthracycline-based chemotherapy has been widely accepted and used as a classic treatment. It has been demonstrated that high doses of cytarabine have a good effect on the prevention of relapse for high-risk patients. However, as the indications of arsenic trioxide (ATO) for APL are being extended from the original relapse treatment to the first-line treatment of de novo APL, we find that the regimen of ATRA, combined with ATO, seems to be a new treatment option because of their targeting mechanisms, milder toxicities and improvements of long-term outcomes; this combination may become a potentially curable treatment modality for APL. We discuss the therapeutic strategies for APL, particularly the novel approaches to newly diagnosed patients and the handling of side effects of treatment and relapse treatment, so as to ensure each newly diagnosed patient of APL the most timely and best treatment.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Cell Transformation, Neoplastic; Central Nervous System Neoplasms; Consolidation Chemotherapy; Drug Synergism; Humans; Induction Chemotherapy; Leukemia, Promyelocytic, Acute; Maintenance Chemotherapy; Oxides; Recurrence; Tretinoin

Acute promyelocytic leukemia (APL), the most rapidly fatal leukemia only two decades ago, has been converted into the most frequently curable leukemia by the advent of all-trans retinoic acid (ATRA) and its combination with anthracycline-based chemotherapy. More recently, arsenic trioxide (ATO) has been shown to be the most effective single agent in this disease and has been approved for the treatment of relapsed patients both in the United States and Europe. Moreover, ATO has been included in the design of several front-line studies, with the aim to reduce therapy-related toxicity while maintaining the potential of cure.. First, this review briefly discusses the mechanisms of action and the toxicity profile of ATO. Furthermore, the reported experience on the use of ATO as single agent or in combinatorial schemes both in relapsed and in newly diagnosed patients with APL is critically reviewed. Finally, the use of this agent in special subsets of patients unfit to receive conventional chemotherapy is discussed, along with its potential role in maintenance therapy.. While the role of ATO as single agent or in combination with ATRA is well established and recommended by the European LeukemiaNet guidelines as a first option for relapsed patients, the role of the drug in newly diagnosed patients is still uncertain and based only on evidence levels mostly originating from non-randomized trials. The results of ongoing randomized studies should better define the role of ATO in front-line therapy.

Topics: Arsenic Trioxide; Arsenicals; Clinical Trials as Topic; Humans; Leukemia, Promyelocytic, Acute; Oxides; Recurrence; Tretinoin

Acute promyelocytic leukemia (APL) has evolved from being a deadly to a highly curable disease, due to targeted molecular therapy with all-trans retinoic acid (ATRA). As a result, the incidence of early hemorrhagic deaths for which APL is notorious has reduced to 5-10% as reported in clinical trials. These results are not replicated outside of clinical trials as is evident from recent population-based registries. High incidence of early hemorrhagic deaths remains the greatest contributor to treatment failure in this otherwise curable leukemia. Additionally, thrombosis is now being increasingly recognized in APL patients and may be associated with ATRA usage.

Topics: Antifibrinolytic Agents; Antineoplastic Agents; Arsenic Trioxide; Arsenicals; Blood Coagulation Tests; Clinical Trials as Topic; Combined Modality Therapy; Cysteine Endopeptidases; Disseminated Intravascular Coagulation; Factor VIIa; Factor VIII; Fibrinogen; Fibrinolysis; Hemorrhage; Heparin; Humans; Leukemia, Promyelocytic, Acute; Multicenter Studies as Topic; Neoplasm Proteins; Oxides; Plasma; Platelet Count; Platelet Transfusion; Recombinant Proteins; Thromboplastin; Thrombosis; Treatment Failure; Tretinoin

Leukemia, a group of hematological malignancies characterized by abnormal proliferation, decreased apoptosis, and blocked differentiation of hematopoietic stem/progenitor cells, is a disease involving dynamic change in the genome. Chromosomal translocation and point mutation are the major mechanisms in leukemia, which lead to production of oncogenes with dominant gain of function and tumor suppressor genes with recessive loss of function. Targeted therapy refers to treatment strategies perturbing the molecules critical for leukemia pathogenesis. The t(15;17) which generates PML-RARα, t(8;21) that produces AML1-ETO, and t(9;22) which generates BCR-ABL are the three most frequently seen chromosomal translocations in myeloid leukemia. The past two to three decades have witnessed tremendous success in development of targeted therapies for acute and chronic myeloid leukemia caused by the three fusion proteins. Here, we review the therapeutic efficacies and the mechanisms of action of targeted therapies for myeloid leukemia and show how this strategy significantly improve the clinical outcome of patients and even turn acute promyelocytic leukemia from highly fatal to highly curable.

Topics: Antineoplastic Agents; Arsenic Trioxide; Arsenicals; Core Binding Factor Alpha 2 Subunit; Fusion Proteins, bcr-abl; Hematopoietic Stem Cells; Humans; Leukemia, Promyelocytic, Acute; Molecular Targeted Therapy; Oncogene Proteins, Fusion; Oxides; RUNX1 Translocation Partner 1 Protein; Translocation, Genetic; Tretinoin; Tumor Cells, Cultured

Acute promyelocytic leukemia (APL) is driven by a chromosomal translocation whose product, the PML/retinoic acid (RA) receptor α (RARA) fusion protein, affects both nuclear receptor signaling and PML body assembly. Dissection of APL pathogenesis has led to the rediscovery of PML bodies and revealed their role in cell senescence, disease pathogenesis, and responsiveness to treatment. APL is remarkable because of the fortuitous identification of two clinically effective therapies, RA and arsenic, both of which degrade PML/RARA oncoprotein and, together, cure APL. Analysis of arsenic-induced PML or PML/RARA degradation has implicated oxidative stress in the biogenesis of nuclear bodies and SUMO in their degradation.

Topics: Animals; Antineoplastic Agents; Arsenic; Humans; Leukemia, Promyelocytic, Acute; Mice; Oncogene Proteins, Fusion; Oxidative Stress; Receptors, Retinoic Acid; Retinoic Acid Receptor alpha; Small Ubiquitin-Related Modifier Proteins; Tretinoin

The introduction of all-trans retinoic acid (ATRA) into routine clinical practice changed the outcome of acute promyelocytic leukemia (APL) from the most fatal to the most curable subtype of acute myeloid leukemia (AML). Patients who do not survive generally succumb within the first 30 days after presentation or diagnosis, often from intracranial or pulmonary hemorrhage caused by the characteristic coagulopathy associated with this disease. For the majority of patients who avoid hemorrhagic complications, the goals of decreasing the side effects of diagnosis and treatment-including pain, inpatient hospital days, and late sequelae of cytotoxic chemotherapy-have emerged as paramount. Here, we discuss novel and provocative observations regarding diagnostic and treatment strategies for APL that are likely to emerge as standards of care in the next 5 years, and that may improve the rate of early hemorrhagic death and decrease diagnosis- and treatment-related morbidity.

Topics: Antineoplastic Agents; Antineoplastic Agents, Hormonal; Arsenic Trioxide; Arsenicals; Biopsy, Fine-Needle; Bone Marrow; Clinical Trials as Topic; Dexamethasone; Granulocyte Precursor Cells; Humans; Leukemia, Promyelocytic, Acute; Oxides; Practice Guidelines as Topic; Prognosis; Pulmonary Edema; Remission Induction; Respiratory Insufficiency; Tretinoin

Retinoids are lipophilic compounds derived from vitamin A, which have been extensively studied in cancer prevention and therapy. In pediatric oncology, they are successfully used for the treatment of acute promyelocytic leukemia (APL) and high-risk neuroblastoma (HR-NBL). APL is a subtype of acute myeloid leukemia (AML) clinically characterized by a severe bleeding tendency with a highrisk of fatal hemorrhage. The molecular hallmark of this disease is the presence of the promyelocytic leukemia (PML)-retinoic acid receptor-α (RAR α) gene fusion that plays a critical role in promyelocytic leukemogenesis and represents the target of retinoid therapy. The introduction in the late 1980s of all-trans retinoic acid (ATRA) into the therapy of APL radically changed the management and the outcome of this disease. Presently, the standard front-line therapeutic approach for pediatric APL includes anthracycline-based chemotherapy and ATRA, leading to a complete remission in almost 90% of the patients. Neuroblastoma (NBL) is an aggressive childhood tumor derived from the peripheral neural crest. More than half of patients have a high-risk disease, with a poor outcome despite intensive multimodal treatment. Although the exact mechanism of action remains unclear, the introduction of 13-cis-retinoic acid (13-cis-RA) in the therapy of NBL has improved the prognosis of this disease. Currently, the standard treatment for HR-NBL consists of myeloablative therapy followed by autologous hematopoietic stem cell transplantation (HSCT) and maintenance with 13-cis-RA for the treatment of minimal residual disease, leading to a 3-year disease-free survival rate (DFS) of about 50%. In this paper the authors provide a review of the peer-reviewed literature on the role of retinoids in the treatment of pediatric APL and HR-NBL, summarizing the most relevant clinical trial results of the last decades, analyzing the ongoing trials, and investigating future therapeutic perspectives of children affected by these diseases.

Topics: Antineoplastic Agents; Child; Disease-Free Survival; Humans; Isotretinoin; Leukemia, Promyelocytic, Acute; Neuroblastoma; Tretinoin

Acute promyelocytic leukemia (APL) is a rare form of acute myeloid leukemia with specific epidemiological, pathogenetic and clinical features. Its frequency varies widely among nations, with a decreased incidence among 'Nordic' origin populations. The molecular hallmark of the disease is the presence of a balanced reciprocal translocation resulting in the PML/RAR-α gene fusion, which represents the target of the all-trans retinoic acid (ATRA) therapy. The introduction of ATRA in conjunction with anthracyclines marked a turning point in the treatment of APL, previously associated with a significant morbidity and mortality. Nowadays the standard front-line therapy for pediatric APL includes ATRA in every phase of the treatment, resulting in a complete remission rate of 90-95%. Here we provide an overview of the role of ATRA in the treatment of pediatric APL, summarizing the most relevant clinical results of recent decades and investigating future therapeutic perspectives for children with APL.

Topics: Anthracyclines; Antibiotics, Antineoplastic; Antineoplastic Agents; Child; Clinical Trials as Topic; Consolidation Chemotherapy; Disease-Free Survival; Humans; Induction Chemotherapy; Leukemia, Promyelocytic, Acute; Maintenance Chemotherapy; Molecular Targeted Therapy; Oncogene Proteins, Fusion; Pseudotumor Cerebri; Remission Induction; Translocation, Genetic; Treatment Outcome; Tretinoin

Topics: Adult; Female; Humans; Leukemia, Promyelocytic, Acute; Sinus Thrombosis, Intracranial; Tretinoin

The advent of all-trans-retinoic acid (ATRA) and its combination with anthracycline-containing chemotherapy have contributed in the past 2 decades to optimize the antileukemic efficacy in acute promyelocytic leukemia (APL), leading to complete remission rates greater than 90%, virtual absence of resistance, and cure rates of nearly 80%. Recently reported studies from large cooperative trials have also shown that more rational delivery of treatment and improved outcomes may derive from the use of risk-adapted protocols. In particular, patients at higher risk of relapse (ie, those presenting with WBC > 10 × 10(9)/L) seem to benefit from treatments that include cytarabine in the ATRA-plus-chemotherapy scheme, whereas patients with standard-risk disease can be successfully managed with less-intensive regimens that contain ATRA and anthracycline-based chemotherapy. After the outstanding results with arsenic trioxide (ATO) in the treatment of APL relapse, several experimental trials have been designed to explore the role of ATO in front-line therapy with the aim not only of minimizing the use of chemotherapy but also to reinforce standard ATRA-plus-chemotherapy regimens and additionally improve therapeutic efficacy. In this review article, we discuss most recent advances in the treatment of patients with newly diagnosed and relapsed APL.

Topics: Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Brain Neoplasms; Cytarabine; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Promyelocytic, Acute; Oxides; Recurrence; Reverse Transcriptase Polymerase Chain Reaction; Tretinoin

Acute promyelocytic leukemia (APL) is a subtype of acute myeloid leukemia. In past decades, intensive studies on the biology and treatment of this disease have resulted in a remarkably thorough understanding of its pathogenesis and improvement of treatment outcomes. In particular, the introduction of all-trans retinoic acid to conventional chemotherapy improved dramatically the remission and survival rates of APL patients and consequently became the major treatment modality for it. In the last decade, the groundbreaking development of arsenic further improved the survival rate of APL patients. As the most active agent in APL, arsenic directly degrades the PML-RARα fusion transcript, leading to the differentiation and apoptosis of leukemia cells and the potential eradication of APL leukemiainitiating cells (LICs), thus making the disease a potentially curable type of leukemia. More notably, the recent development of oral arsenic compounds may further enhance not only clinical outcomes but also the convenience of patients, which may dramatically change the APL clinical scenario in the near future.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Arsenic; Humans; Leukemia, Promyelocytic, Acute; Survival Analysis; Tretinoin

Arsenic trioxide (ATO) and all-trans-retinoic acid (ATRA) could induce apoptosis and differentiation in acute promyelocytic leukemia (APL) cells, respectively, thus the possibility of synergism between them was raised. This meta-analysis assessed the effectiveness and safety of ATO combined with ATRA in the treatment of APL. Compared with ATO alone, induction therapy with ATO/ATRA significantly increased the complete remission (CR) rate (RR: 1.08, 95% CI: 1.00-1.17, P=0.04), shortened the time to achieve CR (WMD: -6.51, 95% CI: -11.32 to -1.70, P=0.008), and improved the molecular remission rate after consolidation therapy (RR: 1.74, 95% CI: 1.14-2.66, P=0.01) and the 1-year disease-free survival rate (RR: 1.22, 95% CI: 1.00-1.50, P=0.05). There were no statistically significant differences between two treatments in terms of early death and main adverse events. These results suggested that ATO/ATRA could synergistically improve the overall outcome of newly diagnosed and relapsed APL patients, supporting the use of ATO/ATRA as an effective treatment for all APL patients previously untreated with ATO.

Topics: Adolescent; Adult; Aged; Algorithms; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Child; Clinical Trials as Topic; Female; Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Oxides; Randomized Controlled Trials as Topic; Survival Analysis; Treatment Outcome; Tretinoin; Young Adult

Acute promyelocytic leukemia (APL), a distinct subtype of acute myelogenous leukemia (AML), results from the arrest of the maturation of hematopoietic progenitors at the promyelocyte stage. It has been shown that APL is associated with a reciprocal chromosomal translocation, involving chromosomes 15 and 17, which fuses the gene encoding the retinoic acid receptor α (RARα) and the promyelocytic leukemia (PML) gene. The resultant PML-RARα fusion protein plays a critical role in the pathogenesis of APL. Although there are many subtypes of AML, all are typically managed using a standard chemotherapy regimen of an anthracycline plus cytarabine arabinoside (CA). Despite high rates of complete remission following standard chemotherapy, most patients relapse and long-term disease-free survival is only 30-40%. The introduction of drugs such as all-trans retinoic acid (ATRA) that promote progenitor differentiation by directly inhibiting the PML-RARα fusion protein has changed the treatment paradigm for APL and markedly improved patient survival. The purposes of the present review are to provide the latest results and future directions of clinical research into APL and to illustrate how new therapies, such as ATRA plus anthracycline-based induction and consolidation therapy, risk-adapted therapy, salvage therapy containing arsenic trioxide-based regimens, and hematopoietic stem cell transplantation, have improved the treatment outcomes for APL patients.

Topics: Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Cell Differentiation; Clinical Trials as Topic; Consolidation Chemotherapy; Cytarabine; Disease-Free Survival; Drug Resistance, Neoplasm; Gene Expression Regulation, Leukemic; Hematopoietic Stem Cell Transplantation; Humans; Induction Chemotherapy; Leukemia, Promyelocytic, Acute; Maintenance Chemotherapy; Multicenter Studies as Topic; Oncogene Proteins, Fusion; Oxides; Risk; Salvage Therapy; Tretinoin

The introduction of all-trans retinoic acid in 1985 combined with anthracycline-based chemotherapy has revolutionized the prognosis of acute promyelocytic leukemia (APL) with current complete response rates of more than 90% and cure rates of approximately 80%. The subsequent advent of arsenic trioxide in 1994 marked an additional milestone in APL treatment and has inspired the design of rationally targeted, chemotherapy-free front-line treatment regimens without compromising the excellent outcome achieved by anthracycline-containing protocols. APL is, therefore, a unique subtype of acute myeloid leukemia potentially curable with targeted therapies without any exposure to conventional DNA-damaging chemotherapy. Cure rates of APL can be further increased by implementing management strategies to reduce early hemorrhagic deaths, which remain the major cause of treatment failure with the current therapy.

Topics: Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Humans; Leukemia, Promyelocytic, Acute; Molecular Targeted Therapy; Remission Induction; Treatment Outcome; Tretinoin

Topics: Animals; Antineoplastic Agents; Arsenic Trioxide; Arsenicals; Humans; Leukemia, Promyelocytic, Acute; Molecular Targeted Therapy; Oxides; Receptors, Retinoic Acid; Retinoic Acid Receptor alpha; Tretinoin

The introduction of all-trans retinoic acid, or ATRA, in 1985, combined with anthracycline-based chemotherapy, has transformed acute promyelocytic leukemia (APL) from a fatal disease to one that is now highly curable. With appropriate contemporary therapy, more than 90% of patients achieve complete remission, and cure rates of approximately 80% and higher response and survival rates can be expected for patients at low and intermediate risk. The introduction of arsenic trioxide, or ATO, in 1994 has provided the opportunity to minimize and even eliminate standard cytotoxic chemotherapy from initial treatment regimens without compromising the excellent outcomes achieved by anthracycline-containing protocols. APL is a unique subtype of acute myeloid leukemia that is curable with targeted therapies and potentially without exposure to conventional DNA-damaging chemotherapy. The omission of conventional cytotoxic chemotherapy may reduce long-term complications such as cardiomyopathy and therapy-related myelodysplastic syndromes. Cure rates of APL may be further increased by adopting management strategies to reduce early hemorrhagic deaths, which now appear to be the major cause of treatment failure.

Topics: Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Humans; Leukemia, Promyelocytic, Acute; Oxides; Treatment Outcome; Tretinoin

Topics: Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Humans; Leukemia, Promyelocytic, Acute; Oxides; Treatment Outcome; Tretinoin

Acute promyelocytic leukemia (APL) is a unique subtype of acute myeloid leukemia (AML). The prognosis of APL has changed from the worst among the AMLs to currently the best. The application of all-trans retinoic acid (ATRA) in the induction therapy of APL decreases the high mortality of newly diagnosed patients, thereby significantly improving the response rate. ATRA combined with anthracycline-based chemotherapy is the current standard treatment, and for high-risk patients, high doses cytarabine have a beneficial effect on relapse prevention. In recent years, the indications of arsenic trioxide (ATO) therapy for APL have been extended from the salvage therapy for relapse patients to the first-line treatment of de novo APL. The introduction of both ATRA and ATO represents great achievements in translational medicine. In this review article, we discuss the therapeutic strategies for this disease, including the initial approaches to newly diagnosed patients, prevention, and treatment of side effects and relapse to ensure the best and timely treatment for each newly diagnosed APL patient.

Topics: Anthracyclines; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Cytarabine; Humans; Leukemia, Promyelocytic, Acute; Oxides; Prognosis; Secondary Prevention; Survival Rate; Tretinoin

Large vessel thrombosis is a very rare clinical presentation of acute leukemia which is usually revealed by hemorrhagic complications or thrombosis of small vessels. We present here the case of a patient with previously undiagnosed acute myeloid leukemia who was referred to our hospital with symptoms of acute ischemia of the left lower limb. Occlusion of the left popliteal artery due to a leucostasis was noted and successfully treated with emergency surgical thromboembolectomy and chemotherapy.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Arterial Occlusive Diseases; Cytarabine; Daunorubicin; Emergencies; Femoral Artery; Humans; Ischemia; Leg; Leukemia, Promyelocytic, Acute; Leukostasis; Male; Popliteal Artery; Remission Induction; Thrombectomy; Tretinoin

Topics: Antineoplastic Agents; Blood Coagulation; Cysteine Endopeptidases; Cytokines; Disseminated Intravascular Coagulation; Fibrinolytic Agents; Humans; Leukemia, Promyelocytic, Acute; Neoplasm Proteins; Neoplasms; Thromboplastin; Tretinoin

Acute promyelocytic leukemia (APL) represents a paradigm of therapeutic success in clinical hematology. Since the introduction of all-trans-retinoic-acid in the early 1980s, complete remission rates exceed 90% and the cure rate is > 70%. Notwithstanding, various questions concerning the management of APL remain unanswered.. The aim of this article is to focus on still controversial issues in the management of APL, such as the role of arsenic trioxide as front-line therapy, the management of older unfit patients, the potential utility of gemtuzumab-ozogamycin and the effectiveness (if any) of maintenance therapy for patients in molecular remission. In addition, the possibility of reducing the intensity of post-remission therapy, which is associated with substantial morbidity in potentially cured patients, is discussed.. Current and future therapeutic options for the treatment of newly diagnosed and relapsed APL.. To date, the therapy of APL is the most successful example of differentiation therapy and its scientific history can serve as a model for subsequent development of similar treatments in other leukemias and cancers. However, treatment strategies continue to evolve rapidly, with particular focus on minimizing the early and late effects of cytotoxic chemotherapy.

Topics: Aminoglycosides; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Gemtuzumab; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Promyelocytic, Acute; Oxides; Remission Induction; Secondary Prevention; Tretinoin

Acute promyelocytic leukemia(APL) is characterized by the t(15;17) chromosomal translocation leading to the formation of the PML-RARalpha oncoprotein. This leukemia has attracted considerable interest in recent years, being the first in which therapies that specifically target the underlying molecular lesion, i.e., all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), leading to induction of differentiation and apoptosis have been successfully used in clinical practice. The advent of ATRA therapy has transformed APL from being a disease with a poor outlook to one of the most prognostically favorable subsets of acute myeloid leukemia. Further improvements in outcome may be achieved with the use of ATO, which achieves high rates of remission in the relatively small proportion of patients now relapsing following standard first-line therapy with ATRA and anthracycline-based chemotherapy. Moreover, recent studies have suggested that ATO and ATRA, or even ATO alone, used as front-line treatment of PML-RARA- associated APL can induce long-term remissions. This raises the possibility that some patients can be cured using differentiation therapies alone, without the need for chemotherapy, thereby potentially reducing treatment-related toxicity. It is clear that the success of such an approach is critically dependent upon molecular diagnostics and monitoring for minimal residual disease (MRD) to distinguish those patients who can potentially be cured with differentiation therapy from those requiring additional myelosuppressive agents. This represents an exciting new phase in the treatment of acute leukemia, highlighting the potential of molecularly targeted and MRD-directed therapies to achieve an individualized approach to patient management.

Topics: Antineoplastic Agents; Apoptosis; Arsenic Trioxide; Arsenicals; Cell Differentiation; Dyspnea; Fever; Gene Expression Regulation, Leukemic; Humans; Leukemia, Promyelocytic, Acute; Leukocytosis; Models, Biological; Neoplasm, Residual; Oncogene Proteins, Fusion; Oxides; Transcription, Genetic; Treatment Outcome; Tretinoin

Acute promyelocytic leukemia (APL) is a distinct subset of acute myeloid leukemia. An abnormal fusion gene, PML/RARA is detected in approximately 98% of patients with APL. PML/RARA confers long-term self-renewal properties to promyelocytes. All-trans retinoic acid (ATRA) and arsenic trioxide (ATO), which are the major molecularly targeted therapies in APL, affect the PML/RARA fusion protein and cause differentiation and apoptosis of APL cells. Although the leukemia-initiating cells of APL may be present in a myeloid progenitor committed compartment, the precise population of those remains to be elucidated. However, recent studies have demonstrated the effect of ATRA and ATO on APL leukemia-initiating cells. Through these studies, we can understand more deeply how current clinical therapies lead to long-lasting remission of APL. ATRA and ATO have improved the prognosis of APL patients and have changed the role of hematopoietic stem cell transplantation (HSCT). At present, HSCT is not indicated for patients with APL in first complete remission, and considered for patients with relapsed APL. In this review, we discuss the three main topics as follows: the leukemia-initiating cells in APL, the current state-of-the-art treatment for newly diagnosed and relapsed APL, and the role of HSCT in APL patients.

Topics: Animals; Apoptosis; Arsenic Trioxide; Arsenicals; Cell Differentiation; Cell Survival; Cell Transformation, Neoplastic; Glutamates; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Promyelocytic, Acute; Myeloid Progenitor Cells; Neoplastic Stem Cells; Nuclear Proteins; Oxides; Prodrugs; Promyelocytic Leukemia Protein; Transcription Factors; Tretinoin; Tumor Suppressor Proteins

The introduction of all-trans retinoic acid (ATRA) and, more recently, arsenic trioxide (ATO) into the therapy of acute promyelocytic leukemia (APL) has revolutionized the management and outcome of this disease. Several treatment strategies using these agents, usually in combination with chemotherapy, but also without or with minimal use of cytotoxic agents, have provided excellent therapeutic results. Cure of APL patients, however, is also dependent on peculiar aspects related to the management and supportive measures that are crucial to counteract life-threatening complications associated with the disease biology and molecularly targeted treatment. The European LeukemiaNet recently appointed an international panel of experts to develop evidence- and expert opinion-based guidelines on the diagnosis and management of APL. Together with providing current indications on genetic diagnosis, modern risk-adapted front-line therapy and salvage treatment, the review contains specific recommendations for the identification and management of most important complications such as the bleeding disorder, APL differentiation syndrome, QT prolongation and other ATRA- and ATO-related toxicities, as well as for molecular assessment of response to treatment. Finally, the approach to special situations is also discussed, including management of APL in children, elderly patients, and pregnant women.

Topics: Antineoplastic Combined Chemotherapy Protocols; Child; Databases, Factual; Europe; Female; Health Planning Guidelines; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Promyelocytic, Acute; Pregnancy; Pregnancy Complications, Hematologic; Recurrence; Societies, Medical; Tretinoin

Since the initial description of the disease, the life-threatening coagulopathy associated with acute promyelocytic leukaemia (APL) has been the defining clinical characteristic. Historically, this uncommon subtype of acute myeloid leukaemia has been associated with a high mortality rate during induction therapy, most frequently attributable to haemorrhage. Since the introduction of all-trans retinoic acid (ATRA) into the therapy of all patients with APL, disease-free survival and overall survival have improved dramatically, such that the disease is now highly curable. However, induction mortality remains a major problem and haemorrhage still accounts for the majority of such early deaths. Pathogenesis of the coagulopathy is complex and includes disseminated intravascular coagulation (DIC), fibrinolysis and proteolysis. As a result, while the predominant clinical manifestation of the coagulopathy is haemorrhage, thromboembolic events may occur both at presentation and during therapy. A major recent finding is the high expression of annexin II in the leukaemic cells from patients with APL. Annexin II is a protein with high affinity for plasminogen and tissue-type plasminogen activator (tPA), and also acts as a cofactor for plasminogen activation by tPA. As a result, both plasminogen and tPA are increased on the cell surface of the leukaemic cell, increasing plasmin activity. Annexin II is expressed in high amounts in cerebral microvascular endothelial cells, perhaps accounting for the relatively high incidence of intracranial haemorrhage in APL compared with other sites. Microparticles are cell-derived membrane fragments originating from normal cells or released from malignant cells involved in activating coagulation. Recent studies have found that microparticles containing tissue factor, tPA, plasminogen activator inhibitor-1 and annexin II have been found in the plasma of APL patients, suggesting a role in pathogenesis of the coagulopathy. Treatment of the coagulopathy remains primarily supportive. Aggressive transfusions of platelets and cryoprecipitate appear to be important. There is no clear role for the routine use of heparin or antifibrinolytic therapy. The most important factor may be the early introduction of ATRA at the first suspicion of a diagnosis of APL, before it is confirmed genetically.

Topics: Annexin A2; Blood Coagulation Disorders; Hemorrhage; Humans; Leukemia, Promyelocytic, Acute; Plasminogen; Survival Analysis; Tissue Plasminogen Activator; Tretinoin

Management of the pregnant patient with acute promyelocytic leukemia (APL) is a challenge. Immediate treatment of APL is critical, as it is an oncologic emergency, with a high risk of morbidity and mortality associated with disseminated intravascular coagulation. However, administration of chemotherapy and differentiating agents in pregnancy is controversial because of potential teratogenic effects. In addition, complications associated with APL, including retinoic acid syndrome, add to the complexity of management. To better understand how to manage this complex patient care situation, we searched the PubMed database (January 1972-May 2008) for English-language articles about maternal and fetal outcomes resulting from APL treatment during pregnancy. A total of 42 cases from 35 articles were identified: 12 first-trimester, 21 second-trimester, and 9 third-trimester cases. The most commonly administered agents were all-trans-retinoic acid (ATRA), anthracyclines, and antimetabolites. Complete remission was reported in 35 (83%) of 42 patients. Administration of ATRA or chemotherapy in the first trimester was associated with an increased risk of fetal malformations and spontaneous abortion, whereas administration in the second and third trimesters was associated with relatively favorable fetal outcomes. The overall treatment of the pregnant patient with APL should include a discussion about pregnancy termination, especially if APL is diagnosed in the first trimester. If the pregnancy is to continue, then the appropriate chemotherapy regimen needs to be determined. Frequent fetal monitoring, along with aggressive management of potential APL-related complications, is necessary to allow for optimal maternal and fetal outcomes.

Topics: Abnormalities, Drug-Induced; Abortion, Therapeutic; Antineoplastic Agents; Female; Humans; Leukemia, Promyelocytic, Acute; Pregnancy; Pregnancy Complications, Hematologic; Pregnancy Complications, Neoplastic; Pregnancy Outcome; Tretinoin

Therapy-related myelodysplastic syndrome (t-MDS) and therapy-related acute myelogenous leukemia (t-AML) in patients with acute promyelocytic leukemia (APL) are rare events. The cumulative exposure to chemotherapy with alkylating agents and topoisomerase II inhibitors is associated with t-AML that may develop any time after the completion of the treatment. We report the case of an acquired AML who previously received therapy for APL, after two years of being diagnosed. The diagnosis was established by morphologic findings, membrane markers, cytogenetic studies, and fluorescence in situ hybridization (FISH). To our knowledge this is the first documented case in Puerto Rico of a patient with APL that developed a t-AML without the characteristic chromosomal and morphologic findings of APL.

Topics: Adult; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Chromosomes, Human, Pair 15; Chromosomes, Human, Pair 17; Chromosomes, Human, Pair 21; Chromosomes, Human, Pair 3; Chromosomes, Human, Pair 7; Cytarabine; Daunorubicin; Drug Synergism; Fatal Outcome; Humans; Leukemia, Myeloid, Acute; Leukemia, Promyelocytic, Acute; Male; Mercaptopurine; Methotrexate; Mitoxantrone; Monosomy; Neoplasms, Second Primary; Translocation, Genetic; Tretinoin

Children with Down syndrome (DS) are at an increased risk of developing acute leukemia. Acute myeloid leukemia predominates among DS children below 4 years of age but acute promyelocytic leukemia (APL) has rarely been reported in DS. Acute myeloid leukemia in DS is extremely sensitive to treatment but the optimum treatment of de novo or relapsed APL in DS is not known. We describe a child with DS and APL, who despite having a multiply relapsing course, achieved a third remission with ATRA and chemotherapy, which is sustained with maintenance therapy. A brief review of literature is also presented.

Topics: Antineoplastic Agents; Child, Preschool; Down Syndrome; Humans; Leukemia, Promyelocytic, Acute; Recurrence; Remission Induction; Tretinoin

Acute promyelocytic leukemia (APL) is a distinct subset of acute myeloid leukemia characterized by an abnormal fusion protein, PML/RARA. All-trans retinoic acid (ATRA) and arsenic trioxide, which are the major molecularly targeted therapies in APL, affect or degrade the PML/RARA fusion protein and cause differentiation and apoptosis of APL cells. These therapies have improved the prognosis of APL patients and are now the main therapeutic options in APL. In addition, gemtuzumab ozogamicin is another targeted therapy in APL. On the other hand, the prognosis of patients with central nervous system (CNS) relapses of APL remains poor. Therefore, CNS relapses have become major concerns, and effective therapeutic approaches for CNS relapses are needed. In fact, possible active roles of molecularly targeted therapies in CNS relapses of APL have been suggested, and several new approaches with molecularly targeted therapies for CNS relapses have been examined in APL. In this review, we discuss three main topics; the relationship between the incidence of CNS relapses and the introduction of molecularly targeted therapies for APL, new approaches with targeted therapies for CNS relapses of APL, and other complications of targeted therapies in CNS such as pseudotumor cerebri induced by ATRA and subarachnoid hemorrhage. These comprehensive understanding would be helpful for better management of patients with APL.

Topics: Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Central Nervous System Neoplasms; Humans; Leukemia, Promyelocytic, Acute; Oxides; Recurrence; Tretinoin

Acute promyelocytic leukemia (APL) is a relatively rare form of acute myelogenous leukemia (AML). In the United States, APL in children constitutes only 5% to 10% of AML. Molecularly, the disease is characterized by a fusion protein, promyelocytic leukemia (PML)-retinoic acid receptor (RAR)-alpha that results from a balanced reciprocal translocation between the PML gene on chromosome 15 and the RAR-alpha (RARA) gene on chromosome 17. A major advance in the field of APL treatment has been the use of all-trans-retinoic acid (ATRA). Advances in the treatment of APL have taken this form of AML from a disease with significant morbidity and mortality to one with an excellent outcome. This has resulted largely from the incorporation of ATRA into frontline regimens with chemotherapy. Anthracyclines remain a cornerstone of treatment at this point. Recent trials have shown a role for arsenic trioxide in both newly diagnosed and relapsed APL.

Topics: Anthracyclines; Antineoplastic Agents; Arsenic Trioxide; Arsenicals; Child; Child, Preschool; Chromosomes, Human, Pair 15; Chromosomes, Human, Pair 17; Humans; Leukemia, Promyelocytic, Acute; Oxides; Prognosis; Translocation, Genetic; Tretinoin

Great progress on insight into genetic aberrations of myeloid leukemia via gene expression profiling has led to better understanding of the pathobiology of this heterogeneous disorder. It enabled the development of specific treatment modalities targeted to underlying oncogenic abnormalities, with well established examples of all-trans retinoic acid for the treatment of acute promyelocytic leukemia and imatinib for chronic myeloid leukemia. However, these strategies have not been completely developed yet in that most of brand new targeted therapies have been somewhat far from achieving cure of leukemia and that many problems with regards to drug resistance and recurrence from minimal residual disease remain to be solved. On the other hand, concept of cancer(leukemic) stem cell and its niche has been shedding new light on oncological field these days. This review summarizes the current clinical trials using new targeted therapies and research trends on myeloid leukemia.

Topics: Animals; Antineoplastic Agents; Benzamides; Chromosome Aberrations; Clinical Trials as Topic; Humans; Imatinib Mesylate; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Acute; Leukemia, Promyelocytic, Acute; Neoplastic Stem Cells; Piperazines; Pyrimidines; Translational Research, Biomedical; Tretinoin

The studies have demonstrated that arsenic trioxide (ATO) in combination with all-trans retinoic acid (ATRA) takes effects in treatment of acute promyelocytic leukemia (APL) through different underlying mechanisms. This has established the molecular foundation of ATO plus ATRA therapy. Currently, ATO plus ATRA has also been widely used in clinical practice.. To assess the efficacy and safety of ATO in combination with ATRA for APL.. The Cochrane Library (Issue 1, 2009), Cochrane Central Register of Controlled Trials (from 1970 to January 2009), MEDLINE (from 1978 to October 2008), EMBASE (from 1950 to March 2009), Chinese Biological Medical Literature Database (from 1978 to December 2008), CNKI (from 1994 to December 2008), China Medical Academic Conference Database (from 1994 to December 2008) were electronically searched. We also searched the Meta-Register of Controlled Trials, Conference Proceedings of American Society of Hematology (from 1946 to December 2008) and Conference Proceedings of American Society of Clinical Oncology (from 1946 to December 2008) on the internet for grey literature. The authors also hand-searched Chinese periodicals potentially related to the question including Chinese Journal of Hematology, Journal of Experimental Hematology and Journal of Clinical Hematology.. All randomized controlled trials comparing ATO plus ATRA with other regimens for the treatment of APL were included. Intervention and comparison regimens include: 1) ATO plus ATRA vs ATO monotherapy; 2) ATO plus ATRA vs ATRA monotherapy; 3) ATO plus ATRA vs ATRA plus chemotherapy; 4) ATO plus ATRA vs ATO+ATRA+chemotherapy.. Related data concerning complete remission rate, overall survival rate, and disease free survival rate, time to complete remission, relapse rate, mortality and adverse reactions were extracted independently by two reviewers. The different statistical methods were applied according to different data type with RevMan 5.0 software.. After merging of the included trials, seven eligible randomized controlled trials with 392 cases were analyzed, among which 6 RCTs were methodologically graded as middle and one as of high risk of bias. The control therapies included ATO monotherapy, ATRA monotherapy and chemotherapy with ATO plus ATRA. Compared with ATO monotherapy, ATO plus ATRA could improve time to complete remission and relapse rate of newly diagnosed APL, but could not improve the complete remission rate, disease free survival rate, mortality and liver dysfunction of relapsed APL patients based on meta-analysis and sensitivity analysis. Compared with ATRA monotherapy, ATO plus ATRA shortened the time to complete remission, improved the disease free survival rate and relapse rate, but increased the incidence of edema during the treatment. Compared with chemotherapy with ATO plus ATRA, ATO plus ATRA could improve the complete remission rate, relapse rate, mortality and adverse reactions.. For newly diagnosed APL, ATO plus ATRA is superior to ATO monotherapy, ATRA monotherapy and chemotherapy with ATO plus ATRA, but due to the lack of data about comparison with the current standard treatment regimen (ATRA plus chemotherapy), it is not enough to recommend ATO plus ATRA as a frontline therapy. For relapsed APL, ATO plus ATRA is not superior to ATO monotherapy, and ATRA plus ATO is not a supportive therapy. Due to limitation of sample size and risk of bias from the included trials, the effects of ATO plus ATRA need to be confirmed by large and high-quality randomized controlled trials.

Topics: Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Humans; Leukemia, Promyelocytic, Acute; Oxides; Randomized Controlled Trials as Topic; Survival Analysis; Treatment Outcome; Tretinoin

All-trans retinoic acid has revolutionized the treatment of acute promyelocytic leukemia, but this therapy is often complicated by the all-trans retinoic acid syndrome. Here we report a patient with newly diagnosed acute promyelocytic leukemia who developed acute focal myositis, synovitis, and possible vasculitis, after receiving all-trans retinoic acid therapy. We review the existing literature on this rare clinical entity, all-trans retinoic acid-induced myositis. This condition can manifest as fever, myalgia, arthralgia, and Sweet syndrome, accompanied by distinct magnetic resonance findings involving the lower extremity musculature. Treatment consists of discontinuation of the offending drug and often high dose corticosteroids.

Topics: Adrenal Cortex Hormones; Antineoplastic Agents; Female; Humans; Leukemia, Promyelocytic, Acute; Middle Aged; Mononeuropathies; Myositis; Synovitis; Treatment Outcome; Tretinoin; Withholding Treatment

All-trans retinoic acid therapy of acute promyelocytic leukemia represents the most successful example of differentiation-induction therapy in clinical oncology. However, acute promyelocytic leukemia represents only a small minority (10-15%) of the myeloid leukemias. Recent studies provide significant insight into why some myeloid leukemias respond dramatically to all-trans retinoic acid mediated differentiation therapy, whereas others do not.. Utilizing in-vitro experimental models of all-trans retinoic acid triggered myeloid leukemia differentiation, specific genes that are important regulators of granulocytic differentiation have been identified including transcription factors, apoptosis regulators, protein synthesis inhibitors and protein degradation factors. Moreover, recent studies have identified repressive chromatin marks generated by the aberrant, acute promyelocytic leukemia specific promyelocytic locus gene-retinoic acid receptor alpha (PML-RARalpha) fusion protein as well as the specific enzymes that mediate these chromatin changes.. The molecular basis for PML-RARalpha- mediated leukemogenesis is complex involving both the repression of numerous potential target genes and critical 'off promoter' functional activity of this fusion protein. The acute promyelocytic leukemia specific repressive chromatin marks related to PML-RARalpha activity may be present in other myeloid leukemias as well. This suggests alternative approaches for treating myeloid leukemia involving therapeutic agents that inhibit heterochromatin formation and enhance transcriptional activity. All-trans retinoic acid or related compounds may also play a significant role in enhancing hematopoietic stem cell self-renewal as well as the production and differentiation of regulatory T cells.

Topics: Animals; Cell Differentiation; Hematopoiesis; Humans; Leukemia, Myeloid; Leukemia, Promyelocytic, Acute; Receptors, Retinoic Acid; Tretinoin

The retinoic acid syndrome (RAS) is an unpredictable but frequent complication which may develop after administration of all-trans retinoic acid (ATRA) most commonly in patients with acute promyelocytic leukaemia (APL). In this review, we describe the incidence, predictive factors, clinical course, outcome and treatment of RAS in patients with APL treated with ATRA. The incidence of RAS in patients receiving ATRA is about 14-16%, with an associated mortality of about 2%. Initial high white blood cell (WBC) count, rapidly increasing WBC count and/or the presence of the CD 13 expression on leukaemic cells may help in identifying patients likely to develop RAS. Concurrent chemotherapy will probably decrease the risk of developing RAS but often exacerbates bleeding, leading to leucocytosis, thrombocytopenia, disseminated intravascular coagulation and fibrinolysis. Prophylactic steroids are not recommended but prompt administration of steroids at the first sign of unexplained dyspnea, fever, weight gain or pulmonary infiltrate, is critical. Liposomal ATRA is being investigated to induce haematological cure in APL without chemotherapy and to reduce the incidence of RAS but further validation of its usefulness is necessary.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; CD13 Antigens; Gene Expression Regulation, Neoplastic; Glucocorticoids; Humans; Incidence; Leukemia, Promyelocytic, Acute; Leukocyte Count; Syndrome; Tretinoin

Ten percent to 15% of adults in the United States with acute myeloid leukemia (AML) are diagnosed with acute promyelocytic leukemia (APL) each year, which amounts to approximately 1,200 newly diagnosed patients. In almost all APL patients, the retinoic acid receptor-alpha (RARalpha) gene on chromosome 17 is involved in a reciprocal translocation with the promyelocytic leukemia gene (PML) on chromosome 15, denoted as t(15;17)(q22;q12). All patients have the PML/RAR-alpha fusion transcript. Identification of this fusion transcript is important for both diagnosis and for detection of minimal residual disease. Overall, more than 80% of APL patients are curable using current strategies. All-trans retinoic acid (ATRA) causes cells to differentiate and arsenic trioxide (ATO) induces both differentiation and apoptosis. Curative treatments that avoid conventional chemotherapeutic agents and/or extended maintenance strategies for low- and intermediate-risk patients appear possible. High-risk patients continue to present a challenge, but a number of innovative agents and strategies are currently under active study.

Topics: Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Clinical Trials as Topic; Cytarabine; Humans; Leukemia, Promyelocytic, Acute; Oxides; Treatment Outcome; Tretinoin

Acute promyelocytic leukemia (APL), a highly curable subtype of acute myeloid leukemia (AML) is characterized by the chromosomal translocation t(15;17) and, consequently, the presence of the PML-RARalpha fusion transcript. Most patients are treated with all-trans retinoic acid (ATRA), which targets the RAR-alpha moiety of the PML/RAR-alpha fusion transcript, and anthracycline-based chemotherapy. Arsenic trioxide (ATO) targets the PML moiety and has different mechanisms of action at different concentrations, and induces differentiation and apoptosis. Several clinical trials have tested the combination of ATRA and ATO with outstanding results. Furthermore, other trials have explored ATO as a single agent in newly diagnosed patients. ATRA plus ATO has emerged as a promising strategy, even for those with high-risk disease. Future studies will compare ATRA and ATO to conventional ATRA and anthracycline-based chemotherapy.

Topics: Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Humans; Leukemia, Promyelocytic, Acute; Oxides; Treatment Outcome; Tretinoin

Advances in high-throughput technologies to measure genome-scale changes of genes, proteins, and other biomolecular components ('omics') in complex biological systems have dramatically revolutionized biomedical research. However, the benefits of utilizing omics information in drug development have not yet been fully realized. Fortunately, the integration of modern systems biology efforts with traditional medicine philosophies, together with integrative bioinformatics, has driven the development of a new drug discovery paradigm. Using leukemia as a disease model, therapeutic synergism between drugs and natural products has been investigated by incorporating transcriptomics and proteomics data into a network-like understanding. Here, these recent advancements will be discussed in detail, along with perspectives in the field of drug synergism.

Topics: Animals; Arsenic Trioxide; Arsenicals; Benzamides; Drug Discovery; Drug Synergism; Gene Expression Profiling; Herb-Drug Interactions; Humans; Imatinib Mesylate; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Promyelocytic, Acute; Oxides; Piperazines; Proteome; Pyrimidines; Tretinoin

For decades, retinoic acid has been known to alter the proliferation and differentiation of myeloid cells. Currently, retinoic acid is a front-line agent in the treatment of certain forms of acute myelogenous leukemia. In this review, we focus on recent advances in our understanding of the mechanisms by which retinoids affect growth and proliferation of myeloid cells and contribute to the pathogenesis of leukemia. We have not attempted to summarize the related clinical literature.. The past 2 years have yielded important understanding of the mechanisms by which retinoids and their nuclear receptors interact with other signal transduction pathways and transcription factors to modify chromatin, alter gene expression, and participate in normal myeloid differentiation and leukemogenesis. Important advances regarding cell biology, molecular biology, biochemistry, and animal studies of retinoids and myeloid differentiation are reviewed.. Greater understanding of the role of retinoids and their receptors in myeloid cell growth and differentiation provides important insight into normal myelopoiesis. These findings have resulted in successful rational approaches to the treatment of acute leukemia and provide the promise of improved treatments in the near future.

Topics: Animals; Cell Differentiation; Cell Transformation, Neoplastic; Chromatin; Gene Expression Regulation; Humans; Leukemia, Myeloid; Leukemia, Promyelocytic, Acute; Mice; Myeloid Cells; Myelopoiesis; Myeloproliferative Disorders; Oncogene Proteins, Fusion; Protein Processing, Post-Translational; Receptors, Retinoic Acid; Retinoids; Signal Transduction; Transcription Factors; Tretinoin

Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia. Morphologically, it is identified as the M3 subtype of acute myeloid leukemia by the French-American-British classification and cytogenetically is characterized by a balanced reciprocal translocation between chromosomes 15 and 17, which results in the fusion between promyelocytic leukemia (PML) gene and retinoic acid receptor alpha (RARalpha). It seems that the disease is the most malignant form of acute leukemia with a severe bleeding tendency and a fatal course of only weeks. Chemotherapy (CT; daunorubicin, idarubicin and cytosine arabinoside) was the front-line treatment of APL with a complete remission (CR) rate of 75% to 80% in newly diagnosed patients. Despite all these progresses, the median duration of remission ranged from 11 to 25 months and only 35% to 45% of the patients could be cured by CT. Since the introduction of all-trans retinoic acid (ATRA) in the treatment and optimization of the ATRA-based regimens, the CR rate was raised up to 90% to 95% and 5-year disease free survival (DFS) to 74%. The use of arsenic trioxide (ATO) since early 1990s further improved the clinical outcome of refractory or relapsed as well as newly diagnosed APL. In this article, we review the history of introduction of ATRA and ATO into clinical use and the mechanistic studies in understanding this model of cancer targeted therapy.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; History, 20th Century; Humans; Leukemia, Promyelocytic, Acute; Oxides; Tretinoin

Topics: Cell Differentiation; Cell Line, Tumor; Drug Resistance, Neoplasm; Genetic Therapy; Humans; Leukemia, Promyelocytic, Acute; Oligonucleotide Array Sequence Analysis; Point Mutation; Reactive Oxygen Species; Receptors, Retinoic Acid; Retinoic Acid Receptor alpha; Tretinoin

We review the role of all-trans retinoic acid (ATRA) in the treatment of acute promyelocytic leukemia (APL). The combination of ATRA and conventional anthracycline-ARA-C chemotherapy (CT) has clearly demonstrated its superiority over CT alone (in terms of relapse and survival) in newly diagnosed APL. Combination treatment probably also reduces the incidence of initial failures, and complete remission (CR) rates greater than 90% are now regularly reported in large multicenter trials. Some randomized studies strongly suggest that prolonged maintenance treatment (for 1 or 2 years) with ATRA and low-dose CT, and possibly very early introduction of anthracycline CT during induction treatment, may reduce the incidence of relapse. With those treatments, the relapse risk appears to be only 10%-15%, although it remains greater in patients who initially have high white blood cell counts (often associated with variant M3 morphology, short bcr3 isoform, etc.) and patients with residual disease detectable by RT-PCR at the end of consolidation courses. In those patients, addition of arsenic derivatives to induction or consolidation treatment (or both treatments together) may prove useful and is currently being tested. ATRA syndrome (now generally called APL differentiation syndrome, as it is also seen with arsenic derivatives) remains the major side effect of ATRA treatment. It occurs in 10%-15% of patients and is currently fatal in at least 10% of them. Rapid onset of CT or high dose steroids (or both) should improve its outcome. A sizeable proportion of APL patients who relapse after ATRA and CT can be durably salvaged by the same treatment followed by allogeneic or autologous stem cell transplantation, provided the transplant (in the autologous setting) is RT-PCR-negative. However, in relapsing APL arsenic derivatives (mainly arsenic trioxide) are now considered to be the reference treatment. Some of the current issues with ATRA treatment in newly diagnosed APL include whether ATRA has a role during consolidation treatment and whether arabinoside (AraC) is required in addition to anthracyclines in the chemotherapy combined to ATRA.

Topics: Antineoplastic Agents; Clinical Trials as Topic; Humans; Leukemia, Promyelocytic, Acute; Treatment Outcome; Tretinoin

Acute promyelocytic leukemia (APL) is an unique subtype of acute myeloid leukemia typically carrying a specific reciprocal chromosome translocation, t(15;17), leading to the expression of a leukemia-generating fusion protein, PML-RARalpha. APL patients are responsive to APL-selective reagents such as all-trans retinoic acid (ATRA) or arsenic trioxide and non-selective cytotoxic chemotherapy. Nearly all de novo APL patients undergo clinical remission when treated with ATRA plus chemotherapy or with the combinational selective therapy, ATRA plus As2O3. Combining ATRA with As2O3 as an induction followed by chemotherapy consolidation results in more profound clinical remissions compared to treatment with any agent alone or any of the other possible combinations. The mechanism of action of each of these agents differs. ATRA induces APL cell differentiation and PML-RARalpha proteolysis. As2O3 induces APL cell partial differentiation, PML-RARalpha proteolysis, and apoptosis. Chemotherapy, mainly using anthracyclines, induces APL cell death. The combined effects of selective APL therapy (ATRA and As2O3) and/or non-selective chemotherapy in APL cells in vitro and their mechanisms in relation to clinical protocol design are discussed.

Topics: Anthracyclines; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Drug Administration Schedule; Enzyme Inhibitors; Histone Deacetylase Inhibitors; Humans; Leukemia, Promyelocytic, Acute; Oxides; Tretinoin

Topics: Antineoplastic Agents; Humans; Leukemia, Promyelocytic, Acute; Recurrence; Remission Induction; Tretinoin

To turn a disease from highly fatal to highly curable is extremely difficult, especially when the disease is a type of cancer. However, we can gain some insight into how this can be done by looking back over the 50-year history of taming acute promyelocytic leukaemia (APL). APL is the M3 type of acute myeloid leukaemia characterized by an accumulation of abnormal promyelocytes in bone marrow, a severe bleeding tendency and the presence of the chromosomal translocation t(15;17) or variants. APL was considered the most fatal type of acute leukaemia five decades ago and the treatment of APL was a nightmare for physicians. Great efforts have been made by scientists worldwide to conquer this disease. The first use of chemotherapy (CT) was unsuccessful due to lack of supportive care and cytotoxic-agent-related exacerbated coagulopathy. The first breakthrough came from the use of anthracyclines which improved the complete remission (CR) rate, though the 5-year overall survival could only be attained in a small proportion of patients. A rational and intriguing hypothesis, to induce differentiation of APL cells rather than killing them, was raised in the 1970s. Laudably, the use of all-trans retinoic acid (ATRA) in treating APL resulted in terminal differentiation of APL cells and a 90-95% CR rate of patients, turning differentiation therapy in cancer treatment from hypothesis to practice. The combination of ATRA with CT further improved the 5-year overall survival. When arsenic trioxide (ATO) was used to treat relapsed APL not only the patients but also the ancient drug were revived. ATO exerts dose-dependent dual effects on APL cells: at low concentration, ATO induces partial differentiation, while at relatively high concentration, it triggers apoptosis. Of note, both ATRA and ATO trigger catabolism of the PML-RARalpha fusion protein which is the key player in APL leukaemogenesis generated from t(15;17), targeting the RARalpha (retinoic acid receptor alpha) or promyelocytic leukaemia (PML) moieties, respectively. Hence, in treating APL both ATRA and ATO represent paradigms for molecularly targeted therapy. At molecular level, ATRA and ATO synergistically modulate multiple downstream pathways/cascades. Strikingly, a clearance of PML-RARalpha transcript in an earlier and more thorough manner, and a higher quality remission and survival in newly diagnosed APL are achieved when ATRA is combined with ATO, as compared to either monotherapy, making APL a curable diseas

Topics: Antineoplastic Agents; Arsenic Trioxide; Arsenicals; Humans; Leukemia, Promyelocytic, Acute; Oxides; Tretinoin

Pathogenesis of acute promyelocytic leukemia appears to be one of the best understood among human malignancies. The ability of retinoic acid (RA) and arsenic trioxide to directly target the oncogenic promyelocytic leukemia-retinoic receptor A (PML-RARA) fusion protein also made this disease the first model for oncogene-targeted therapies. A set of recent data has significantly increased the complexity of our view of acute promyelocytic leukemia pathogenesis, as well as of therapeutic response. This review summarizes and discusses these findings, which yield novels questions and models.

Topics: Arsenic Trioxide; Arsenicals; Humans; Leukemia, Promyelocytic, Acute; Models, Biological; Oncogene Proteins, Fusion; Oxides; Tretinoin

Topics: Drug Therapy, Combination; Humans; Leukemia, Promyelocytic, Acute; Recurrence; Remission Induction; Tretinoin

A 19-year-old man was referred to our hospital with pancytopenia and disseminated intravascular coagulation (DIC). Bone marrow aspiration revealed 93.6% of atypical promyelocytes and marked hemophagocytosis by macrophages. The diagnosis of acute promyelocytic leukemia (APL) associated with hemophagocytic syndrome (HPS) was made. As there was no evidence of infection, collagen diseases, or abuse of medicine, his HPS was classified as malignancy-associated HPS (MAHS). The DIC improved after administration of idarubicin and all-trans-retinoic acid (ATRA). On the 11th day, however, DIC and elevation of serum LDH recurred with the appearance of hepatosplenomegaly. Although APL cells had decreased in the bone marrow, hemophagocytes persisted. After administration of dexamethasone and etoposide, DIC and HPS improved, and complete remission of APL was obtained. ATRA was implicated in the aggravation of APL-induced MAHS in the present case.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Disseminated Intravascular Coagulation; Etoposide; Humans; Idarubicin; Leukemia, Promyelocytic, Acute; Lymphohistiocytosis, Hemophagocytic; Male; Pancytopenia; Treatment Outcome; Tretinoin

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Idarubicin; Leukemia, Promyelocytic, Acute; Male; Mercaptopurine; Methotrexate; Middle Aged; Mitoxantrone; Myocarditis; Tretinoin

The rapid rise of chemical biology aimed at studying signaling networks for basic cellular activities using specific, active small molecules as probes has greatly accelerated research on pathological mechanisms and target therapy of diseases. This research is especially important for malignant tumors such as leukemia, a heterogeneous group of hematopoietic malignancies that occurs worldwide. With the use of a chemical approach combined with genetic manipulation, great progress has been achieved over the past few decades on the biological, molecular and cytogenetic aspects of leukemia, and in its diagnosis and therapy. In particular, discoveries of the clinical effectiveness of all-trans retinoic acid and arsenic trioxide in the treatment of acute promyelocytic leukemia and the kinase inhibitors Imatinib and Dasatinib in the treatment of chronic myelogenous leukemia not only make target therapy of leukemia a reality, but also push mechanisms of leukemogenesis and leukemic cell activities forward. This review will outline advances in chemical biology that help our understanding of the molecular mechanisms of cell differentiation and apoptosis induction and target therapy of leukemia.

Topics: Antineoplastic Agents; Apoptosis; Arsenic Trioxide; Arsenicals; Benzamides; Dasatinib; Growth Inhibitors; Humans; Imatinib Mesylate; Leukemia; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Promyelocytic, Acute; Oxides; Piperazines; Protein Kinase Inhibitors; Pyrimidines; Thiazoles; Tretinoin

All-trans-retinoic acid (ATRA) has been proved to be an effective treatment for acute promyelocytic leukemia (APL), inducing remission in more than 90% of cases. Treatment of APL in pregnancy is controversial as the use of ATRA has been questioned due to the teratogenic effect of retinoids. We report a case of pregnancy in a woman exposed to ATRA during the first trimester. The baby was born healthy, without any anomalies. Review of all reported cases of the use of ATRA in pregnancy revealed no serious adverse outcomes or congenital anomalies although only very few cases had exposure in the first trimester.

Topics: Adult; Female; Humans; Infant, Newborn; Leukemia, Promyelocytic, Acute; Pregnancy; Pregnancy Complications, Neoplastic; Pregnancy Outcome; Pregnancy Trimester, First; Tretinoin

Acute promyelocytic leukemia (APL) is characterized by generation of the PML-RARalpha fusion gene. PML-RARalpha can homodimerize with another PML-RARalpha, and the hybrid binds the histone-deacetylase recruiting co-repressor complex with higher affinity than the wild-type RARalpha. However, the co-repressor complex is releasable by pharmacological doses of all-trans retinoic acid (ATRA). More than 90% of patients with APL achieve a complete remission (CR) with differentiation therapy consisting of ATRA combined with chemotherapy. A new synthetic retinoid, tamibaroten, showed therapeutic effectiveness in patients with ATRA-resistant APL with increased expression of cellular retinoic acid binding protein (CRABP), and about 60% of patients with relapsed APL achieved a CR. Arsenic trioxide triggers the rapid degradation of PML-RARalpha through the targeting of the PML moieties of the fusion protein and showed a high CR rate in relapsed APL. The combination of ATRA, chemotherapy, and/or new agents improved the long-term survival in patients with APL.

Topics: Animals; Antineoplastic Agents; Arsenic Trioxide; Arsenicals; Benzoates; Humans; Leukemia, Promyelocytic, Acute; Oncogene Proteins, Fusion; Oxides; Tetrahydronaphthalenes; Tretinoin

To identify the side effect of all-trans retinoic acid (ATRA), and improve early therapeutic response in patients with acute promyelocytic leukemia (APL).. The first case of Sweet's syndrome (SS) developed in a APL patient treated with ATRA was reported in mainland of China, and reviewed correlative literature.. Only 14 cases of SS associated with ATRA therapy in APL have been reported in the literature, including the present case. The median age was 49.5 years (9 -84) and 10 were women and 4 men. Of them, SS was restricted to the skin in 10 case, the other 4 muscle, fascia, kidney, and lung were involved. SS appeared after a median of 18 days of ATRA therapy (6 - 34 days). The median WBC count was 7.05 (0.80 - 23.00) x 10(9)/L. Four patients continued with the ATRA therapy without interruption, 13 patients treated with steroids and 12 responded. One patient improved without any treatment. Two cases of SS developed retinoic acid syndromes after ATRA therapy.. Sweet's syndrome is a rare adverse effect of ATRA, and has similar features with inflammatory or infective dermatosis. The corticosteroids treatment could improve the systemic and cutaneous symptoms. When ATRA therapy was restarted after SS subsided, no recurrence of rashes was observed.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Child; Female; Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Sweet Syndrome; Tretinoin

Until the late 1980s, chemotherapy with anthracyclines and cytarabine (AraC) was the only treatment approach for acute promyelocytic leukemia (APL), as for other types of acute myeloid leukemia. Many studies have shown that treatment with all-trans retinoic acid (ATRA), followed by anthracycline-AraC chemotherapy, significantly decreases the incidence of relapse and improves survival in newly diagnosed APL, compared with this chemotherapy alone. This approach was associated with consistent morbidity and mortality during consolidation and maintenance treatment, however, mainly resulting from myelosuppression induced by anthracycline-AraC courses. Several groups have reported high rates of complete remission and low rates of relapse with ATRA and chemotherapy using anthracyclines alone, suggesting that AraC could be avoided in the chemotherapy of APL, reducing toxicity. These results were not confirmed in other studies, however, raising the issue of the role of AraC in treatment of patients with newly diagnosed APL.

Topics: Adult; Anthracyclines; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Combined Modality Therapy; Cytarabine; Humans; Leukemia, Promyelocytic, Acute; Middle Aged; Multicenter Studies as Topic; Randomized Controlled Trials as Topic; Remission Induction; Treatment Outcome; Tretinoin

The outcome of acute promyelocytic leukemia (APL) has improved dramatically during the past 40 years. Insights into the genetic and biologic mechanisms of APL lead to the development of specific and effective therapeutic strategies. This article discusses the therapeutic interventions that transformed APL from one of the most lethal leukemias to one that is highly curable.

Topics: Antibiotics, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Humans; Leukemia, Promyelocytic, Acute; Oxides; Treatment Outcome; Tretinoin

Leukemia is a multistep process involving accumulation of genetic alterations over time. These genetic mutations destroy the delicate balance between cell proliferation, differentiation, and apoptosis. Traditional approaches to treatment of leukemia involve chemotherapy, radiation, and bone marrow transplantation. In recent years, specific targeted therapies have been developed for the treatment of leukemia. The success of treatment of acute promyelocytic leukemia with All Trans Retinoic Acid (ATRA) and CML with imatinib have lead to increased efforts to identify targets that can be inhibited by small molecules for treatment of hematological malignancies. In this review, we describe the current advances in the development of targeted therapy in acute myeloid leukemia.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Benzamides; Cell Cycle; Humans; Imatinib Mesylate; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid; Leukemia, Promyelocytic, Acute; Piperazines; Pyrimidines; ras Proteins; Receptor Protein-Tyrosine Kinases; Translocation, Genetic; Tretinoin

Topics: Adult; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Blood Component Transfusion; Child; Child, Preschool; Female; Hemorrhage; Humans; Leukemia, Myeloid, Acute; Leukemia, Promyelocytic, Acute; Male; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Tretinoin

Despite the development of highly effective treatment strategies for acute promyelocytic leukaemia around 10% of patients die in the presentation period as a consequence of the associated bleeding diathesis. The cause of the coagulopathy is complex resulting from a combination of tissue factor (TF) and cancer procoagulant (CP) induced disseminated intravascular coagulation, exaggerated fibrinolysis due predominantly to enhanced expression of annexin II on APL blast cell membranes and blast cell production of cytokines. All-trans retinoic acid (ATRA) has revolutionised the treatment of APL. When combined with chemotherapy long term survival rates of up to 80% can be achieved. Commencement of ATRA induces APL blast cell differentiation and is associated with a rapid resolution of the bleeding tendency through a combination of effects which include up regulation of thrombomodulin and down regulation of TF and CP production and cell surface expression of annexin II.

Topics: Cell Differentiation; Combined Modality Therapy; Hemorrhagic Disorders; Humans; Leukemia, Promyelocytic, Acute; Tretinoin

Retinoid is a collective term for compounds which bind to and activate retinoic acid receptors (RARalpha, beta, gamma and RXRalpha, beta, gamma), members of nuclear hormone receptor superfamily. The most important endogeneous retinoid is all-trans-retinoic acid (ATRA) which is an RARalpha, beta and gamma ligand. ATRA and its mimics have been in clinical use for treatment of acute promyelocytic leukemia (APL) and some skin diseases. Many synthetic retinoids have been developed and attempts to improve their medicinal properties have been made. Among them, tamibarotene (Am80) is an RARalpha- and RARbeta-specific (but RARgamma- and RXRs-nonbinding) synthetic retinoid that is effective in the treatment of psoriasis patients and relapsed APL. Experimentally, this compound is also active in animal models of rheumatoid arthritis and experimental autoimmune encephalomyelitis. On this background, possible application of retinoids for the treatment of autoimmune diseases was discussed. In particular, Th1 dominant autoimmune diseases may be the targets of the retinoids.

Topics: Animals; Arthritis, Rheumatoid; Autoimmune Diseases; Benzoates; Humans; Leukemia, Promyelocytic, Acute; Receptors, Retinoic Acid; Retinoids; Skin Diseases; T-Lymphocytes; Tetrahydronaphthalenes; Tretinoin

Topics: Aminoglycosides; Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Arsenic Trioxide; Arsenicals; Benzoates; Clinical Trials as Topic; Combined Modality Therapy; Drug Resistance, Neoplasm; Enzyme Inhibitors; Gemtuzumab; Hematopoietic Stem Cell Transplantation; Humans; Hydroxamic Acids; Leukemia, Promyelocytic, Acute; Oxides; Practice Guidelines as Topic; Recurrence; Remission Induction; Tetrahydronaphthalenes; Tretinoin

This review focuses on the treatment of acute promyelocytic leukemia (APL) in elderly patients and offers recommendations for improving outcomes. Nineteen percent of patients with APL are > or =60 years. Rates of response and survival are lower in elderly compared with younger patients, owing to a higher incidence of early deaths or deaths in remission. However, relapse-free survival rates are similar in both groups. Ongoing trials assess the role of reduced-intensity regimens. All-trans retinoic acid (ATRA) and concurrent arsenic trioxide is associated with high rates of response and molecular remission and low rates of induction deaths. We propose this combination as the treatment of choice in patients with APL, including the elderly. Patients with elevated leukocyte counts may also benefit from gemtuzumab ozogamicin therapy, with or without leukapheresis. Monitoring major organ function and toxicity is essential. Patients should be assessed for minimal residual disease using polymerase chain reaction testing for promyelocytic leukemia-retinoic acid receptor alpha. If molecular relapse is evident, treatment with ATRA and idarubicin, with or without gemtuzumab ozogamicin, is recommended.

Topics: Aged; Antineoplastic Agents; Arsenic Trioxide; Arsenicals; Drug Therapy, Combination; Humans; Leukemia, Promyelocytic, Acute; Oxides; Prognosis; Tretinoin

Leukocytosis or hyperleukocytosis occurs during ATRA or arsenic trioxide differentiation therapy, which is related to the RA syndrome. The number of WBC often increased by ten or more times as high as that of pretreatment, around 7 to 20 days after treatment with ATRA or arsenic trioxide. Usually, when number of WBC tended to peak, there was concomitance with down-regulation of promyelocytes, up-regulation of myelocytes and more mature neutrophils. The same trend of classification of BM was observed in most of the patients with APL to whom leukocytosis happened. Although the mechanism of leukocytosis has not been demonstrated clearly, so far the proliferation hypothesis by cytokines and rheological hypothesis by adhesion molecules were taken into consideration. Otherwise, hypothesis about more divisions of differentiated myelocytes induced by ATRA or arsenic trioxide remains unclear. Usually, this kind of leukocytosis or hyperleukocytosis itself requires no additional cytotoxic treatment.

Topics: Antineoplastic Agents; Arsenic Trioxide; Arsenicals; Cytokines; Humans; Leukemia, Promyelocytic, Acute; Leukocytosis; Oxides; Tretinoin

Most reviews on the state-of-the-art treatment in acute promyelocytic leukemia (APL) have focused mainly on the comparison of therapeutic approaches, including all-trans retinoic acid (ATRA) and chemotherapy. However, outcome of individual patients also depends on appropriate knowledge of several aspects related to APL management that are less appreciated and/or are underestimated in the literature. These aspects include appropriate diagnostic strategy, use of supportive care, early recognition and treatment of life-threatening complications typically associated with APL and its specific treatment, tools and timing for adequate evaluation of response, and, finally, management of the disease in special conditions such as older patients and pregnant women. Besides reviewing current consensus and controversies on the use of ATRA and chemotherapy in the distinct treatment phases (eg, induction, consolidation, maintenance), this article addresses the aforementioned issues on APL management ("tricks of the trade") with special emphasis on several peculiar aspects that distinguish APL from other acute myeloid leukemias.

Topics: Antineoplastic Agents; Humans; Leukemia, Promyelocytic, Acute; Tretinoin

Topics: Apoptosis; Cell Differentiation; Cell Line, Tumor; Humans; Intracellular Signaling Peptides and Proteins; Leukemia, Promyelocytic, Acute; Ligands; Membrane Proteins; Signal Transduction; Tretinoin

Topics: Antineoplastic Agents; Arsenic; Drug Therapy, Combination; Humans; Leukemia, Promyelocytic, Acute; Tretinoin

Topics: Evidence-Based Medicine; Hematopoietic Stem Cell Transplantation; Histocompatibility; HLA Antigens; Humans; Leukemia, Myeloid, Acute; Leukemia, Promyelocytic, Acute; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Remission Induction; Transplantation, Autologous; Transplantation, Homologous; Treatment Outcome; Tretinoin

Leukemia, a group of hematological malignancies characterized by clonal expansion of hematopoietic cells with uncontrolled proliferation, decreased apoptosis and blocked differentiation, is one of the most notorious enemies of mankind which accounts for some 300,000 new cases and 222,000 deaths each year worldwide. Leukemia can be divided into acute or chronic, lymphoid or myeloid types, based on the disease progression and hematopoietic lineages involved 5. The responses of leukemia to therapies differ from one type or subtype to another. Hence, to improve the clinical outcome, the therapeutic strategies should be disease pathogenesis-based and individualized. The close collaboration between bench and bedside may not only shed new lights on leukemogenesis, gain insights into therapeutic mechanisms, but also provide opportunities for designing more rational therapies. The development of curative approaches for acute promyelocytic leukemia (APL) may serve as a paradigm.

Topics: Arsenic Trioxide; Arsenicals; Cell Differentiation; Drug Delivery Systems; Drug Synergism; Humans; Leukemia, Promyelocytic, Acute; Oxides; Tretinoin

Topics: Adolescent; Adult; Aged; Female; Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Tretinoin

In the past, acute promyelocytic leukemia (APL) was associated with a high risk of early mortality resulting from severe coagulopathy, frequently inducing fatal cerebral hemorrhage. With the introduction of the differentiating agent all-trans retinioc acid (ATRA) APL has changed to the best curable subtype of acute myeloid leukemia (AML). With ATRA and chemotherapy approximately 70-80% of patients with newly diagnosed APL achieve long-term remission and are probably cured. PML/RARalpha, the molecular fusion transcript of the specific translocation t(15;17) represents not only the target for ATRA but also permits a precise diagnosis and provides a marker for the identification of minimal residual or recurrent disease (MRD). During the last decade, substantial progress has been made with regard to the recognition of prognostic factors and the optimization of the combination of ATRA and chemotherapy. Remaining questions are the role of arsenic and of ara-C in first line therapy of APL as well as the indication of maintenance therapy in the individual patient. Several treatment options exist for patients with APL who have relapsed after ATRA and chemotherapy. Approximately 50% of the patients in first relapse can achieve long-lasting second remission and might be cured with salvage regimens. Currently, arsenic compounds and transplantation procedures seem to be the most promising options in relapsed disease. The role of CD33 antibodies has to be determined in future studies. Refining the molecular monitoring of MRD by quantitative RT-PCR, better elucidation of the biologic mechanisms, and the identification of prognostic factors might be helpful to make further progress in the treatment of APL.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Hemorrhage; Humans; Leukemia, Promyelocytic, Acute; Neoplasm Proteins; Neoplasm, Residual; Oncogene Proteins, Fusion; Oxides; Prognosis; Recurrence; Risk Factors; Stem Cell Transplantation; Thrombosis; Translocation, Genetic; Transplantation, Homologous; Tretinoin

Acute promyelocytic leukemia (APL) is characterized by onset at a young age and a life-threatening hemorrhagic diathesis, which is attributed to a disseminated intravascular coagulation (DIC)-like coagulopathy. The discovery of all-trans-retinoic acid has changed the course of APL treatment by reducing the onset of DIC and inducing a complete and durable remission in more than 90% of patients. The occurrence of APL during pregnancy is not a frequent event, but the management of these patients raises many therapeutic and ethical dilemmas and requires a careful clinical case evaluation of fetal and maternal risk, coagulation status, the parents' wishes, and therapeutic options. Here we describe 3 patients with APL diagnosed during pregnancy. Clinical data and the therapeutic approaches are presented. In the discussion, we analyze clinical decisions and therapeutic options and compare our cases with those found in the literature.

Topics: Abnormalities, Drug-Induced; Abortion, Therapeutic; Adult; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Case Management; Cesarean Section; Fatal Outcome; Female; Gestational Age; Humans; Idarubicin; Infant, Newborn; Leukemia, Promyelocytic, Acute; Male; Pregnancy; Pregnancy Complications, Neoplastic; Remission Induction; Risk; Safety; Tretinoin

Topics: Antineoplastic Agents; Humans; Leukemia, Promyelocytic, Acute; Tretinoin

Topics: Antineoplastic Agents; Benzamides; Clinical Trials as Topic; Cytarabine; Drug Monitoring; Fusion Proteins, bcr-abl; Gene Targeting; Genes, Wilms Tumor; Genetic Therapy; Hematopoietic Stem Cell Transplantation; Humans; Imatinib Mesylate; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Promyelocytic, Acute; Neoplasm Proteins; Neoplasm, Residual; Oncogene Proteins, Fusion; Pharmacogenetics; Piperazines; Pyrimidines; Recombinant Fusion Proteins; Therapeutic Equivalency; Tretinoin

Over the recent years, treatment of acute promyelocytic leukemia (APL) with all-trans retinoic acid (ATRA) has become a widely accepted therapeutic regimen and is considered a model of differentiation therapy in malignant diseases. However, the role of ATRA treatment beyond that of the induction of differentiation of leukemic blasts is still far from being fully understood. Data from in vivo and in vitro studies have demonstrated that during ATRA treatment of APL there are significant changes not only in the expression of the apoptotic molecules Fas and Fas ligand, but also in the expression of other molecules involved both in the regulation of apoptosis and in interactions between host immune and leukemia cells. These effects may thus contribute, at least in part, to the beneficial effects of ATRA therapy in APL. In this report we review the current status of studies that contribute to our understanding of treatment with ATRA. We focus on ATRA-induced changes in apoptotic pathways, particularly as it relates to the Fas/Fas ligand system.

Topics: Fas Ligand Protein; fas Receptor; Humans; Leukemia, Promyelocytic, Acute; Membrane Glycoproteins; Tretinoin

Acute promyelocytic leukemia (APL) is distinguished from other acute myeloid leukemias (AMLs) by cytogenetic, clinical, as well as biological characteristics. The hallmark of APL is the t(15;17), which leads to the expression of the PML/RARalpha fusion protein. PML/RARalpha is the central leukemia-inducing lesion in APL and is directly targeted by all trans retinoic acid (t-RA) as well as by arsenic, both compounds able to induce complete remissions. This review focuses on potential stem cell involvement in APL outlining the knowledge about the APL-initiating stem cell and the influence of PML/RARalpha on the biology of the hematopoietic stem cell. Moreover, the importance of the blockage of t-RA signaling by the PML/RARalpha for the pathogenesis of APL is discussed, taking the relevance of the t-RA signaling pathway for the global hematopoiesis into account.

Topics: Apoptosis; Hematopoiesis; Humans; Leukemia, Promyelocytic, Acute; Neoplasm Proteins; Neoplastic Stem Cells; Oncogene Proteins, Fusion; Signal Transduction; Tretinoin

We encountered a 12-year-old girl with acute promyelocytic leukemia (APL) that occurred 21 months after a living donor partial orthotopic liver transplantation from her father for ornithine transcarbamylase deficiency. FK-506 had been administered for prophylaxis against graft-versus-host reaction. The bone marrow specimen revealed a massive infiltration of promyelocytic blasts (M3 by FAB classification) with chromosome 46, XX, t (15; 17) (q22; q12), being the recipient origin. A PML/RAR alpha chimeric gene was detected by RT-PCR. The patient was diagnosed as having APL and successfully induced to complete remission by chemotherapy including daunorubicin (DNR), cytarabine (araC), and all-trans retinoic acid (ATRA). She has been in continuous remission for 12 months after the treatment. Leukemia after liver transplantation is generally taken as a rare complication. However, recent advances in the survival rate of patients who have undergone liver transplantation will lead to an increase of such cases.

Topics: Antineoplastic Combined Chemotherapy Protocols; Child; Cytarabine; Daunorubicin; Female; Graft vs Host Disease; Humans; Immunosuppressive Agents; Leukemia, Promyelocytic, Acute; Liver Transplantation; Living Donors; Ornithine Carbamoyltransferase Deficiency Disease; Remission Induction; Tacrolimus; Tretinoin

Acute promyelocytic leukemia (APL) has become the most curable subtype of acute myeloid leukemia in adults. It represents the only established example of successful differentiation therapy. With current therapy which includes all-trans retinoic acid (ATRA) and anthracycline-based chemotherapy for induction, anthracycline-based consolidation and maintenance with ATRA and/or low-dose chemotherapy, approximately 75-85% of patients with acute promyelocytic leukemia (APL) remain alive and disease-free at 5 years, and most patients are likely to be cured, an unprecedented achievement in the field of hematologic malignancies. However, several causes for failure to be cured need to be addressed. The first is early death which occurs in approximately 10% and is frequently attributable to hemorrhage due to the characteristic coagulopathy. The second is relapse, particularly in intermediate- and high-risk patients. Analyses of new prognostic factors may permit refinement of current risk classification and identify patients warranting alternative therapy. Finally, long-term consequences of current treatment will be important to recognize, including delayed cardiomyopathy, extramedullary relapse related to sanctuary sites, and the potential for second malignancies. For patients who do relapse, arsenic trioxide appears to be the treatment of choice since the majority of patients achieve a second complete morphologic, cytogenetic, and even molecular remission. While some patients achieving a second complete remission have prolonged disease-free survival with consolidation and maintenance arsenic, high-dose chemotherapy with autologous hematopoietic stem cell transplantation appears to offer the highest likelihood of cure. Such a strategy or anti-CD33 antibodies, recently shown to be active in APL, might be considered for high-risk patients in first remission.

Topics: Antineoplastic Agents; Humans; Leukemia, Promyelocytic, Acute; Prognosis; Tretinoin

Acute promyelocytic leukemia (APL) is an unique subtype of acute myeloid leukemia typically carrying a specific reciprocal chromosome translocation t(15;17) leading to the expression of a leukemia-generating fusion protein, PML-RARalpha. Nearly all de novo APL patients undergo disease remission when treated with all trans retinoic acid (ATRA) plus chemotherapy. APL patients that relapse following this type of therapy respond to As2O3 with disease remission once again. The mechanism of action of both ATRA and As2O3 appears to be by inducing granulocytic differentiation and this cellular differentiation seems to depend on PML-RARalpha proteolysis. ATRA treatment results in partial cleavage and complete degradation of PML-RARalpha protein in differentiation sensitive, but not in differentiation resistant APL cells. As2O3 treatment results in only complete degradation of PML-RARalpha protein in both ATRA-sensitive and -resistant APL cells. PML-RARalpha appears to cause leukemia by acting as a transcriptional repressor of RARalpha target genes and by inhibiting activity of transcription factor C/EBPalpha. Therefore, PML-RARalpha proteolysis induced by ATRA and As2O3 may play an important role in overcoming the repressive activity of PML-RARalpha and allowing cellular differentiation to proceed. This review will focus on the status of the PML-RARalpha fusion protein and its relationship to gene and differentiation induction as well as differentiation resistance of APL cells.

Topics: Arsenic Trioxide; Arsenicals; Cell Differentiation; Drug Delivery Systems; Humans; Leukemia, Promyelocytic, Acute; Neoplasm Proteins; Oncogene Proteins, Fusion; Oxides; Tretinoin

Studies utilizing experimental animals, epidemiological approaches, cellular models, and clinical trials all provide evidence that retinoic acid and some of its synthetic derivatives (retinoids) are useful pharmacological agents in cancer therapy and prevention. In this chapter, we first review the current knowledge of retinoic acid receptors (RARs) and their role in mediating the actions of retinoic acid. We then focus on a discussion of RARalpha and acute promyelocytic leukemia followed by a discussion of the role of RARs, in particular RARbeta expression, in other cancer types. Loss of normal RAR function in the presence of physiological levels of RA (either due to alterations in the protein structure or level of expression) is associated with a variety of different cancers. In some cases treatment with pharmacological doses of RA can be effective.

Topics: Animals; Antineoplastic Agents; Humans; Leukemia, Promyelocytic, Acute; Neoplasms; Receptors, Retinoic Acid; Tretinoin

Substantial progress has occurred in the treatment of acute promyelocytic leukemia (APL) because of improved understanding of the pathophysiology of the disease and identification of a molecular target. Novel agents such as all-trans retinoic acid (ATRA) (alone or combined with chemotherapy) and, more recently, arsenic trioxide have produced complete remission in most patients with newly diagnosed APL and/or relapsed or refractory disease, respectively. Use of these targeted therapies has resulted in evolution of the disease from one that was historically one of the most fatal subtypes of acute myeloid leukemia (AML) to one that appears curable in 70% to 80% of patients. The targeted approach to treatment of this disease can serve as a paradigm for the treatment of other leukemias.

Topics: Arsenic Trioxide; Arsenicals; Drug Delivery Systems; Humans; Leukemia, Promyelocytic, Acute; Oxides; Treatment Outcome; Tretinoin

Chemoprevention is the use of noncytotoxic therapeutic intervention at the early stages of carcinogenesis against the development and progression of mutant clones to invasive cancer. Retinoids are the most extensively studied and one of the most prominent groups of chemopreventive agents to reach clinical trials. Acute promyelocytic leukemia is the first human malignancy that is successfully treated with all-trans retinoic acid. The t(15;17)(q22;q21) gene rearrangement and PML/RARalpha fusion product in acute promyelocytic leukemia played the key role to leukemogenesis and to sensitivity to differentiation-inducing therapy of all-trans retinoic acid. This review focuses on retinoid-based chemoprevention and therapy of cancer, and use acute promyelocytic leukemia as a model to illustrate the molecular mechanisms of retinoid signaling pathway.

Topics: Animals; Anticarcinogenic Agents; Cell Nucleus; Humans; Leukemia, Promyelocytic, Acute; Neoplasms; Receptors, Retinoic Acid; Retinoic Acid Receptor alpha; Signal Transduction; Translocation, Genetic; Tretinoin; Vitamin A

Topics: Humans; Leukemia, Promyelocytic, Acute; Recurrence; Tretinoin

The use of arsenic trioxide (As2O3, ATO) combined with all-trans retinoic acid (ATRA) has recently been reported to induce remission in patients with acute promyelocytic leukemia (APL). However, its efficiency remains inconclusive mainly due to the small number of the available cases. In this study, therefore, we present a clinical study using a combination of ATO with low-dose ATRA (LD-ATRA) to treat 108 APL patients (80 newly diagnosed patients, 28 relapsed patients). Therapeutic outcomes using the ATO/LD-ATRA approach were compared with those of APL patients treated either with ATO alone (65 patients) or ATRA alone (51 patients). The results showed that the ATO/LD-ATRA approach provided significantly better therapeutic outcomes as compared to either ATO or ATRA alone, as evidenced by lower mortality, a higher CR rate and a reduced period to CR. In addition, the toxic side-effects have been no worse with the combined ATO/LD-ATRA treatment than with either ATO or ATRO alone and in some cases have been reduced. These data suggest that the ATO/LD-ATRA regimen is superior to either regimen given alone to patients with APL.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Female; Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Oxides; Recurrence; Remission Induction; Treatment Outcome; Tretinoin

Acute promyelocytic leukemia (APL) is the most curable subtype of AML yet it is not known to what extent newer therapies will succeed in the very elderly. Conventional chemotherapeutic induction regimens are usually too toxic for older patients, however, all trans-retinoic acid (ATRA) and arsenic trioxide (ATO) may be useful therapeutic options if used judiciously. This case series describes three octogenarians with APL all treated with ATRA and achieved complete remissions. The last patient received ATO at the time of first relapse and achieved a second remission. To our knowledge, this is the first report of successful use of ATO for induction in an octogenarian with APL.

Topics: Aged; Aged, 80 and over; Female; Humans; Leukemia, Promyelocytic, Acute; Remission Induction; Treatment Outcome; Tretinoin

We report a 27-year-old man with HIV-1 infection who developed acute promyelocytic leukemia (APL) with a novel complex three-way chromosomal translocation t(15;16;17). Induction of remission and consolidation with all-trans-retinoic acid (ATRA)- and anthracycline-based chemotherapy was followed by maintenance therapy consisting of ATRA, 6-mercaptopurine (6-MP), and methotrexate (MTX). Highly active antiretroviral therapy (HAART) was continued with brief interruptions. He remains in complete remission 40 months after diagnosis.

Topics: Adult; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Antiretroviral Therapy, Highly Active; HIV Infections; HIV-1; Homosexuality, Male; Humans; Leukemia, Promyelocytic, Acute; Male; Mercaptopurine; Methotrexate; Treatment Outcome; Tretinoin

Acute promyelocytic leukemia is a form of acute myelogenous leukemia, characterized by the t(15;17) chromososmal translocation and the presence of the abnormal PML-RARalpha fusion protein. All-trans-retinoic acid is a potent agent for the treatment of this fatal subtype of AML, and is particularly effective when combined with cytotoxic chemotherapy. The important biological activities of all-trans-retinoic acid in vitro and in vivo have provoked extensive studies over the years, aimed to define the mechanisms by which it induces its antileukemic effects. It is now well established that all-trans-retinoic acid when administered at pharmacological doses can reverse the dominant-negative effects that the PML-RARalpha oncoprotein exhibits on the functions of the wild type PML and RARalpha proteins. All-trans-retinoic acid induces gene transcription via retinoic acid responsive elements (RARE) that are present in the promoters of retinoid-responsive genes that ultimately result in the production of protein products that regulate leukemic cell differentiation and induce cell-cycle arrest. There is now accumulating evidence that additional signalling pathways are activated during all-trans-retinoic acid-treatment of cells, involving Stat-proteins, tyrosine kinases and mitogen-activated protein (Map) kinases. This review summarizes the current knowledge on the signalling cascades activated by all-trans-retinoic acid in APL cells. The clinical implications and potential translational applications from the accumulating knowledge in the field are also discussed.

Topics: Animals; Cell Cycle; Cell Differentiation; Cell Line, Tumor; Dimerization; Genes, Dominant; Humans; Leukemia, Promyelocytic, Acute; MAP Kinase Signaling System; Recombinant Fusion Proteins; Response Elements; Signal Transduction; Translocation, Genetic; Tretinoin

We describe a case of acute promyelocytic leukemia (APL) with t(15;17)(q22;q12) and trisomy 21 as an additional change in a patient who died at relapse after achieving complete remission (CR) for the duration of 20 months. A survey of 42 cases of APL with cytogenetic study performed at our institutionover the past 10 years showed 12 cases (28.6%) having chromosomal changes in addition to t(15;17). Trisomy 8 and trisomy 21 as additional changes were noted in 4 and 2 cases, respectively, with one patient showing both trisomies simultaneously. Two cases showed t(15;17) in hyperdiploid clones. Among the 10 patients with follow-up data, all eventually relapsed and none achieved continuous complete remission 1. Survival analysis performed in APL patients with adequate follow-up data showed no significant difference in overall and disease free survival between those with and without additional cytogenetic changes. After excluding cases with one induction death, the overall survival was significantly in favor of the group without additional cytogenetic abnormalities (P = 0.022). Late relapses may therefore be significantly more common in APL patients with additional cytogenetic abnormalities, and may not be reflected by analysis focused at three-year survival only. As APL is now considered a curable disease, any confirmed long-term survival impact of additional cytogenetic changes is expected to have important management implications.

Topics: Adolescent; Adult; Antineoplastic Agents; Chromosome Aberrations; Chromosome Banding; Chromosomes, Human, Pair 15; Chromosomes, Human, Pair 17; Chromosomes, Human, Pair 21; Death, Sudden; Fatal Outcome; Female; Hong Kong; Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Pulmonary Embolism; Remission Induction; Retrospective Studies; Survival Analysis; Translocation, Genetic; Tretinoin; Trisomy

All trans retinoic acid is the drug of choice in the treatment of acute promyelocytic leukemia. But this drug has some side effects, some of which may be life-threatening. Retinoic acid syndrome is the most frequent and dangerous side effect of this differentiation inducing agent. Other side effects include Sweet's syndrome, vasculitis, hypercalcemia, bone marrow necrosis and fibrosis, thromboembolic events, erythema nodosum, granulomatous proliferation and some pulmonary complications. Here, we report vasculitis in a case with APL treated with ATRA and review the literature.

Topics: Adult; Anti-Inflammatory Agents; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Fever; Humans; Leukemia, Promyelocytic, Acute; Male; Methylprednisolone; Remission Induction; Tretinoin; Vasculitis

The relapse-free survival of patients with acute promyelocytic leukemia (APL) has significantly increased during the last decade. The introduction of all-trans retinoic acid (ATRA) doubled the survival of patients with this disease. However, despite ATRA and anthracycline-based chemotherapy, 12%-30% of patients will still relapse. Arsenic trioxide (ATO) has demonstrated efficacy and safety in patients with first and subsequent relapsed or refractory APL, regardless of the disease-free interval. Treatment of relapsed and refractory patients with this novel therapy produces complete remission in 87% of patients and molecular remission in 83%. Studies have documented the efficacy of autologous and allogeneic transplantation as salvage therapy in relapsed and refractory APL. The introduction of ATO into the treatment regimen for APL has stimulated discussion on its role in the transplantation setting. Investigators recently met to discuss the issue and make recommendations regarding ATO therapy in patients who are in their second or subsequent complete remission and are candidates for transplantation. This article describes the pivotal studies of this novel agent, discusses risk factor stratification for relapse in patients with APL, and proposes protocols for treatment incorporating ATO therapy. In addition, it describes scientific issues in ongoing and proposed clinical trials of ATO therapy for this disease.

Topics: Antineoplastic Agents; Arsenic Trioxide; Arsenicals; Clinical Trials as Topic; Combined Modality Therapy; Europe; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Promyelocytic, Acute; Neoplasm Regression, Spontaneous; Oxides; Practice Guidelines as Topic; Risk Factors; Tretinoin; United States

Retinoid therapy for acute promyelocytic leukemia (APL) is one of the major achievements of leukemia research in the last 15 years. Use of all trans retinoic acid (ATRA) has changed the prognosis of APL from a fatal leukemia to a highly curable disease. This case-based review examines the available clinical and scientific data to form evidence-based decisions in the management of APL. The main aim of this review is to highlight recent progress made in the management of APL and address the role of maintenance therapy, prognostic factors for relapse and treatment of relapsed disease.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Case Management; Evidence-Based Medicine; Humans; Idarubicin; Leukemia, Promyelocytic, Acute; Male; Methotrexate; Neoplasm Proteins; Oncogene Proteins, Fusion; Prognosis; Recurrence; Remission Induction; Salvage Therapy; Syndrome; Tretinoin

Acute promyelocytic leukaemia (APL) is characterised by the fusion gene transcript PML-RAR-alpha and is now the most frequently curable acute leukaemia in adults if promptly diagnosed and adequately treated. The clinical presentation is associated with a haemorrhagic diathesis and the blasts almost always have Auer rods. Poor prognostic factors include older age, elevated white blood cell count, low platelet count, and CD56 expression. The introduction of all-trans retinoic acid (ATRA), which leads to the differentiation of leukaemic blasts into mature granulocytes has been the major breakthrough in the treatment of APL. Induction treatment with concurrent ATRA and chemotherapy leads to a rapid resolution of the characteristic life-threatening coagulopathy, high complete remission rates and excellent survival rates, compared to chemotherapy alone. However, treatment with ATRA is associated with the retinoic acid syndrome (RAS), which is a major toxicity and may lead to mortality. The role of cytarabine as a part of initial induction regimen remains unclear. After achievement of complete remission (CR), there is a definitive role of maintenance therapy with ATRA with or without low-dose chemotherapy. In relapsed patients, arsenic trioxide is considered the treatment of choice. However, the best postremission treatment for patients with second CR remains unknown. With the continued improvement in the field of stem cell transplantation, it may play an important role in the few patients with relapsed/refractory disease or those in second CR.

Topics: Adult; Animals; Antineoplastic Agents; Humans; Leukemia, Promyelocytic, Acute; Prognosis; Recurrence; Stem Cell Transplantation; Tretinoin

Acute promyelocytic leukemia (APL) has become a curable disease by all-trans retinoic acid (ATRA)-based induction therapy followed by two or three courses of consolidation chemotherapy. Currently around 90% of newly diagnosed patients with APL achieve complete remission (CR) and over 70% of patients are curable. To further increase the CR and cure rates, detection and diagnosis of this disease at its early stage is very important, hopefully before the appearance of APL-associated coagulopathy. In induction therapy, concomitant chemotherapy is indispensable, except for patients with low initial leukocyte counts. Prophylactic use of intrathecal methotrexate and cytarabine should be done, particularly for patients with hyperleukocytosis. If patients relapse hematologically or even molecularly, arsenic trioxide will be the treatment of choice under careful electrocardiogram monitoring. Am80, liposomal ATRA, gemtuzumab ozogamicin or ATRA in combination with cytotoxic drugs may be used at this stage or later. Allogeneic SCT will be the treatment of choice after patients of age <50 years have relapsed, provided that they have HLA-identical family donors or DNA-identical unrelated donors.

Topics: Antineoplastic Agents; Humans; Leukemia, Promyelocytic, Acute; Remission Induction; Sarcoma, Myeloid; Treatment Outcome; Tretinoin

The vitamin A derivative, all-trans retinoic acid (ATRA), induces differentiation of leukaemic promyelocytes in patients with acute promyelocytic leukaemia (APL). As a result, the majority of patients achieve complete remission either with ATRA alone or with combined ATRA and chemotherapy. The most important complication is the retinoic acid syndrome, which is usually successfully treated with the early administration of dexamethasone. Prospective randomized trials have shown that ATRA is better than conventional chemotherapy in newly diagnosed patients, that ATRA combined with chemotherapy confers an advantage with respect to relapse rate, compared to ATRA alone for induction followed by chemotherapy for consolidation, and that maintenance therapy with ATRA or ATRA plus low-dose chemotherapy is beneficial. The presence of adverse prognostic factors, including older age, presenting white blood cell count and platelet count, expression of CD56 and presence of mutations in the FLT3 gene, identify patients at risk for relapse for whom new strategies are needed.

Topics: Drug Resistance, Neoplasm; Humans; Leukemia, Promyelocytic, Acute; Prognosis; Remission Induction; Treatment Outcome; Tretinoin

Cure of acute promyelocytic leukaemia (APL) is now a reality for most patients through the use of combined all-trans retinoic acid (ATRA) and chemotherapy. The simultaneous administration of ATRA and anthracycline-based chemotherapy is currently considered the most appropriate induction therapy. However, no consensus has been reached on the consolidation strategy. Therapeutic efficacy apparently did not differ according to the number of cycles and types of drug combined with anthracyclines. Encouraging results have been reported recently using less-intensive chemotherapy with anthracyclines alone, leading to a significant reduction in treatment-related toxicity during the consolidation phase and a high degree of compliance. Some ongoing risk-adapted protocols are now exploring the potential synergistic effect of ATRA and chemotherapy given simultaneously in consolidation. Preliminary data suggest that higher molecular remission rates post-consolidation and improved outcome may be obtained through this strategy. Persistence or recurrence of molecular disease at the end of consolidation is strongly associated with impending relapse and poor prognosis, indicating the need for further aggressive therapy. As for maintenance therapy, once demonstrated, the advantage of using ATRA with or without low-dose methotrexate and 6-mercaptopurine has encouraged most groups to incorporate such treatment into their protocols for APL.

Topics: Antineoplastic Agents; Humans; Leukemia, Promyelocytic, Acute; Remission Induction; Secondary Prevention; Treatment Outcome; Tretinoin

All-trans retinoic acid (ATRA) is a potent differentiation agent that is effective therapy in acute promyelocytic leukaemia. Although ATRA is generally well tolerated, some patients develop retinoic acid syndrome. This syndrome is manifested by unexplained fever, weight gain, respiratory distress, interstitial pulmonary infiltrates, pleural and pericardial effusion, episodic hypotension, and acute renal failure. However, if identified early enough, effective therapy can be administered. This chapter discusses the clinical aspects and pathogenesis of retinoic acid syndrome.

Topics: Chemotaxis, Leukocyte; Dexamethasone; Humans; Leukemia, Promyelocytic, Acute; Leukemic Infiltration; Respiration Disorders; Syndrome; Tretinoin

Life-threatening bleeding, which remains a challenging complication of acute leukaemia, is particularly characteristic of the subtype, acute promyelocytic leukaemia (APL). The clinical picture and laboratory abnormalities are most compatible with the diagnosis of disseminated intravascular coagulation (DIC). Evidence for diffuse activation of the coagulation system, hyperfibrinolysis and systemic elaboration of non-specific protease activity can usually be demonstrated and occurs most commonly during induction chemotherapy. While both host- and tumour-associated mechanisms can be implicated in the pathogenesis of the coagulopathy, leukaemic cell properties appear to be the proximate cause of activation of the haemostatic mechanisms. In this chapter we summarize the current state of knowledge of the pathogenesis of the coagulopathy of APL and the therapeutic approaches that have proved most useful for the management of this complication. Special attention is devoted to the use of all-trans-retinoic acid (ATRA), which has revolutionized the treatment of APL and markedly ameliorated the APL-related coagulopathy.

Topics: Disseminated Intravascular Coagulation; Hemorrhagic Disorders; Heparin; Humans; Leukemia, Promyelocytic, Acute; Platelet Transfusion; Tretinoin

Bleeding is a common complication during initial induction treatment for acute promyelocytic leukemia (APL). Administration of all-trans-retinoic acid (ATRA), which is in routine use for APL in the past decade improves the bleeding tendency dramatically. Nevertheless, thrombotic events have still been reported in a small proportion of APL patients treated with ATRA. Here we describe a case of splenic infarction and life threatening thrombosis in a young patient with APL treated with ATRA. We review the relevant literature and discuss the pathophysiology, risk factors and treatment of this complication occurring during therapy, for APL.

Topics: Adult; Anticoagulants; Humans; Leukemia, Promyelocytic, Acute; Male; Pulmonary Embolism; Remission Induction; Splenic Infarction; Syndrome; Thrombophilia; Tretinoin; Venous Thrombosis

All-trans-retinoic acid (RA)-based differentiation therapy induces clinical remissions in acute promyelocytic leukemia (APL). This has propelled interest in elucidating the molecular mechanisms responsible for these remissions. The t(15;17) rearrangement results in the expression of the PML/RARalpha fusion transcript that is paradoxically linked to the etiology and clinical retinoid response in APL. PML/RARalpha expression blocks terminal myeloid differentiation in APL. Treatment with pharmacological RA dosages overcomes the dominant-negative effects of PML/RARalpha to activate transcription of retinoid target genes. This regulation is linked directly to RA effects in APL, including PML/RARalpha degradation and induction of differentiation. Identifying retinoid target genes is an important step in developing a mechanistic understanding of RA effects in APL. RA target genes have been uncovered through the use of molecular genetic approaches as well as unique cellular and transgenic APL models. Recent developments in the proteomic and functional genomic fields are providing useful tools for elucidating mechanisms of RA response or resistance in APL. These target genes represent potential therapeutic targets in APL and other retinoid-responsive diseases. Previous spotlights in Leukemia have highlighted the importance of cytokine effects and signal transduction crosstalk in retinoid response in APL and in normal hematopoiesis. This review builds on prior work by addressing the role of retinoid target genes in mediating retinoid response or resistance in APL.

Topics: Animals; Antineoplastic Agents; Cell Differentiation; Gene Expression Regulation, Neoplastic; Gene Targeting; Humans; Leukemia, Promyelocytic, Acute; Receptors, Retinoic Acid; Retinoic Acid Receptor alpha; Tretinoin

The WHO classification of adultory acute myeloid leukemia puts the main emphasis on prognosis, based mainly upon cytogenetic findings and gene-expression profiles. The complex prognostic assessment provides a more solid basis for early therapeutic stratification. This review focuses mainly on medical therapy. Induction phase is quite uniform, it consists of antracyclin and cytosin arabinosid. High-dose cytosin arabinosid is the predominant tool of postinduction therapy, especially in the favorable cytogenetic pattern cases. All-trans retinoic acid resulted in extremely good results in the promyelocytic cases, and this therapy seems to be advantageous in respect of acute DIC, too. Arsenic trioxide could be the drug of choice in relapsed promyelocytic leukemia. Some new agents are promising in refractory or relapsed cases, i.e. antibodies (Mylotarg) or farnesyltransferase inhibitors. The near future may bring about new therapeutic approaches, involving immunotherapy (dendritic cell vaccines) or gene-therapy as well.

Topics: Adult; Anthracyclines; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Cytarabine; Drug Resistance, Neoplasm; Gene Expression Profiling; Humans; Leukemia, Myeloid, Acute; Leukemia, Promyelocytic, Acute; Oligonucleotide Array Sequence Analysis; Oxides; Palliative Care; Prognosis; Remission Induction; Tretinoin

Acute promyelocytic leukemia (APL) is a form of acute myelogenous leukemia characterized by chromosomal alterations involving the retinoic acid receptor-alpha (RARalpha) gene that generate unique chimeric proteins (N-RARalpha) and by clinical responsiveness to all-trans-retinoic acid (ATRA) treatment. APL cells are notable for differentiation block and resistance to apoptosis. While increasing evidence suggests that N-RARalpha fusion proteins interfere with normal RARalpha transcription function at retinoic acid response elements (RAREs) resulting in inhibition of normal myeloid differentiation, the mechanism for apoptosis resistance remains unexplained. Recently, we and others have reported that APL-fusion proteins can augment STAT3 transcriptional activity. Constitutive STAT3 activation has been observed in a number of hematopoietic and non-hematopoietic malignancies where it contributes to apoptosis resistance. In this review, we summarize a series of recent observations concerning cross talk between the retinoic acid and STAT3 signaling pathways in APL cells. These findings support the hypothesis that apoptosis resistance in APL may be mediated through the effects of APL fusion proteins on STAT3 signaling and suggest that targeting of STAT3 may be a useful adjunctive treatment strategy in APL.

Topics: Animals; Apoptosis; DNA-Binding Proteins; Humans; Leukemia, Promyelocytic, Acute; Models, Biological; Protein Structure, Tertiary; Receptors, Retinoic Acid; Recombinant Fusion Proteins; Retinoic Acid Receptor alpha; Signal Transduction; STAT3 Transcription Factor; Trans-Activators; Tretinoin; Up-Regulation

Acute promyelocytic leukemia (APL) characterized by the translocation t(15;17) is uniquely sensitive to the differentiation-inducing effects of all-trans-retinoic acid (ATRA). All-trans-retinoic acid therapy induces complete clinical remissions (CRs) in most of patients with APL. However, chronic daily oral administration of ATRA results in accelerated metabolism of ATRA, leading to a progressive decline in plasma drug concentrations. These lower drug levels are associated with relapses and resistance to oral ATRA in patients with APL; thus the use of ATRA as a single agent is precluded. Liposomal ATRA (Lipo-ATRA) was designed to maintain high and stable plasma concentrations and to further improve the outcome of the APL disease by overcoming the development of ATRA resistance. Liposomal ATRA was shown to circumvent accelerated drug metabolism in the liver of rats in an animal model. In a phase I clinical study, intravenous (i.v.) administration of lipo-ATRA was shown to produce a significantly better pharmacokinetic profile than oral ATRA (non-liposomal) and to maintain higher and sustained plasma drug concentrations, with a similar side effects. More importantly, lipo-ATRA as a single agent induces PCR-negative molecular remissions in a high proportion of newly diagnosed patients with APL and maintain remissions up to 15-17 months or longer. In this review, we discuss the pharmacological features of lipo-ATRA and the molecular remissions induced by lipo-ATRA in newly diagnosed patients with APL or patients previously treated with ATRA or chemotherapy, and the possible impact of lipo-ATRA on the outcome of APL.

Topics: Antineoplastic Agents; Arsenic Trioxide; Arsenicals; Cell Differentiation; Clinical Trials as Topic; Drug Carriers; Histone Deacetylase Inhibitors; Humans; Leukemia, Promyelocytic, Acute; Liposomes; Oxides; Tretinoin

Acute myeloid leukemia (AML) is characterized by the arrest of differentiation leading to the accumulation of immature cells. This maturation arrest can be reversed by certain agents. Although differentiation therapy for patients with acute promyelocytic leukemia (APL) using all-trans retinoic acid (ATRA) has been established, the clinical response of AML patients other than those with APL to ATRA is limited. We must consider novel therapeutic drugs against other forms of AML for the development of a differentiation therapy for leukemia. Regulators that play an important role in the differentiation and development of plants or invertebrates may also affect the differentiation of human leukemia cells through a common signal transduction system, and might be clinically useful for treating AML. Cotylenin A, a plant growth regulator, is a potent and novel inducer of the monocytic differentiation of human myeloid leukemia cell lines and leukemia cells freshly isolated from AML patients.

Topics: Animals; Antigens, Differentiation; Antineoplastic Agents, Phytogenic; Cell Differentiation; Cholecalciferol; Diterpenes; Drug Screening Assays, Antitumor; Drug Synergism; HL-60 Cells; Humans; Leukemia, Myeloid; Leukemia, Promyelocytic, Acute; Mice; Neoplastic Stem Cells; Retinoids; Structure-Activity Relationship; Tretinoin; Tumor Cells, Cultured

Acute promyelocytic leukemia (APL) has become the most potentially curable subtype of acute myeloid leukemia (AML) in adults. With current treatment strategies that incorporate all-trans retinoic acid (ATRA), long-term disease-free survival and potential cure rates of 70% to 80% can be expected. Such progress reflects what can be accomplished with insights into the molecular pathogenesis of leukemia, identification of a molecular target, and rapid accrual to a series of clinical trials. The leukemic promyelocytes from patients with APL are uniquely susceptible to a variety of novel agents in addition to ATRA, including arsenic trioxide, and in preliminary studies, gemtuzumab ozogamicin, the immunoconjugate comprised of an anti-CD33 monoclonal antibody linked to the potent cytotoxic agent calicheamicin. Incorporation of such agents into the treatment of patients with high-risk disease may be an important future direction to pursue.

Topics: Antibiotics, Antineoplastic; Antineoplastic Agents; Arsenic Trioxide; Arsenicals; Daunorubicin; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Promyelocytic, Acute; Oxides; Remission Induction; Tretinoin

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Central Nervous System; Combined Modality Therapy; Cranial Irradiation; Cytarabine; Daunorubicin; Humans; Idarubicin; Leukemia, Promyelocytic, Acute; Leukemic Infiltration; Male; Methotrexate; Tretinoin

Primary resistance of PML-RARalpha-positive acute promyelocytic leukemia (APL) to the induction of clinical remission (CR) by all-trans retinoic acid (ATRA) is rare but markedly increases in frequency after > or =2 relapses from chemotherapy-induced CRs. Nevertheless, even in de novo cases, the primary response of ATRA-naive cases is variable by several measures, suggesting involvement of heterogeneous molecular elements. Secondary, acquired ATRA resistance occurs in most patients treated with ATRA alone and in many patients who relapse from combination ATRA chemotherapy regimens despite limited ATRA exposure. Although early studies suggested that an adaptive hypercatabolic response to pharmacological ATRA levels is the principal mechanism of ATRA resistance, recent studies suggest that molecular disturbances in APL cells have a predominant role, particularly if disease relapse occurs a few months after discontinuing ATRA therapy. This review summarizes the systemic and APL cellular elements that have been linked to clinical ATRA resistance with emphasis on identifying areas of deficient information and important topics for further investigation. Overall, the subject review strongly supports the hypothesis that, although APL is an infrequent and nearly cured disease, much can be gained by understanding the complex relationship of ATRA resistance to the progression and relapse of APL, which has important implications for other leukemias and malignancies.

Topics: Antineoplastic Agents; Drug Resistance, Neoplasm; Humans; Leukemia, Promyelocytic, Acute; Tretinoin

Topics: Animals; Apoptosis; Arsenic; Cell Cycle; Humans; Leukemia, Promyelocytic, Acute; Mutation; Neoplasm Proteins; Neutrophils; Nuclear Proteins; Promyelocytic Leukemia Protein; Receptors, Retinoic Acid; Transcription Factors; Tretinoin; Tumor Suppressor Proteins

To review the role of all-trans retinoic acid (ATRA) and arsenic trioxide in central nervous system (CNS) relapses of acute promyelocytic leukemia (APL).. A 69-year-old white man diagnosed with APL presented with bleeding diathesis. His molecular and cytogenetic studies were positive for promyelocytic leukemia-retinoic acid receptoralpha (PML-RARalpha) and t(15;17) transformation. Complete molecular and cytogenetic remission was achieved with ATRA, daunorubicin, and cytarabine. Within 6 months, the patient was readmitted for investigation of severe global headaches and an ataxic gait. His peripheral blood and cerebral spinal fluid were positive for PML-RARalpha fusion protein. Intrathecal chemotherapy and radiation, as well as ATRA, were the main treatment modalities provided. Molecular and cytogenetic remission was again obtained. Three months later, a second relapse occurred in the CNS and the peripheral blood.. APL is typically treated with anthacycline-based chemotherapy and ATRA. Approximately 85-95% of patients achieve complete remission (CR); however, the relapse rate has been reported to be about 30-40%. A thorough literature search (MEDLINE, EMBASE, CANCERLIT, 1966-January 2002) revealed only 54 cases of extramedullary disease, of which 35 involved the CNS.. The introduction of ATRA has improved patient survival dramatically. APL relapse, in general, has been in part attributable to repetitive or prolonged exposure to ATRA and the possibility of additional chromosomal changes, making the disease more refractory to treat. Given the evidence, one could argue that, with repeated ATRA treatment, CR duration may be shortened. However, limited data are available to guide the appropriate management of APL relapsed to the CNS with either ATRA, chemotherapy, or arsenic trioxide. In our opinion, treatment using arsenic trioxide is an unconventional option worthy of exploring.

Topics: Aged; Antineoplastic Agents; Central Nervous System Neoplasms; Fatal Outcome; Humans; Leukemia, Promyelocytic, Acute; Male; Recurrence; Treatment Outcome; Tretinoin

A 69-year-old woman developed microgranular acute promyelocytic leukemia (APL-M3) 10 months after receiving adjuvant cyclophosphamide, doxorubicin, and paclitaxel for breast cancer. Replicate bone marrow aspirate karyotypes contained a translocation between the long arms of chromosomes 15 and 17, but not at breakpoints typical for APL. Fluorescence in situ hybridization paints and RARalpha/PML cosmid probes verified that the breakpoints on chromosomes 15 and 17 were proximal to both the PML and RARalpha genes; t(15;17)(q13;12). Although the patient received induction chemotherapy and a several month trial of all-trans retinoic acid (ATRA), there was no clinical improvement or hematological remission. We suspect that this patient developed postchemotherapy secondary APL with an atypical t(15;17), which rendered her leukemic cells unresponsive to ATRA therapy.

Topics: Aged; Bone Marrow; Breast Neoplasms; Chromosome Breakage; Chromosomes, Human, Pair 15; Chromosomes, Human, Pair 17; Drug Resistance, Neoplasm; Female; Humans; In Situ Hybridization, Fluorescence; Leukemia, Promyelocytic, Acute; Receptors, Retinoic Acid; Retinoic Acid Receptor alpha; Translocation, Genetic; Tretinoin

Acute promyelocytic leukemia (APL) is now the most curable subtype of acute myeloid leukemia in adults. All-trans retinoic acid (ATRA), which induces differentiation of the leukemic cells into mature granulocytes, represents the important advance. The incorporation of ATRA in induction results in a high complete remission rate, leads to rapid resolution of the characteristic life-threatening coagulopathy, and, most importantly, decreases the relapse rate compared with treatment with chemotherapy alone. However, ATRA is associated with unique toxicities not observed with conventional cytotoxic chemotherapy. A number of clinical trials have been performed to define the optimal role of ATRA in the treatment of patients. The therapeutic strategies have rapidly evolved as a result of both single institution and large cooperative group trials. Arsenic trioxide and stem cell transplantation are effective treatments for patients with APL who relapse after or are refractory to ATRA-based therapy. As experience with ATRA and arsenic trioxide in patients with APL accumulates, a number of important questions arise that need to be addressed.

Topics: Animals; Antineoplastic Agents; Arsenic Trioxide; Arsenicals; Humans; Leukemia, Promyelocytic, Acute; Oxides; Practice Guidelines as Topic; Randomized Controlled Trials as Topic; Remission Induction; Tretinoin

The presence of the characteristic fusion transcript gene, promyelocytic leukemia-retinoic acid receptor-alpha (PML-RARalpha), provided hematologists with a rationale for the use of all-trans retinoic acid (ATRA) for differentiation therapy for acute promyelocytic leukemia (APL). Multiple studies have established that combination of ATRA and chemotherapy in newly diagnosed patients has increased the cure rate to 70% from 35% in patients treated with chemotherapy alone. However, still about 30% of the patients relapse and are often resistant to ATRA retreatment. Consequently, a number of novel agents that include several differentiation agents and monoclonal antibodies have been studied to provide improved outcomes for patients with APL who have relapsed. In particular, arsenic trioxide has shown great promise for the induction, consolidation, and maintenance of complete remission in relapsed patients with APL. The unique mechanisms of action by which arsenic trioxide exerts its effects are complementary to those of ATRA, potentially allowing for combination therapies with additive or even synergistic results. Within this context autologous or allogeneic bone marrow transplantations are also considered in second or subsequent relapse, especially after arsenic trioxide-induced complete remission in relapsing patients. Furthermore, molecular monitoring for the PML-RARalpha fusion protein permits prompt intervention for early molecular relapse of APL before clinical relapse, ultimately improving chances of prolonged remission.

Topics: Antineoplastic Agents; Arsenic Trioxide; Arsenicals; Bone Marrow Transplantation; Combined Modality Therapy; Humans; Leukemia, Promyelocytic, Acute; Neoplasm, Residual; Oxides; Recurrence; Tretinoin

Topics: Adult; Anti-Inflammatory Agents; Antineoplastic Agents; Dexamethasone; Female; Humans; Leukemia, Promyelocytic, Acute; Myositis; Sweet Syndrome; Tretinoin

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Cesarean Section; Cytarabine; Disseminated Intravascular Coagulation; Female; Gestational Age; Humans; Idarubicin; Infant, Newborn; Leukemia, Promyelocytic, Acute; Pregnancy; Pregnancy Complications, Hematologic; Pregnancy Complications, Neoplastic; Remission Induction; Risk; Tretinoin

Acute promyelocytic leukemia (APL), once considered the most devastating subtype of acute myeloid leukemia, is now the most treatable of all subtypes as a result of intensive research into its molecular pathogenesis. This research has led to a rational approach to treatment in which the use of the differentiating agent all-trans-retinoic acid (ATRA) has proven to be effective first-line treatment for inducing complete remission. Arsenic trioxide (ATO) is currently used to treat relapsed disease, further enhancing survival rates in a patient population for which limited salvage options exist. This review discusses the molecular mechanisms responsible for development of APL and the evolution of treatment options over the last three decades, including the major advances using ATRA and ATO in the last 12 years. The mechanism of action of ATO is also described in view of this agent's potential for broader therapeutic application in a variety of hematologic malignancies.

Topics: Antineoplastic Agents; Arsenic Trioxide; Arsenicals; Clinical Trials as Topic; Hematologic Neoplasms; Humans; Leukemia, Promyelocytic, Acute; Multiple Myeloma; Myelodysplastic Syndromes; Oxides; Recurrence; Remission Induction; Survival Analysis; Treatment Outcome; Tretinoin

Topics: Antineoplastic Agents; Arsenic Trioxide; Arsenicals; Humans; Leukemia, Promyelocytic, Acute; Oxides; Recurrence; Remission Induction; Tretinoin

Considerable progress has been made over the past decade in the understanding and management of acute promyelocytic leukemia (APL). At the laboratory level, molecular mechanisms underlying the arrest of differentiation that typically features in this malignancy, have been clarified and currently provide important models for addressing future investigation aimed at releasing the maturation block in other malignancies. In the clinic, advances in the management of APL have converted this rapidly fatal disease into the most frequently curable leukemia in adults. Use of retinoids in combinatorial protocols with anthracycline-based chemotherapy for front line treatment currently results in long-term survival and potential cure in at least 60% of newly diagnosed patients. Even after relapse, the disease is still curable in a high percentage of cases by various approaches including combinations of chemotherapy, retinoids, arsenic trioxide, stem cell transplantation and antibody-targeted chemotherapy. Genetic testing for identification of the disease-specific gene rearrangement and monitoring of residual disease have proved critical in establishing correct diagnosis and better evaluate the response to therapy at the molecular level. Current 'hot' issues for clinical investigation include: (i) better understanding and management of the severe coagulopathy present at diagnosis in most patients; (ii) the definition of risk categories to improve identification of patients at highest risk of relapse and (iii) the translation of successful differentiation therapy to other leukemia subsets.

Topics: Cytogenetic Analysis; Disease Management; Humans; Immunophenotyping; Leukemia, Promyelocytic, Acute; Treatment Outcome; Tretinoin

Acute progranulocytic leukemia (APL) is characterized by unique biologic and clinical features. Understanding of these unique features has resulted in dramatic improvements in therapy for patients with APL. Current therapy with all-trans-retinoic acid (ATRA) plus an anthracycline with or without cytosine-arabinoside has yielded complete response rates of 85% or greater and long-term disease-free survival rates of 70% or greater. Arsenic trioxide has also surfaced as an effective induction therapy for relapsed APL. Further progress in the care of patients with APL awaits better definition of optimal schedules for ATRA plus chemotherapy, the role of arsenic trioxide, the use of current molecular monitoring for minimal residual disease, optimal therapy for minimal residual disease, and improved methods to address complications of APL including early hemorrhagic deaths and ATRA toxicities.

Topics: Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Biomarkers, Tumor; Clinical Trials as Topic; Cytarabine; Humans; Leukemia, Promyelocytic, Acute; Neoplasm, Residual; Oxides; Prognosis; Salvage Therapy; Survival Analysis; Tretinoin

The most impressive clinical feature of acute promyelocytic leukemia (APL) at diagnosis is the presence in 80% to 90% of patients of a severe hemorrhagic syndrome. Recent data favor a fibrinolytic/proteolytic process rather than a disseminated intravascular coagulation as the mechanism mainly responsible for the hemorrhagic diathesis in APL. Morphologically, two main cytologic variants have been Identified: the classical hypergranular APL (M3), which represents the great majority of all APL, and the microgranular variant (M3v), which accounts for about 15% to 20% of all APL. A rare basophilic variant has also been described. With regard to prognosis, it has markedly changed from that of a rapidly fatal acute leukemia to that of a highly curable disease. This revolutionary progress was mainly due to the introduction during the 1990s of all-trans retinoic acid (ATRA) for the treatment of this disease. After the introduction of ATRA, in addition to clinical features such as hyperleukocytosis (white blood cell count > 10 x 10(9)/L) or thrombocytopenia (platelet count < 10 x 10(3)/L) at presentation, immunophenotype markers and polymerase chain reaction status for promyelocytic leukemia/retinoic acid receptor-alpha during follow-up also had an impact on prognosis.

Topics: Antineoplastic Agents; Humans; Leukemia, Promyelocytic, Acute; Prognosis; Tretinoin

All-trans retinoic acid (ATRA) can induce complete remission (CR) in most patients with acute promyelocytic leukemia (APL) through in vivo differentiation of APL-blasts. However, it cannot eliminate the leukemic clone and must be used in combination with anthracycline-based chemotherapy. Experience accumulated over the last 10 years has clearly shown that the combination of ATRA and chemotherapy gave better survival than chemotherapy alone in newly diagnosed APL because of fewer relapses and a slightly higher CR rate. It is also strongly suggested that maintenance treatment with ATRA, and possibly with low-dose chemotherapy, can further reduce the incidence of relapse. Overall, more than 90% of patients with newly diagnosed APL can achieved CR, and about 75% can be cured by the combination of ATRA and chemotherapy. ATRA syndrome remains the major side effect of ATRA treatment, which should be prevented by addition of chemotherapy and/or dexamethasone in case of increasing white blood cell (WBC) counts. Current issues in the treatment of newly diagnosed APL include the role of early addition of chemotherapy to ATRA, whether or not ara-C is useful in combination with anthracycline, and a possible interest of arsenic trioxide during consolidation in patients remaining at relatively high risk of relapse.

Topics: Antineoplastic Agents; Clinical Trials as Topic; Humans; Leukemia, Promyelocytic, Acute; Treatment Outcome; Tretinoin

In most cases of acute promyelocytic leukemia (APL), a fusion of the promyelocytic leukemia (PML) and the retinoic acid receptor-alpha (RARalpha) genes occurs, resulting in the expression of a PML-RARalpha chimeric protein. In approximately 1% of the cases of APL, variant chromosomal aberrations may be found fusing RARa with other genes. Four variant mutations have been described, and the t(11;17)(q21;q23) translocation generating a promyelocyte leukemia zinc finger (PLZF)-RARalpha fusion gene is the most common. PLZF-RARalpha-positive APL forms a clinically distinct group because unlike PML-RARalpha-positive leukemia, it does not respond to retinoic acid with terminal granulocytic differentiation of the cells, and remissions cannot be achieved with retinoids alone. At the molecular level, this has been explained by the retinoic acid-insensitive binding of corepressor proteins to the PLZF part of the fusion protein, leading to sustained repression of target genes that are important for cellular differentiation. Targeting of the PLZF-RARalpha-bound corepressor complexes using a combination of all-trans retinoic acid (ATRA) and deacetylase inhibitors has shown that the repression of target genes can be relieved, allowing differentiation of the cells. In addition, when a combination of retinoic acid and the hematopoietic growth factor granulocyte colony-stimulating factor (G-CSF) is applied, the cells may be forced to undergo terminal differentiation, both in vitro and in vivo. This suggests that signals from the activated G-CSF receptor may induce the release of corepressor proteins from PLZF. Together, these findings indicate that PLZF-RARalpha-positive leukemia is not completely resistant to differentiation induction if the proper costimuli are given.

Topics: Antineoplastic Agents; Cell Differentiation; Humans; Leukemia, Promyelocytic, Acute; Neoplasm Proteins; Oncogene Proteins, Fusion; Tretinoin

During recent years, reports have shown that biological responses of acute promyelocytic leukemia (APL) cells to retinoids are more complex than initially envisioned. PML-RARalpha chimeric protein disturbs various biological processes such as cell proliferation, differentiation, and apoptosis. The distinct biological programs that regulate these processes stem from specific transcriptional activation of distinct (but overlapping) sets of genes. These programs are sometimes mutually exclusive and depend on whether the signals are delivered by RAR or RXR agonists. Furthermore, evidence that retinoid nuclear signaling by retinoid, on its own, is not enough to trigger these cellular responses is rapidly accumulating. Indeed, work with NB4 cells show that the fate of APL cells treated by retinoid depends on complex signaling cross-talk. Elucidation of the sequence of events and cascades of transcriptional regulation necessary for APL cell maturation will be an additional tool with which to further improve therapy by retinoids. In this task, the classical techniques used to analyze gene expression have proved time consuming, and their yield has been limited. Global analyses of the APL cell transcriptome are needed. We review the technical approaches currently available (differential display, complementary DNA microarrays), to identify novel genes involved in the determination of cell fate.

Topics: Apoptosis; Cell Differentiation; Gene Expression Profiling; Humans; Leukemia, Promyelocytic, Acute; Oligonucleotide Array Sequence Analysis; Tretinoin

Over the past 20 years, there has been a marked increase in our knowledge of the molecular mechanisms of human hematological malignancies. The development of mechanism-based therapy is expected to extend the frontiers of chemotherapy. All-trans retinoic acid (ATRA) therapy for acute promyelocytic leukemia (APL), initially established as differentiation therapy, has been recognized to target PML-RAR alpha protein, an APL-specific chimeric transcriptional factor, and to modulate the function. Recently, encouraging results have emerged in the treatment of chronic myeloid leukemia with a tyrosine-kinase inhibitor. In addition to the oncoprotein-targeted therapy, the clinical effectiveness of humanized monoclonal antibodies to differentiation antigens has been recognized. Molecule-targeted therapy is reviewed herein.

Topics: Antibodies, Monoclonal; Humans; Leukemia, Promyelocytic, Acute; Protein-Tyrosine Kinases; Tretinoin

Acute promyelocytic leukemia (APL) is a disease associated with fusion oncoproteins invariably involving the retinoic acid receptor (Raralpha). Retinoic acid induces differentiation in APL cells and is successfully used in conjunction with chemotherapy to treat and cure a significant percentage of patients with APL. APL is also a model for disruption of normal retinoid-mediated transcription resulting in blocked differentiation. The study of the molecular mechanisms of APL oncogenesis has revealed novel interactions between fusion oncoproteins and transcriptional coregulators, already leading to new treatment strategies.

Topics: Animals; Drug Resistance, Neoplasm; Humans; Leukemia, Promyelocytic, Acute; Mice; Models, Animal; Neoplasm Proteins; Oncogene Proteins, Fusion; Receptors, Retinoic Acid; Tretinoin

We review improvements achieved in the treatment of acute promyelocytic leukaemia (APL) over the last ten years. The combination of all- trans retinoic acid (ATRA) and conventional anthracycline-ARA-C chemotherapy (CT) has clearly demonstrated its superiority over CT alone (in terms of relapse and survival) in newly diagnosed APL. Combination treatment probably also reduces the incidence of initial failures, and complete remission (CR) rates greater than 90% are now regularly reported in large multicentre trials. Some randomized studies strongly suggest than prolonged maintenance treatment (for 1 or 2 years) with ATRA and low dose CT, and possibly very early introduction of anthracycline CT during induction treatment (i.e. not after ATRA) may reduce the incidence of relapse. With those treatments, the risk of relapse appears to be only 10-15%, although it remains greater in patients who initially have white blood cell counts (often associated with variant M(3)morphology, short bcr(3)isoform etc.) and patients with residual disease detectable by RT-PCR at the end of consolidation courses.ATRA syndrome remains the major side effect of ATRA treatment. It occurs in 10-15% of patients and is currently fatal in at least 10% of them. Rapid onset of CT and/or high dose steroids should improve its outcome.A sizeable proportion of APL patients who relapse after ATRA and CT can be durably salvaged by the same treatment followed by allogeneic or autologous stem cell transplantation, provided the transplant (in the autologous setting) is RT-PCR negative. Arsenic trioxide can induce CR in most APL patients refractory to ATRA and CT. It acts mainly by inducing apoptosis of APL cells. A place for arsenic trioxide earlier in the treatment of APL must currently be more precisely defined. Another issue in the treatment of APL is reducing the toxicity of first line treatment without increasing the relapse risk. Preliminary findings suggest that this could be achieved by consolidation CT using an anthracycline alone, without cytarabine.

Topics: Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Humans; Leukemia, Promyelocytic, Acute; Prognosis; Treatment Outcome; Tretinoin

Recent discoveries have identified key molecular events in the pathogenesis of acute promyelocytic leukemia (APL), caused by chromosomal rearrangements of the transcription factor RAR (resulting in a fusion protein with the product of other cellular genes, such as PML). Oligomerization of RAR, through a self-association domain present in PML, imposes an altered interaction with transcriptional co-regulators (NCoR/SMRT). NCoR/SMRT are responsible for recruitment of histone deacetylases (HDACs), which is required for transcriptional repression of PML-RAR target genes, and for the transforming potential of the fusion protein. Oligomerization and altered recruitment of HDACs are also responsible for transformation by the fusion protein AML1-ETO, extending these mechanisms to other forms of acute myeloid leukemias (AMLs) and suggesting that HDAC is a common target for myeloid leukemias. Strikingly, AML1-ETO expression blocks retinoic acid (RA) signaling in hematopoietic cells, suggesting that interference with the RA pathway (genetically altered in APL) by HDAC recruitment may be a common theme in AMLs. Treatment of APLs with RA, and of other AMLs with RA plus HDAC inhibitors (HDACi), results in myeloid differentiation. Thus, activation of the RA signaling pathway and inhibition of HDAC activity might represent a general strategy for the differentiation treatment of myeloid leukemias.

Topics: Acute Disease; Animals; Cell Differentiation; Enzyme Inhibitors; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Leukemia, Myeloid; Leukemia, Promyelocytic, Acute; Tretinoin

In the post genome era it will soon be possible to associate a specific tumor type with a specific gene expression profile and to define each molecular lesion characteristic of any given cancer. It is intuitive that a successful therapeutic strategy for cancer should aim at blocking the aberrant biochemical activity triggered by the oncogene or the lack of tumor suppressor gene activity that ultimately leads to full-blown neoplastic transformation. However, an attractive alternative approach entails the blockade of the transcriptional consequences of such oncogenic activities irrespective of their original biochemical nature, thus antagonizing the key transcriptional events underlying cancer pathogenesis in any specific neoplastic cellular population. This approach is now rendered possible by major advances along several lines of investigation: (i) the possibility of analysing gene expression through high throughput methods; (ii) a more detailed knowledge of the regulatory regions and of the transcription factors that control gene expression also facilitated in the future by a comprehensive whole genome comparative analysis of these regulatory sequences; (iii) the ability of modulating gene expression at the single gene level through various approaches both pharmacological and biochemical; (iv) the opportunity of directly antagonizing the aberrant activities of oncogenic transcription factors through a detailed knowledge of their abnormal transcriptional function; (v) the possibility of validating, in vivo, in animal models the relevance for neoplastic transformation of specific transcriptional events as well as of testing the efficacy of 'transcription therapy' in faithful animal models of human cancer. Here, we will review the facts, the existing applications and the hypothesis underlying such therapeutic modality for cancer therapy.

Topics: Animals; Humans; Leukemia, Promyelocytic, Acute; Neoplasms; Transcription, Genetic; Tretinoin

Acute promyelocytic leukemia (APL) is characterized by a specific gene rearrangement and the generation of the PML-RARalpha fusion transcript which results from a translocation between chromosomes 15 and 17. Targeted therapy with all-trans retinoic acid (ATRA) and anthracycline-based chemotherapy results in an apparent cure in 70-80% of patients. Both allogeneic (ALLO) and autologous (AUTO) hematopoietic stem cell transplantation (HSCT) are effective in acute myeloid leukemia (AML), but their role in APL is not clear given the excellent outcome with ATRA and chemotherapy. Several retrospective studies have analyzed the outcome of patients undergoing AUTO or ALLO-HSCT in first (CR1) or second (CR2) complete remission. Most of these studies have shown significant transplant-related mortality (TRM) with ALLO-HSCT, but a reduction in relapse rate compared with AUTO-HSCT. The high TRM with ALLO-HSCT and the excellent outcome with ATRA and chemotherapy do not justify recommending this procedure for the majority of patients in CR1. The role of AUTO-HSCT in CR1 also is unclear. A small subset of patients at high risk of relapse, possibly identifiable by a high white blood cell count at presentation may benefit from HSCT. Most patients with relapsed disease achieve CR2 with ATRA, arsenic trioxide, or combination therapy. However, it is not known if these responses are sustained or if consolidation with HSCT has a place in this setting. The outcome of AUTO-HSCT in CR2 using stem cells that are negative for PML-RARalpha is excellent. It is unclear whether ALLO-HSCT from an HLA-identical sibling is superior to AUTO-HSCT with PML-RARalpha-negative cells in CR2 since the former would be associated with graft-versus-leukemia effects and the latter with lower TRM. Alternatively, arsenic trioxide or re-treatment with ATRA, followed by intensive chemotherapy may also be effective. A randomized prospective clinical trial, or a retrospective analysis of the available data would be useful in answering this critical question.

Topics: Bone Marrow Transplantation; Humans; Leukemia, Promyelocytic, Acute; Recurrence; Remission Induction; Survival Analysis; Tretinoin

Life-threatening bleeding is frequent in acute leukemias, particularly in acute promyelocytic leukemia (APL), a distinct subtype of acute myelogenous leukemia, characterized by the balanced reciprocal translocation between chromosomes 15 and 17. Laboratory assessments show profound hemostatic imbalance compatible with the clinical picture of disseminated intravascular coagulation. Activation of the coagulation system, hyperfibrinolysis and nonspecific proteases activity can be observed in this condition. An important pathogenetic role is attributed to the leukemic cell properties for activating hemostatic mechanisms. This review will summarize what is currently known about the coagulopathy of APL, the principal pathogenetic mechanisms, and the therapeutic tools for the management of this complication. Special attention will be devoted to the new therapy with all-trans retinoic acid, which has completely changed the natural history of APL and APL-related coagulopathy.

Topics: Disseminated Intravascular Coagulation; Fibrinolysis; Hemostasis; Hemostatic Disorders; Humans; Leukemia, Promyelocytic, Acute; Tretinoin

Translocations involving a variety of fusion partners, such as promyelocytic leukemia gene, promyelocytic leukemia zinc finger, nucleophosmin, nuclear matrix protein, and signal transducer and activator of transcription protein 5B, with the retinoic acid receptor alpha gene are commonly associated with development of acute promyelocytic leukemia. Through the development of transgenic mouse models, some retinoic acid receptor alpha translocation fusion proteins have been shown to be capable of initiating acute promyelocytic leukemia development, and dictate the leukemias' responsiveness to retinoic acid. Transgenic mouse models also have identified the influence of reciprocal translocation fusion proteins on acute promyelocytic leukemia development, and have demonstrated that additional mutations can contribute to the development of acute promyelocytic leukemia. In this review, the authors summarize current mouse models of acute promyelocytic leukemia and describe current knowledge about additional genetic alterations that occur during development of acute promyelocytic leukemia in the mouse.

Topics: Animals; Antineoplastic Agents; Arsenic; Chromosome Deletion; Disease Models, Animal; Leukemia, Promyelocytic, Acute; Mice; Models, Biological; Mutation; Neoplasm Proteins; Oncogene Proteins, Fusion; Tretinoin

Acute promyelocytic leukemia (APL) is characterized by the expansion of malignant myeloid cells blocked at the promyelocytic stage of hemopoietic development and is invariably associated with reciprocal chromosomal translocations involving the retinoic acid receptor alpha (RARalpha) gene on chromosome 17. RARalpha variably fuses to PML, PLZF, NPM, NuMA, and Stat5B genes (X genes/proteins). These translocations are balanced and reciprocal, thus leading to the generation of X-RARalpha and RARalpha-X fusion genes of which the products coexist in the APL blast. The invariable involvement in these translocations of RARalpha, a prototypical transcription factor, makes APL a compelling example of aberrant transcriptional mechanisms in the etiopathogenesis of cancer. This paper focuses on the recent progress in defining the molecular mechanisms underlying APL pathogenesis and addresses how this new understanding has allowed the proposal and development of novel therapeutic strategies with compounds such as histone deacetylase inhibitors and inorganic arsenicals such as As2O3 which are currently being tested in murine leukemia models as well as in human APL patients. In particular, the crucial role played by the aberrant transcriptional activities of X-RARalpha and RARalpha-X fusion proteins in APL pathogenesis is discussed by reviewing the relevant therapeutic implications resulting from this analysis.

Topics: Animals; Antineoplastic Agents; Arsenic Trioxide; Arsenicals; Histone Deacetylase Inhibitors; Humans; Leukemia, Promyelocytic, Acute; Mice; Neoplasm Proteins; Oncogene Proteins, Fusion; Oxides; Receptors, Retinoic Acid; Retinoic Acid Receptor alpha; Transcription, Genetic; Tretinoin

Topics: Antineoplastic Agents; Apoptosis; Dose-Response Relationship, Drug; Drug Therapy; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Promyelocytic, Acute; Prognosis; Reverse Transcriptase Polymerase Chain Reaction; Translocation, Genetic; Tretinoin

Here the relationship between all-trans retinoic acid (ATRA)-resistance and P-glycoprotein (P-gp)-associated multidrug resistance (MDR) is discussed in acute promyelocytic leukemia (APL). First, the remission rates of ATRA therapy are similar in relapsed/refractory APL to the preceding chemotherapy given and in newly diagnosed APL. Second, MDR1 cDNA-transduced NB4 (NB4/MDR) cells accumulate less Rhodamine-123 (Rh123) than NB4 cells, but there is no difference in the intracellular ATRA concentration between them. PSC833 or MS209. MDR modifiers, increases the intracellular accumulation of Rh123 in NB4/MDR and APL cells expressing P-gp, but not of ATRA. Third, the expression of CD11b, the NBT reduction activity, the proportion of apoptotic cells and the morphology are not different between NB4/MDR and NB4 cells, and between APL cells expressing P-gp and not. APL cells express little P-gp, and mainly express CD33 but no CD34. Despite previous reports that ATRA-resistant APL cells express more P-gp than ATRA-sensitive ones, P-gp and ATRA-resistance seems to exist independently.

Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Cell Differentiation; Drug Resistance, Multiple; Humans; Leukemia, Promyelocytic, Acute; Multicenter Studies as Topic; Recurrence; Tretinoin; Tumor Cells, Cultured

Topics: Antineoplastic Agents; Arsenic Trioxide; Arsenicals; Cell Differentiation; Cell Nucleus; Cellular Senescence; Humans; Inclusion Bodies; Leukemia, Promyelocytic, Acute; Multigene Family; Neoplasm Proteins; Oncogene Proteins, Fusion; Oxides; Receptors, Retinoic Acid; Retinoic Acid Receptor alpha; Tretinoin

All trans retinoic acid (ATRA) is able to induce complete remission (CR) in almost all patients with acute promyelocytic leukemia (APL) through in vivo differentiation of APL blasts. However, it cannot eliminate the leukemic clone and to be effective must be used in combination with anthracycline-based chemotherapy. Experience accumulated over the last 10 years has clearly shown that the combination of ATRA and chemotherapy gives better survival in newly diagnosed APL than chemotherapy alone because of fewer relapses and a higher CR rate experienced by these patients. It is also strongly suggested that maintenance treatment with ATRA, and possibly in combination with low-dose chemotherapy, can further reduce the incidence of relapse. Overall, more than 90% of patients with newly diagnosed APL can achieve CR and about 75% can be cured by the combination of ATRA and chemotherapy.

Topics: Age Factors; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Cell Differentiation; Humans; Immunophenotyping; Karyotyping; Leukemia, Promyelocytic, Acute; Prognosis; Randomized Controlled Trials as Topic; Remission Induction; Secondary Prevention; Survival Rate; Tretinoin

Acute promyelocytic leukemia (APL) is an interesting model in cancer research, because it can respond to the differentiation/apoptosis induction therapy using all-trans retinoic acid (ATRA) and arsenic trioxide (As(2)O(3)). Over the past 5 years, it has been well demonstrated that As(2)O(3) induces a high complete remission (CR) rate in both primary and relapsed APL patients (around 85 to 90%). The side effects are mild to moderate in relapsed patients, while severe hepatic lesions have been found in some primary cases. After CR obtained in relapsed patients, chemotherapy in combination with As(2)O(3) as post-remission therapy has given better survival than those treated with As(2)O(3) alone. The effect of As(2)O(3) has been shown to be related to the expression of APL-specific PML-RARalpha oncoprotein, and there is a synergistic effect between As(2)O(3) and ATRA in an APL mouse model. Cell biology studies have revealed that As(2)O(3) exerts dose-dependent dual effects on APL cells. Apoptosis is evident when cells are treated with 0.5 approximately 2.0 microM of As(2)O(3) while partial differentiation is observed using low concentrations (0.1 approximately 0.5 microM) of the drug. The apoptosis-inducing effect is associated with the collapse of mitochondrial transmembrane potentials in a thiol-dependent manner, whereas the mechanisms underlying APL cell differentiation induced by low dose arsenic remain to be explored. Interestingly, As(2)O(3) over a wide range of concentration (0.1 approximately 2.0 microM) induces degradation of a key leukemogenic protein, PML-RARalpha, as well as the wild-type PML, thus setting up a good example of targeting therapy for human cancers.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Arsenic Trioxide; Arsenicals; Cell Differentiation; Disease Models, Animal; Drug Synergism; Humans; Leukemia, Promyelocytic, Acute; Mice; Mitochondria; Neoplasm Proteins; Nuclear Proteins; Oncogene Proteins, Fusion; Oxides; Promyelocytic Leukemia Protein; Remission Induction; Survival Rate; Transcription Factors; Tretinoin; Tumor Suppressor Proteins

In recent years, discovery of the in vitro and in vivo differentiation of APL blasts by all-trans retinoic acid (ATRA) has modified the therapeutic approach of APL and lead to important advances in understanding the biology of APL. Since it became apparent that differentiation therapy of APL with ATRA was indeed a true model of targetted therapy, evidencing the molecular targets of retinoic acid efficacy became crucial. These molecular targets are closely related to the biological features of APL cells, some of which are well-known and have contributed to the morphological and cytogenetic definition of the leukemia, others have just been defined or re-discovered in the light of a better understanding of molecular controls of cell growth and differentiation. The aims of characterizing the biological features of APL cells should allow a better management of APL therapy and the identification of potential markers for differentiation therapies in other leukemias or solid tumors.

Topics: Biomarkers, Tumor; Cell Differentiation; Cell Division; Disease Management; Granulocytes; Hematopoiesis; Humans; Leukemia, Promyelocytic, Acute; Signal Transduction; Tretinoin

Acute promyelocytic leukemia (APL) has been recognized as a distinct clinical entity for over 40 years. Although relatively rare among hematopoietic malignancies (approximately 10% of AML cases), this disease has attracted a particularly good share of attention by becoming the first human cancer in which all-trans-retinoic acid (ATRA), a physiologically active derivative of vitamin A, was able to induce complete remission (CR). ATRA induced remission is not associated with rapid cell death, as in the case of conventional chemotherapy, but with a restoration of the 'normal' granulocytic differentiation pathway. With this remarkable medical success story APL has overnight become a paradigm for the differentiation therapy of cancer. A few years later, excitement with APL was further enhanced by the discovery that a cytogenetic marker for this disease, the t(15:17) reciprocal chromosomal translocation, involves a fusion between the retinoic acid receptor alpha (RARalpha) gene and a previously unknown locus named promyelocytic leukemia (PML). Consequence of this gene rearrangement is expression of the PML-RARalpha chimeric oncoprotein, which is responsible for the cellular transformation as well as ATRA response that is observed in APL. Since this initial discovery, a number of different translocation partner genes of RARalpha have been reported in rarer cases of APL, strongly suggesting that disruption of RARalpha underlies its pathogenesis. This article reviews various rearrangements of the RARalpha gene that have so far been described in literature, functions of the proteins encoded by the different RARalpha partner loci, and implications that these may have for the molecular pathogenesis of APL.

Topics: Antigens, Nuclear; Cell Cycle Proteins; DNA-Binding Proteins; Humans; Leukemia, Promyelocytic, Acute; Milk Proteins; Neoplasm Proteins; Nuclear Matrix-Associated Proteins; Nuclear Proteins; Nucleophosmin; Oncogene Proteins, Fusion; Receptors, Retinoic Acid; Retinoic Acid Receptor alpha; STAT5 Transcription Factor; Trans-Activators; Translocation, Genetic; Tretinoin

Although there is evidence to suggest that PML/RARalpha expression is not the sole genetic event required for the development of acute promyelocytic leukemia (APL), there is little doubt that the fusion protein plays a central role in the initiation of leukemogenesis. The two therapeutic agents, retinoic acid and arsenic, that induce clinical remissions in APL, both target the oncogenic fusion protein, representing the first example of oncogene-directed cancer therapy. This review focuses on the molecular mechanisms accounting for PML/RARalpha degradation. Each drug targets a specific moiety of the fusion protein (RARalpha for retinoic acid, PML for arsenic) to the proteasome. Moreover, both activate a common caspase-dependent cleavage in the PML part of the fusion protein. Specific molecular determinants (the AF2 transactivator domain of RARalpha for retinoic acid and the K160 SUMO-binding site in PML for arsenic) are respectively implicated in RA- or arsenic-triggered catabolism. The respective roles of PML/RARalpha activation versus its catabolism are discussed with respect to differentiation or apoptosis induction in the context of single or dual therapies.

Topics: Animals; Arsenic Trioxide; Arsenicals; Binding Sites; Caspases; Cell Differentiation; Cysteine Endopeptidases; Humans; Leukemia, Promyelocytic, Acute; Multienzyme Complexes; Neoplasm Proteins; Oncogene Proteins, Fusion; Oxides; Proteasome Endopeptidase Complex; Protein Structure, Tertiary; Remission Induction; Tretinoin

In the past two decades, there has been a tremendous increase in our understanding of the molecular mechanism of human leukemias. Leukemias are now recognized as a deregulated state of cell proliferation, differentiation and apoptosis, which is induced by gene alterations, including chromosomal translocations. Many of the mechanisms are potentially exploited as new targets for drug development. All-trans retinoic acid therapy for acute promyelocytic leukemia, which was initially developed as a differentiation therapy in an experienced-based manner, is currently known to be the first successful oncoprotein-directed therapy. Basic and clinical research into ATRA-resistance provides new directions for acute myeloid leukemia therapy. Anti-leukemia therapy will continue to lead the field of chemotherapy in the coming decades.

Topics: Antineoplastic Agents; Drug Resistance; Humans; Leukemia; Leukemia, Promyelocytic, Acute; Recombinant Fusion Proteins; Transcription Factors; Translocation, Genetic; Tretinoin

In the last decade our understanding of acute promyelocytic leukemia (APL) has advanced tremendously. The recognition of all-trans retinoic acid (ATRA) as a powerful therapeutic agent paralleled the cloning of the t(15;17) breakpoint. RtPCR for the PML-RARA hybrid mRNA has become the hallmark of molecular diagnosis and molecular monitoring in APL. Current techniques are useful in predicting complete remission and a possible cure in many patients who repeatedly test negative by PCR. Standardizing techniques and improving the sensitivity of the assay are important. Doing this in a way so that clinically relevant minimal residual disease can be distinguished from "indolent disease" remains among the future challenges in APL.

Topics: Bone Marrow Transplantation; Humans; Interferons; Leukemia, Promyelocytic, Acute; Neoplasm, Residual; Polymerase Chain Reaction; Translocation, Genetic; Tretinoin

Topics: Animals; Artificial Gene Fusion; Bone Marrow Cells; Cell Differentiation; Humans; Leukemia, Promyelocytic, Acute; Receptors, Retinoic Acid; Transcription, Genetic; Translocation, Genetic; Tretinoin

Topics: Animals; Arsenic Trioxide; Arsenicals; Cell Differentiation; Histone Deacetylase Inhibitors; Leukemia, Promyelocytic, Acute; Oxides; Remission Induction; Transcription, Genetic; Tretinoin

This review briefly summarizes literature noteworthy in the field of adult acute leukemia published during 1999. The relationship between specific cytogenetic abnormalities and response to treatment was explored within a clinical framework. In particular, detailed analyses of the abnormalities seen in acute promyelocytic leukemia were examined. Two case reports of special interest were published: one shed light on the role of histone deacetylase inhibitors in combination with all-trans retinoic acid, and the other, on the role of granulocyte colony-stimulating factor in this disease. The clinical activity of arsenic was also reported and its mechanism of action explored. In acute lymphoblastic leukemia, attention was focused on occult translocations, and the importance of minimal residual disease was again emphasized. Lastly, results of early clinical trials using an anti-CD19 antibody were reported, with provocative results.

Topics: Acute Disease; Adolescent; Adult; Antibodies, Monoclonal; Antigens, CD19; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Child; Chromosome Aberrations; Clinical Trials as Topic; Combined Modality Therapy; DNA, Neoplasm; Drug Design; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Humans; Infant; Leukemia; Leukemia, Myeloid; Leukemia, Promyelocytic, Acute; Middle Aged; Multicenter Studies as Topic; Neoplasm Proteins; Neoplasm, Residual; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; Randomized Controlled Trials as Topic; Treatment Outcome; Tretinoin

Extramedullary disease (EMD) is a rare clinical event in acute promyelocytic leukemia (APL). Although the skin is involved in half of the reported EMD cases, the occurrence of cutaneous promyelocytic sarcoma (PS) has been described very rarely. We report here three cases of PS which have the peculiarity of appearing at sites of punctures for arterial and venous blood and marrow samples (sternal manubrium, antecubital fossa, wrist over the radial artery pulse, catheter insertion scar). At presentation, all patients had hyperleukocytosis and a morphologic diagnosis of microgranular acute promyelocytic leukemia variant confirmed at the genetic level by demonstration of the specific chromosomal translocation t(15;17). A BCR3 type PML/RARa transcript was documented in the two patients for whom diagnostic RT-PCR was available. Patients had morphologic bone marrow remission at the time the PS appeared. A predilection for the development of cutaneous PS at sites of previous vascular damage has been noted, but the pathogenesis remains largely unknown. A potential role for all-trans retinoic acid has been advocated, although one of the three patients in our series had received no ATRA. A review of the literature revealed six similar cases and hyperleukocytosis at diagnosis was a consistent finding in all of them. A careful physical examination of these particular sites in the follow-up of patients at risk, as well as cutaneous biopsy and laboratory examination of suspected lesions are strongly recommended.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Biopsy, Needle; Catheterization, Central Venous; Endothelium, Vascular; Female; Granulocytes; Humans; Leukemia, Promyelocytic, Acute; Leukemic Infiltration; Leukocytosis; Male; Middle Aged; Punctures; Sarcoma; Skin Neoplasms; Tretinoin

Acute promyelocytic leukemia (APL) is characterized by a block in differentiation of hematopoietic cells at the promyelocytic stage of development. This disease is uniquely sensitive to treatment with pharmacological doses of all-trans retinoic acid (ATRA), and the combination of ATRA with chemotherapy has improved the durable disease-free survival in these patients to up to 80%. APL is characterized by chromosomal translocations that lead to the fusion of the retinoic acid receptor-alpha (RARalpha) to various partner genes. RARalpha functions as a ligand-inducible transcription factor and the aberrant RARalpha fusion proteins contribute to leukemic transformation by dominant inhibition of the expression of target genes that are important for cellular differentiation. This may at least in part be explained by an abnormally strong interaction with corepressor proteins leading to deacetylation of DNA and silencing of target genes. Most RARalpha fusion proteins can still be induced to transactivate genes, but only at very high doses of ligand, explaining why pharmacological doses of ATRA are necessary to obtain a therapeutic effect in these patients.

Topics: Hematopoiesis; Humans; Leukemia, Promyelocytic, Acute; Mutation; Receptors, Retinoic Acid; Recombinant Fusion Proteins; Retinoic Acid Receptor alpha; Transcriptional Activation; Tretinoin

Acute promyelocytic leukemia (APL) cells carry a mutated gene that is the result of a translocation in which the retinoic acid receptor alpha (RAR alpha) gene is fused to the promyelocytic leukemia (PML) gene, coding for a fusion protein, PML/RAR alpha. Its presence is the single event that causes APL in transgenic mice. All-trans-retinoic acid (atRA) induces the proteolytic degradation of PML/RAR alpha by ubiquitination and proteolysis. RAR alpha itself is also degraded by atRA treatment, a process representing a possible feedback mechanism to turn off RAR alpha's stimulation of transcription.

Topics: Antineoplastic Agents; Artificial Gene Fusion; Humans; Leukemia, Promyelocytic, Acute; Neoplasm Proteins; Nuclear Proteins; Promyelocytic Leukemia Protein; Receptors, Retinoic Acid; Transcription Factors; Translocation, Genetic; Tretinoin; Tumor Suppressor Proteins; Vitamin A

Retinoic acids (RA) play a key role in myeloid differentiation through their agonistic nuclear receptors (RAR alpha/RXR) to modulate the expression of target genes. In acute promyelocytic leukemia (APL) cells with rearrangement of retinoic acid receptor a (RAR alpha) (including: PML-RAR alpha, PLZF-RAR alpha, NPM-RAR alpha, NuMA- RAR alpha or STAT5b-RAR alpha) as a result of chromosomal translocations, the RA signal pathway is disrupted and myeloid differentiation is arrested at the promyelocytic stage. Pharmacologic dosage of all-trans retinoic acid (ATRA) directly modulates PML-RAR alpha and its interaction with the nuclear receptor co-repressor complex, which restores the wild-type RAR alpha/RXR regulatory pathway and induces the transcriptional expression of downstream genes. Analysing gene expression profiles in APL cells before and after ATRA treatment represents a useful approach to identify genes whose functions are involved in this new cancer treatment. A chronologically well coordinated modulation of ATRA-regulated genes has thus been revealed which seems to constitute a balanced functional network underlying decreased cellular proliferation, initiation and progression of maturation, and maintenance of cell survival before terminal differentiation.

Topics: Antineoplastic Agents; Cell Differentiation; Gene Expression Regulation, Leukemic; HL-60 Cells; Humans; Leukemia, Promyelocytic, Acute; Neoplasm Proteins; Nuclear Proteins; Nuclear Receptor Co-Repressor 1; Oncogene Proteins, Fusion; Receptors, Retinoic Acid; Repressor Proteins; Retinoic Acid Receptor alpha; Retinoid X Receptors; Signal Transduction; Transcription Factors; Transcription, Genetic; Translocation, Genetic; Tretinoin; Tumor Cells, Cultured

Transcription factors are proteins that regulate gene transcription and expression. In many cases of acute leukaemia chromosomal aberrations are translocations of transcription factors which change their expression and induce the leukaemic phenotype. These abnormal transcription factors are tumour-specific and can be targets for novel treatments approaches. Acute promyelocytic leukaemia (APL) is a distinct and unique subtype of acute myeloid leukaemia (AML) characterised by a reciprocal translocation between chromosomes 15 and 17 t(15q22;17q21). The breakpoints of chromosome 15 and 17 are in the PML and RARalpha genes, respectively, forming the fusion PML-RARalpha gene expressed exclusively and universally in APL. The normal RARalpha is an all-trans retinoic acid- (ATRA-)dependent transcription factor involved in the normal differentiation of myeloid cells. The aberrant fusion PML-RARalpha protein remains sensitive to ATRA and underlies the pathogenesis of the APL. ATRA modulation of gene transcription mediated by PML-RARalpha results in a major clinical response. Almost all newly diagnosed APL cases can be induced into complete remission with ATRA with or without chemotherapy by in vivo differentiation of the APL cells. Randomised clinical trials have shown that the most significant effect of ATRA is an additive or synergistic activity with chemotherapy to improve the long-term outcome of the disease. On the other hand, ATRA with or without induction chemotherapy did not increase the complete remission rate compared to chemotherapy alone. In addition, the relapse rate was significantly lower for patients randomised to induction with concurrent ATRA/chemotherapy than with ATRA followed by chemotherapy. Chemotherapy and/or ATRA maintenance may further improve the long-term outcome compared to no maintenance. PML-RARalpha fusion transcripts can be assayed by RT-PCR to identify PCR positive cells during remission, which are highly predictable of a subsequent haematological relapse. The goal of therapy has been modified to induce a molecular remission with a negative PCR to the PML-RARalpha transcript. This is the first example of an effective response to treatment with a ligand binding to a mutated form of its natural transcription factor. The transcription factor mutation, caused by translocation to another gene, underlies the pathogenesis of the disease.

Topics: Antineoplastic Agents; Clinical Trials as Topic; Gene Expression; Gene Rearrangement; Humans; Leukemia, Promyelocytic, Acute; Neoplasm Proteins; Nuclear Proteins; Oncogene Proteins, Fusion; Promyelocytic Leukemia Protein; Receptors, Retinoic Acid; Transcription Factors; Tretinoin; Tumor Suppressor Proteins

To identify the chromosomal translocation common in M3 and discuss its diagnostic use to: Compare acute leukemia with chronic leukemia and other forms of cancer. Describe the molecular defect including the fusion gene and fusion protein produced from the translocation. Discuss the proposed mechanism of leukemogenesis in M3. Discuss the proposed mechanism of differentiation induction stimulated by ATRA therapy. Present the future direction of this and other forms of therapy.. Current literature.. Acute promyelocytic leukemia (AML-M3) is a form of acute leukemia that presents with a less dramatic leukocytosis, anemia, and thrombocytopenia than other acute leukemias. However, AML-M3 has a lower first remission rate and a higher morbidity and mortality rate than most of the other acute leukemias when treated with conventional chemotherapy. AML-M3 frequently stimulates a serious concomitant coagulation disorder, disseminated intravascular coagulation, which is a major contributor to the high mortality rate. This and other devastating sequela of M3 have prompted clinicians and investigators to develop methods of improving diagnosis and therapy. In 1977 the method of diagnosis confirmation was improved by the identification of a consistent chromosomal translocation involving the long arms of chromosomes 15 and 17. Identification of the specific molecular lesion that produced the t(15;17) translocation occurred in 1990 and was shown to involve the retinoic acid receptor alpha gene (RAR alpha). Because the RAR alpha gene is mutated in all AML-M3 patients studied so far and because it is often the only mutation identified, several proposed mechanisms of leukemogenesis have evolved. From these discoveries a novel approach to cancer treatment focusing on differentiation therapy instead of traditional chemotherapy emerged. All-trans retinoic acid (ATRA) has been shown to stimulate differentiation of promyelocytes from the malignant clone and has become an important element in the treatment of patients with AML-M3.. Since the discovery of the t(15;17) translocation, the identification of the fusion gene containing the retinoic acid receptor alpha, and the success of ATRA as a form of differentiation therapy, the diagnosis and treatment of AML-M3 has dramatically improved. In addition, AML-M3 has become a model system used to study the mechanisms that produce uncontrolled growth and lack of differentiation in leukemic cells (leukemogenesis) and the mechanisms of therapeutic reversal of this block in differentiation (differentiation therapy).

Topics: Antineoplastic Agents; Chromosomes, Human, Pair 15; Chromosomes, Human, Pair 17; Humans; Leukemia, Promyelocytic, Acute; Neoplasm Proteins; Oncogene Proteins, Fusion; Translocation, Genetic; Tretinoin

The objectives of this review paper are to: Compare acute leukemia with chronic leukemia and other forms of cancer. Review the pathophysiology and discuss the clinical and diagnostic features of M3. Describe the variant of M3 (M3m or M3v). Compare conventional chemotherapy with all-trans retinoic acid differentiation therapy (ATRA) in the treatment of M3. Discuss the future direction of differentiation therapy.. Current literature.. Until the late 1970s, the methods of diagnosis and treatment of AML-M3 were similar to the other forms of acute myelocytic leukemia. One notable difference between M3 and other acute myelocytic leukemias involved the common occurrence of life-threatening consumptive coagulopathies in M3 patients that dramatically affected patient outcomes. In 1977 the method of diagnosis confirmation was altered by the identification of a consistent chromosomal translocation involving the long arms of chromosomes 15 and 17. Reports in the 1970s and 1980s indicated that certain types of active metabolites of vitamin A, collectively termed retinoids, could induce differentiation in a variety of cancer derived cell lines, in vitro. It was shown in the early 1980s that 13-cis-retinoic acid (13cRA) could stimulate differentiation in bone marrow cells collected from patients with various acute leukemias, including M3. The first clinical trial of a retinoid, given as a remission induction therapeutic regimen, involved all-trans retinoic acid (ATRA) administered to M3 patients in 1988. Since then, ATRA therapy has been shown to reduce tumor burden by stimulating differentiation of the leukemic cells, induce long-term clinical remission when administered in conjunction with chemotherapy, and lower the incidence of consumptive coagulopathies in patients with AML-M3.. The diagnosis and treatment of AML-M3 has improved dramatically in the past decade, which has greatly enhanced the prognosis of patients with this disease. First remission rates have increased to greater than 85% world wide, the incidence of disseminated intravascular coagulation (DIC) has declined dramatically, and 60% to 70% of patients with AML-M3 have achieved long term survival and are potentially cured.

Topics: Antineoplastic Agents; Humans; Leukemia, Promyelocytic, Acute; Prognosis; Tretinoin

A differentiation block with accumulation of immature myeloid cells characterizes acute myelogenous leukemia (AML). However, native AML cells often show some morphological signs of differentiation that allow a classification into different subsets, and further differentiation may be induced by exposure to various soluble mediators, e.g., all trans-retinoic acid (ATRA) and several cytokines. Combination therapy with ATRA and chemotherapy should now be regarded as the standard treatment for the acute promyelocytic leukemia variant of AML. Several agents can induce leukemic cell differentiation for other AML subtypes, although these effects differ between patients. Differentiation may then be associated with induction of apoptosis, and differentiation-inducing therapy may therefore become useful in combination with intensive chemotherapy to increase the susceptibility of AML blasts to drug-induced apoptosis. However, it should be emphasized that differentiation and apoptosis can occur as separate events with different regulation in AML cells, and future studies in AML should therefore focus on: A) the identification of new agents with more predictable effects on differentiation and apoptosis; B) the use of clinical and laboratory parameters to define new subsets of AML patients in which differentiation/apoptosis induction has a predictable and beneficial effect, and C) further characterization of how AML blast sensitivity to drug-induced apoptosis is modulated by differentiation induction.

Topics: Adult; Apoptosis; Cell Differentiation; Genes, Tumor Suppressor; Humans; Leukemia, Myeloid, Acute; Leukemia, Promyelocytic, Acute; Prognosis; Proto-Oncogene Proteins c-bcl-2; Tretinoin

Acute promyelocytic leukemia (APL) is the most potentially curable type of acute myeloid leukemia. It is characterized by the chromosomal translocation t(15;17), which results in the fusion gene PML-RAR-alpha. The introduction of all-trans- retinoic acid (ATRA) was a major advance in treatment of this disease. This agent induces terminal differentiation of malignant myeloid cells to mature neutrophils, and its side effects are usually well tolerated in children. ATRA does not eradicate the malignant myeloid clone in APL and, eventually, resistance develops. Arsenic trioxide induces nonterminal differentiation of malignant promyelocytes and promotes apoptosis. APL patients treated with ATRA or arsenic trioxide have rapid resolution of their coagulopathy. Because both of these drugs are well tolerated in children and their synergy has been shown in animal models, the possibility of combining ATRA and arsenic trioxide in front-line therapy for children with APL is being considered.

Topics: Animals; Antineoplastic Agents; Arsenic Trioxide; Arsenicals; Cell Differentiation; Child; Disease Models, Animal; Drug Therapy, Combination; Humans; Leukemia, Promyelocytic, Acute; Oxides; Tretinoin

Induction of differentiation and/or apoptosis is a new and promising approach to cancer therapy, well illustrated by the treatment of acute promyelocytic leukaemia with all-trans-retinoic acid and arsenic compounds. Treatment with all-transretinoic acid results in complete remission in 92 - 95% of patients with this disease. Using the recently advocated combination of all-transretinoic acid and chemotherapy, adverse effects such as retinoic acid syndrome have decreased, and long-term survival has improved. Chemotherapy in combination with all-trans-retinoic acid seems to be the best postremission treatment protocol, with a 5-year relapse-free survival rate of 50 - 60%. Arsenic compounds have recently proved effective in newly diagnosed and relapsed acute promyelocytic leukaemia, with complete remission rates of 80 - 90% according to most reports. As2O3, the most studied arsenic compound, can be given by intravenous infusion at a dose of 0.08 - 0.16 mg/kg daily. A course of 28 - 44 days is required to induce remission. Although the drug is safe in patients who have relapsed, severe liver damage has been observed in some newly diagnosed patients. Combined use of chemotherapy and arsenic as postremission treatment results in longer survival than arsenic alone. Although their mechanisms of action are distinct, both all-trans-retinoic acid and arsenic can modulate PML-RARalpha, an oncoprotein that has a central role in leukaemogenesis, and both can relieve ranscriptional repression by modifying chromatin structure.

Topics: Animals; Antineoplastic Agents; Apoptosis; Arsenicals; Cell Differentiation; Hemorrhagic Disorders; Humans; Leukemia, Promyelocytic, Acute; Neoplasm Proteins; Neoplasm, Residual; Oncogene Proteins, Fusion; Tretinoin

The treatment of acute promyelocytic leukemia (APL) is different from other subtypes of acute myelocytic leukemia (AML). All trans-retinoic acid (ATRA) is an essential component of the standard remission induction for all newly diagnosed APL patients. Remission induction with ATRA and chemotherapy given concurrently appears to be associated with fewer relapses. With further consolidation chemotherapy without high-dose cytosine arabinoside, the disease-free survival rate can reach 70% to 80%, and many of these patients are cured, more so than in any other AML subtype. APL is especially sensitive to anthracyclines, which should be included in the chemotherapy cycles at a higher dose than in other AML subtypes. Maintenance with low-dose chemotherapy (oral daily 6-mercaptopurine with weekly methotrexate) or ATRA further improves the long-term outcome. New approaches are also available for relapsing patients, although the optimal treatment is unknown. Patients who did not receive oral ATRA in first relapse can be treated with this agent, as can first relapsing patients who have been off the drug for more than 1 year. Because of poor remission rates, ATRA should not be used in patients with second or subsequent relapses (whether ATRA was given in the past), in patients with relapses early after ATRA discontinuation, or in patients relapsing while on ATRA therapy. Arsenic trioxide can also be used, especially in patients resistant to ATRA. Because arsenic trioxide is still experimental and not yet widely available, patients who are unlikely to respond to ATRA or who unsuccessfully undergo ATRA reinduction should be treated with chemotherapy. Patients in second or subsequent remission induced with ATRA or chemotherapy should receive consolidation chemotherapy. When arsenic trioxide is used for reinduction, the drug should be continued for several cycles; however, adding consolidation chemotherapy might improve the results. Because it is unknown whether APL in second or subsequent remission is curable with salvage therapy, allogeneic hematopoietic stem cell transplantation is often considered for patients with a human leukocyte antigen (HL-A)-identical sibling and autologous transplantation when a donor does not exist. However, compared with the new treatments, the role of transplantation for relapse is unclear. In first remission, there is no role for transplantation. A new liposomal formulation of intravenous ATRA is being investigated and seems effective in lat

Topics: Antineoplastic Agents; Clinical Trials as Topic; Combined Modality Therapy; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Promyelocytic, Acute; Survival Rate; Treatment Outcome; Tretinoin

The preceding two years have witnessed an explosion in the accumulation of knowledge relating to the molecular pathogenesis of APL. Critical advances include: The molecular delineation of atypical APL cases with alternative RAR alpha fusion partners, and the demonstration that cells from 2 of the 3 types of 'atypical' APL retain sensitivity to ATRA. Perhaps the key question is why such cases are so rare. However, at a minimum, the presence of such cases argues persuasively that disruption of the retinoid signaling pathway is a (perhaps the) key pathogenetic feature of APL. Although certainly not 'passive' partners, it is likely that PML, PLZF, NPM, and NuMA serve similar functions in the pathogenesis of APL. The demonstration, in transgenic mice, that PML-RAR alpha (and PLZF-RAR alpha) can disrupt normal hematopoiesis and, given sufficient time, cause an APL-like syndrome. the variation in phenotype of the mice, which appears to be a consequence of the specific expression vector used, emphasizes the cell-type-specific nature of PML-RAR alpha function. Continuing functional analysis of PML, PLZF, and RAR alpha. In particular, the demonstration that PML and PLZF can form heterodimers provides a critical functional link between these proteins and offers a tantalizing glimpse at how both, when linked with RAR alpha, can cause APL. The demonstration that PML-RAR alpha is degraded, perhaps via a ubiquitin-dependent pathway, in response to ATRA. This result offers a unifying, if not yet proven, hypothesis to explain the sensitivity of leukemic promyelocytes to ATRA. Unfortunately, it is not known if ATRA can also cause degradation of NPM-RAR alpha or NuMA-RAR alpha (atypical cytogenetic APL variants that retain ATRA responsiveness). Whether PML-RAR alpha degradation is a cause, or consequence, of promyelocytic maturation remains unclear. Continuing insight into retinoid resistance, including the first demonstration of mutations in the PML-RAR alpha molecule from ATRA-resistant patients. The definitive demonstration that the two major PML-RAR alpha isoforms, while having subtle differences in biological activity and producing slightly different APL phenotypes, nevertheless do not, in and of themselves, have prognostic significance in patients treated with ATRA/chemotherapy combinations. Further functional analysis of PML-RAR alpha in vitro. The fascinating finding that PML-RAR alpha is cytotoxic to most cell types suggests that it must function as an oncogene in

Topics: Animals; DNA; Drug Resistance, Neoplasm; Humans; Leukemia, Promyelocytic, Acute; Mice; Neoplasm Proteins; Nuclear Proteins; Oncogene Proteins, Fusion; Prognosis; Promyelocytic Leukemia Protein; Proto-Oncogene Proteins c-bcl-2; Receptors, Retinoic Acid; Retinoic Acid Receptor alpha; Transcription Factors; Transcription, Genetic; Tretinoin; Tumor Suppressor Proteins

Topics: Clinical Trials as Topic; Gene Expression Regulation; Humans; Leukemia, Promyelocytic, Acute; Prognosis; Tretinoin

Acute progranulocytic leukemia (APL) is one of the most curable of all human cancers. Combination treatment with retinoic acid (RA) and anthracycline-based chemotherapy is safe and effective for the vast majority of patients, and several novel treatment approaches are under investigation for high-risk or relapsed patients. The APL-specific oncogenes PML-RAR alpha and PLZF-RAR alpha both bind nuclear corepressors and recruit histone deacetylase activity to promoters of RA target genes. The differential sensitivity of binding of these oncogenes to nuclear corepressors in the presence of RA appears to explain the resistance of PLZF-RAR alpha-related APL to RA and at the same time explains the effectiveness of RA in PML-RAR alpha-positive APL. Transcriptional repression of RA target genes, mediated by histone deacetylase activity, may thus be a key pathogenetic event in APL. Cure of the minority of resistant patients requires further refinement of current treatment approaches and appropriately timed incorporation of novel therapies, such as arsenic trioxide or histone deacetylase inhibitors.

Topics: Cell Transformation, Neoplastic; DNA-Binding Proteins; Histone Deacetylases; Humans; Interleukin-6; Kruppel-Like Transcription Factors; Leukemia, Promyelocytic, Acute; Models, Biological; Neoplasm Proteins; Oncogene Proteins, Fusion; Oncogenes; Promyelocytic Leukemia Zinc Finger Protein; Randomized Controlled Trials as Topic; Receptors, Retinoic Acid; Retinoic Acid Receptor alpha; Transcription Factors; Tretinoin

Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia characterized by hypergranular leukemic cells, bleeding diathesis and t(15; 17) translocation. The t(15; 17) translocation leads to the production of the PML-RAR alpha fusion protein which plays a vital role in the pathogenesis of APL by arresting normal differentiation of myeloid precursors. However, in the presence of high concentrations of all-trans-retinoic acid (ATRA), the PML-RAR alpha fusion protein serves to stimulate cell differentiation. The diagnosis of APL and the detection of residual disease are based on the t(15; 17) translocation. Treatment with a combination of ATRA and anthracycline-AraC chemotherapy has shown a higher rate of complete remission in APL. We report the case of a 71-year-old male with the rare microgranular variant of APL to illustrate these findings. The patient was treated with a combination of ATRA and Daunorubicin-AraC chemotherapy and achieved complete remission. He developed retinoic acid syndrome as a complication of therapy with ATRA. The methods for diagnosis, the molecular mechanisms in the oncogenesis of APL, rationale of treatment of APL with ATRA, complications of therapy and the new concepts in the treatment of ATRA-resistant APL are discussed.

Topics: Aged; Antibiotics, Antineoplastic; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Chromosomes, Human, Pair 15; Chromosomes, Human, Pair 17; Cytarabine; Daunorubicin; Humans; Leukemia, Promyelocytic, Acute; Male; Translocation, Genetic; Tretinoin

All-trans retinoic acid (ATRA) is currently recommended as standard treatment for acute promyelocytic leukemia (APL). However there has been increasing concern that ATRA is associated with unusual sites of relapse. Although there is insufficient evidence so far to substantiate this, we review the potential mechanisms by which ATRA may increase the incidence of extramedullary and, in particular, central nervous system (CNS) relapse.

Topics: Adult; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Central Nervous System Neoplasms; Female; Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Recurrence; Tretinoin

Although acute leukemia is generally thought to be characterized by maturation arrest, it has been shown that differentiation occurs in blast cells of acute myelogenous leukemia (AML) in vitro as well as in vivo, and that morphologically abnormal mature polymorphonuclear neutrophils (PMNs) often seen in patients with AML are possibly derived from spontaneously differentiating leukemic cells. Acute promyelocytic leukemia (APL) is an unique example in which these features of AML are evident in an almost complete form; administration of all-trans retinoic acid (ATRA) induces differentiation of neoplastic cells into mature neutrophils and successfully induce complete remission in most patients. However, PMNs appearing during ATRA treatment are morphologically abnormal, as indicated not only by the presence of Auer rods but also by neutrophil secondary-granule deficiency that is commonly seen in AML. Moreover, ATRA has heterogeneous effects on the growth of blast progenitors in APL in different patients, being inhibitory, stimulatory or ineffective, which might account in part for the leukemia relapse in patients treated with ATRA alone. Hematopoietic growth factors regulate the growth of blast progenitors in APL. Among them, granulocyte colony-stimulating factor (G-CSF) is unique in that it preferentially stimulates clonal growth, but not self-renewal, in many APL cases, and synergistically enhances the differentiation-inducing effect of ATRA when used in combination. Many other compounds also exert such synergistic effects with ATRA, for which a variety of mechanisms have been suggested. It is crucial to precisely elucidate the functions of these molecules governing the growth/differentiation balance of AML blast progenitors and the mechanisms underlying their deregulated differentiation program in order to achieve effective differentiation therapy for patients with AML, not restricted to APL.

Topics: Antineoplastic Agents; Cell Differentiation; Cell Division; Hematopoietic Cell Growth Factors; Hematopoietic Stem Cells; Humans; Leukemia, Promyelocytic, Acute; Neutrophils; Tretinoin

The remarkable success of retinoic acid in the treatment of acute promyelocytic leukemias and the subsequent discovery that mutant forms of a retinoid acid receptor (RARalpha) are invariably associated with this disease has generated considerable interest among both clinicians and basic scientists. Studies both in cell culture and in transgenic animals suggest that mutant RARs interfere with normal retinoid-mediated transactivation and granulocytic differentiation. More recently, a pivotal link between transcriptional silencing, the oncogenic functions of RAR mutants, and hormonal responses in APL patients has been established. These studies have greatly advanced our understanding of the molecular changes involved in leukemogenesis, have helped to reveal new aspects of cellular differentiation, and might lead to improved treatment strategies for human leukemias.

Topics: Animals; Humans; Leukemia, Promyelocytic, Acute; Mice; Mice, Transgenic; Molecular Biology; Mutation; Receptors, Retinoic Acid; Retinoic Acid Receptor alpha; Translocation, Genetic; Tretinoin

Topics: Antineoplastic Agents; Biomarkers, Tumor; Gene Expression Regulation, Neoplastic; Humans; Leukemia, Promyelocytic, Acute; Neoplasm Proteins; Oncogene Proteins, Fusion; Polymerase Chain Reaction; Tretinoin

Topics: Acetylation; Antineoplastic Agents; Cell Differentiation; Chromatin; Chromosomal Proteins, Non-Histone; Core Binding Factor Alpha 2 Subunit; DNA-Binding Proteins; Enzyme Inhibitors; Gene Expression Regulation, Leukemic; Histone Deacetylase Inhibitors; Histone-Lysine N-Methyltransferase; Histones; Humans; Leukemia; Leukemia, Promyelocytic, Acute; Models, Genetic; Myeloid-Lymphoid Leukemia Protein; Neoplasm Proteins; Nucleic Acid Conformation; Nucleosomes; Oncogene Proteins, Fusion; Protein Processing, Post-Translational; Proto-Oncogenes; Recombinant Fusion Proteins; RUNX1 Translocation Partner 1 Protein; Static Electricity; Transcription Factors; Translocation, Genetic; Tretinoin

Retinoic acid (RA) and interferon (IFN) potentiate each other to induce biological responses. Their combination has shown synergistic differentiating, antiproliferative and antiviral activities in various cell lines including those derived from the acute promyelocytic leukemia (APL). IFNs have demonstrated broad applications in cancer, as well as in virologic diseases. RA has variable effectiveness in therapy. Its real success is in APL where it provides the first example of a differentiation therapy. However, complete clinical remission with RA alone is always transient as RA resistance develops in the treated patients as well as in vitro. In various cell lines, including those derived from APL, RA induces directly the expression of two transcription factors, Stat1 and IRF-1 which play central roles in the IFN signal transduction. In addition, RA induces IFN-alpha synthesis and enhances the IFN-induced Stat activation. Here, we review the molecular mechanisms by which RA and IFNs can cooperate in inducing differentiation, inhibition of cell growth or viral replication focusing on recent results derived from normal and RA-resistant APL cells.

Topics: Antineoplastic Agents; Drug Resistance, Neoplasm; Humans; Interferons; Leukemia, Promyelocytic, Acute; Receptor Cross-Talk; Receptors, Interferon; Receptors, Retinoic Acid; Signal Transduction; Tretinoin

Neutrophil maturation occurs in well defined morphological stages that correlate with the acquisition of molecular markers associated with neutrophil function. A variety of factors are known to play a role in terminal neutrophil maturation, including the vitamin A derivative, retinoic acid. Retinoic acid can directly modulate gene expression via binding to its nuclear receptors, which can, in turn, activate transcription of target genes. A role for retinoic acid during neutrophil maturation has been suggested from a variety of sources. Here we present a review of the mechanism of retinoic acid receptor action and the major evidence showing that normal retinoid signaling is required for neutrophil maturation.

Topics: Animals; Biological Transport; Cell Differentiation; Cell Nucleus; Dimerization; DNA-Binding Proteins; Gene Expression Regulation; HL-60 Cells; Humans; Leukemia, Promyelocytic, Acute; Mice; Mice, Knockout; Neoplasm Proteins; Neutrophils; Nuclear Proteins; Nuclear Receptor Co-Repressor 1; Nuclear Receptor Co-Repressor 2; Oncogene Proteins, Fusion; Receptors, Retinoic Acid; Repressor Proteins; Retinol-Binding Proteins; Structure-Activity Relationship; Transcription Factors; Tretinoin; Tumor Cells, Cultured

Differentiation-inducing therapy by all-trans retinoic acid (RA) is now a standard therapy in patients with acute promyelocytic leukemia (APL). Nearly all patients achieve complete remission by the treatment of all-trans RA, however, clinical remissions are usually of brief duration, and these patients often develop RA-resistant disease. The mechanisms of RA-resistance in APL cells are poorly understood and most clinical approaches have not been successful in overcoming RA-resistance. We have recently established a novel APL cell line (UF-1) with RA-resistant features. In addition, we have established human GM-CSF-producing transgenic (hGMTg) SCID mice system. UF-1 cells were inoculated either intraperitoneally or subcutaneously into hGMTg SCID mice and made the first RA-resistant murine APL model. These RA-resistant APL model systems in vitro and in vivo may be useful for investigating the molecular studies on the block of leukemic cell differentiation and as means to investigate the mechanisms of RA-resistance. Moreover, this murine model system will be important for developing novel therapeutic strategies in RA-resistant APL.

Topics: Animals; Antineoplastic Agents; Disease Models, Animal; Drug Resistance, Neoplasm; Humans; Leukemia, Promyelocytic, Acute; Mice; Mice, SCID; Tretinoin

Chinese clinical investigators in 1986 demonstrated the therapeutic potential of tretinoin and in 1992 that of arsenic trioxide in the treatment of acute promyelocytic leukaemia. These observations have been confirmed in European and American centres. In acute promyelocytic leukaemia there is an abnormal receptor for retinoids, designated PML/RAR-alpha. This receptor binds retinoids inadequately so that extra retinoids (in the form of tretinoin) are required to restart the normal cellular maturation, after which the promyelocytes can mature into granulocytes. Arsenic trioxide has a different mode of action, possibly related to its effects on sulfhydryl-rich proteins, resulting in dysplastic leukaemic promyelocytes, ending up in apoptotic cell death. Since 1990 tretinoin has been included worldwide in the treatment of acute promyelocytic leukaemia. The use of arsenic trioxide has not yet been included in treatment protocols for promyelocytic leukaemia in western medicine.

Topics: Antineoplastic Agents; Arsenic Trioxide; Arsenicals; Drug Resistance, Neoplasm; Humans; Leukemia, Promyelocytic, Acute; Oxides; Tretinoin

Topics: Animals; Antineoplastic Agents; Disease Models, Animal; Humans; Leukemia, Promyelocytic, Acute; Tretinoin

Acute promyelocytic leukemia (APL) is characterized by the expansion of malignant myeloid cells blocked at the promyelocytic stage of hemopoietic development, and is associated with reciprocal chromosomal translocations always involving the retinoic acid receptor alpha (RARalpha) gene on chromosome 17. As a consequence of the translocation RARalpha variably fuses to the PML, PLZF, NPM and NUMA genes (X genes), leading to the generation of RARalpha-X and X-RARalpha fusion genes. The aberrant chimeric proteins encoded by these genes may exert a crucial role in leukemogenesis. Retinoic acid (RA), a metabolite of vitamin A, can overcome the block of maturation at the promyelocytic stage and induce the malignant cells to terminally mature into granulocytes resulting in complete albeit transient disease remission. APL has become, for this reason, the paradigm for 'cancer differentiation therapy'. Furthermore, APL associated with translocation between the RARalpha and the PLZF genes (PLZF-RARalpha) shows a distinctly worse prognosis with poor response to chemotherapy and little or no response to treatment with RA, thus defining a new APL syndrome. Here we will focus our attention on the recent progresses made in defining the molecular mechanisms underlying the pathogenesis of this paradigmatic disease in vivo in the mouse. We will review the critical contribution of mouse modeling in unraveling the transcriptional basis for the differential response to RA in APL. We will also discuss how this new understanding has allowed to propose, develop and test in these murine leukemia models as well as in human APL patients novel therapeutic strategies.

Topics: Animals; Antineoplastic Agents; Disease Models, Animal; Humans; Leukemia, Promyelocytic, Acute; Mice; Neoplasm Proteins; Oncogene Proteins, Fusion; Tretinoin

Arsenic compounds have been utilised in medicine for over 2,000 years. Recently, arsenic trioxide has been shown to induce complete remission in up to 90% of patients with acute promyelocytic leukemia (APL), including those resistant to standard therapy. Randomised studies are currently investigating the potential clinical utility of this drug in APL. In vitro, arsenic trioxide exhibits antitumoral properties with respect to various other tumor species as well, although assessment of clinical effects will require further study. This article reviews clinical results and possible mechanisms of action of the drug.

Topics: Antineoplastic Agents; Arsenicals; Drug Resistance, Neoplasm; Humans; Leukemia, Promyelocytic, Acute; Tretinoin

Topics: Acetylation; Adult; Antineoplastic Agents; Arsenic Trioxide; Arsenicals; Child; China; Chromatin; Drug Evaluation; Drug Resistance, Neoplasm; Enzyme Inhibitors; Gastrointestinal Diseases; Histone Deacetylase Inhibitors; Humans; Leukemia, Promyelocytic, Acute; Leukocytosis; Melarsoprol; Neoplasm Proteins; Neoplasms; Nervous System Diseases; Oxides; Phenylbutyrates; Protein Processing, Post-Translational; Salvage Therapy; Tretinoin

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Chromosomes, Human, Pair 15; Chromosomes, Human, Pair 17; Clinical Trials as Topic; Combined Modality Therapy; Cytarabine; Forecasting; Humans; Leukemia, Promyelocytic, Acute; Multicenter Studies as Topic; Neoplasm Proteins; Oncogene Proteins, Fusion; Randomized Controlled Trials as Topic; Remission Induction; Salvage Therapy; Translocation, Genetic; Treatment Outcome; Tretinoin

To summarize the experiences in using all-trans retinoic acid (ATRA) for the differentiation therapy for acute promyelocytic leukemia (APL) since our introduction of its use in clinic in 1986.. Data resources came from Chinese Journal of Hematology, English-language literature using MEDLINE (1988-1998), book entitled "Treatment of Malignancies by Inducing Differentiation and Apoptosis" published by Shanghai Publishing House on Sciences and Technology, and our recent data to be published.. Thirty-five articles related to the purpose of this review were reviewed.. Data were checked for their quality, reliance and originality.. ATRA combined with chemotherapy can decrease the incidence of retinoic acid syndrome and produce a very high remission rate (90%-95%). Post-remission treatment should include chemotherapy and ATRA, the 5-year survival probability was able to attain 0.71 +/- 0.06. The main problem in the treatment is early tolerance to ATRA and relapse of the disease. The most effective treatments for relapsed APL is to use arsenic trioxide.. The combination of ATRA, chemotherapy and arsenic oxide in the treatment of APL for elevating the remission rate and prolonging survival time deserves further study.

Topics: Antineoplastic Agents; Cell Differentiation; Humans; Leukemia, Promyelocytic, Acute; Remission Induction; Survival Rate; Tretinoin

The current situation and perspectives for the treatment of acute myelogenous leukemia in adults were summarized. Due to the recent progress of chemotherapy, the complete remission (CR) rate is close to 80% in adults with newly diagnosed acute myelogenous leukemia in Japan. On the other hand, the long-term disease-free survival rate is 30-40% in CR cases. The allogeneic bone marrow transplantation (allo BMT) during the first CR has a low relapse rate compared with that of chemo therapy. However, the therapy-related mortality is not inconsiderable, so, the time of allo BMT is controversial. Idarubicin has a superior CR rate as well as long-term disease-free survival in comparison with daunorubicin, and it is becoming the first line treatment for acute myelogenous leukemia in adults.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Clinical Trials as Topic; Combined Modality Therapy; Disease-Free Survival; Drug Administration Schedule; Humans; Idarubicin; Leukemia, Myeloid, Acute; Leukemia, Promyelocytic, Acute; Remission Induction; Survival Rate; Tretinoin

Topics: Antineoplastic Agents; Cell Differentiation; Humans; Leukemia, Promyelocytic, Acute; Protein Binding; Recombinant Fusion Proteins; Translocation, Genetic; Tretinoin

Topics: Disseminated Intravascular Coagulation; Fibrinolysis; Hemostasis; Humans; Leukemia, Promyelocytic, Acute; Tretinoin

The introduction of treatment with tretinoin (all-trans retinoic acid) and its combination with antineoplastic therapy has improved the outcome of acute promyelocytic leukaemia (APL). Retinoic acid syndrome is the major adverse effect of tretinoin and it occurs in about 25% of treated APL patients in the absence of prophylactic measures and is often fatal. Generally, the retinoic acid syndrome is associated with increasing leucocyte counts and is probably caused by the release of several cytokines by maturing blast cells. The retinoic acid syndrome gives a clinical picture of bodyweight gain, respiratory distress, serous effusions and cardiac and renal failure. Adequate prophylaxis, based on the addition to tretinoin of dexamethasone and also, according to most authors, antineoplastic therapy (in case of rapidly increasing leucocyte counts) has decreased the incidence of retinoic acid syndrome to about 15%. Most importantly, these measures have reduced its mortality to about 1% of all treated patients.

Topics: Anti-Inflammatory Agents; Antineoplastic Agents; Clinical Trials as Topic; Cytokines; Dexamethasone; Heart Failure; Humans; Infant, Newborn; Leukemia, Promyelocytic, Acute; Leukocyte Count; Renal Insufficiency; Respiratory Distress Syndrome, Newborn; Syndrome; Tretinoin; Weight Gain

Acute promyelocytic leukaemia is a key model system in cancer biology. Its exquisite sensitivity to retinoic acid constitutes the first example of differentiation therapy. The PML/RAR alpha fusion protein generated by the t(15; 17) translocation is the molecular basis of transformation. PML/RAR alpha induces transformation most likely through a dominant negative interference with the function of nuclear receptors leading to a differentiation block. The fusion protein also delocalizes PML and other nuclear body antigens and this alteration of nuclear protein traffic seems to play a role in growth control and apoptosis. The clinical response of this disease to retinoids and arsenic trioxide, both of which induce the degradation of the fusion protein, constitute the first example of a therapy directly targeted to a specific genetic lesion in a human cancer.

Topics: Antineoplastic Agents; Arsenic; Humans; Leukemia, Promyelocytic, Acute; Tretinoin

Acute promyelocytic leukemia (APL) has been regarded as the paradigm for therapeutic approaches utilizing differentiating agents, due to the fact that almost 95% of patients undergo complete remission when treated with all-trans retinoic acid (ATRA). However, complete clinical remission with ATRA alone is always transient, and relapse in APL is almost invariably associated with the acquisition of resistance to ATRA. Acquired resistance to ATRA in APL cell lines and in some APL clinical cases can be partially overcome by interferons (IFNs), cytokines which have well established tumor-growth suppressive activities. APL is associated in 99% of cases with a 15;17 translocation that fuses the PML and Retinoic Acid Receptor alpha (RARalpha) genes. RARalpha is one of the Retinoic Acid (RA) nuclear receptors which mediates, at the transcriptional level, ATRA differentiating and growth suppressive activity. PML is a tumor-growth suppressor whose expression is directly regulated by IFNs. Here we review the molecular mechanisms by which IFNs and RA can cooperate in controlling cell growth and differentiation of normal hemopoietic cells and leukemic cells, focusing on APL as a model system.

Topics: Drug Synergism; Gene Expression Regulation, Neoplastic; Humans; Interferons; Leukemia, Promyelocytic, Acute; Models, Biological; Remission Induction; Signal Transduction; Tretinoin

All-trans retinoic acid (ATRA) and interferons (IFNs) are active anticancer agents. ATRA is capable of inducing complete remission in acute promyelocytic leukemia (APL) patients, whereas IFNalpha is successfully used in the treatment of the stable phase of chronic myeloid leukemia. ATRA and IFNs have shown synergistic interactions in various experimental conditions and represent a potentially useful therapeutic combination in the treatment of various types of leukemias and solid tumors. The molecular basis of these interactions are poorly understood and need to be elucidated. In this review, we summarize a series of recent observations concerning the molecular mechanisms underlying the cross-talk between the intracellular pathways activated by ATRA and IFNs in APL cells. In APL blasts, IFNs regulate the expression of retinoic acid receptors, and ATRA, in turn, modulates the levels and the state of activation of members of the Jak-STAT second messenger pathway. This demonstrates a two-way interaction between ATRA and IFNs, which leads to cross-modulation of genes normally under the control of the retinoid and the cytokine. These data may be relevant in the context of a rational use of the combination between ATRA and IFNs in the clinical management of myeloid leukemias.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Drug Synergism; Forecasting; Gene Expression Regulation, Neoplastic; Humans; Interferons; Leukemia, Promyelocytic, Acute; Receptors, Retinoic Acid; Tretinoin

Acute promyelocytic leukemia (APL) originate from chromosomal translocations generating two types of fusion proteins both involving the retinoic acid receptor alpha (RAR alpha) and either the gene PML (t(15;17)) or PLZF (t(11;17)). Recent publications cast a new light on the detailed molecular mechanism underlying the oncogenic activity of these fusion proteins which block myeloid terminal differentiation by recruiting histone deacetylases to the promoters of target genes through co-repressor proteins. They also explain the different responses to treatment by all-trans retinoic acid (ATRA) of these two variants which are otherwise clinically indistinguishable.

Topics: Antineoplastic Agents; Histone Deacetylases; Humans; Leukemia, Promyelocytic, Acute; Neoplasm Proteins; Oncogene Proteins, Fusion; Tretinoin

Acute promyelocytic leukaemia is a key model system in cancer biology. Its exquisite sensitivity to retinoic acid constitutes the first example of differentiation therapy. The PML/RAR alpha fusion protein generated by the t(34, 35) translocation is the molecular basis of transformation. PML/RAR alpha induces transformation most likely through a dominant negative interference with the function of nuclear receptors leading to a differentiation block. The fusion protein also delocalises PML and other nuclear body antigens and this alteration of nuclear protein traffic seems to play a role in growth control and apoptosis. The clinical response of this disease to retinoids and arsenic trioxide, both of which induce the degradation of the fusion protein, constitute the first example of a therapy directly targeted to a specific genetic lesion in a human cancer.

Topics: Antineoplastic Agents; Arsenic; Humans; Leukemia, Promyelocytic, Acute; Neoplasm Proteins; Nuclear Proteins; Promyelocytic Leukemia Protein; Receptors, Retinoic Acid; Recombinant Fusion Proteins; Retinoic Acid Receptor alpha; Transcription Factors; Translocation, Genetic; Tretinoin; Tumor Suppressor Proteins

Acute promyelocytic leukemia (APL) is the most potentially curable subtype of acute myeloid leukemia (AML). APL is highly sensitive to induction chemotherapy with anthracyclines. In addition, it now has been established that all-trans retinoic acid (ATRA), alone or in combination with chemotherapy for induction, improves the disease-free interval compared with chemotherapy alone. Large, prospective clinical studies have demonstrated complete remission rates ranging from 72% to 95% with ATRA therapy in patients with newly diagnosed APL. An important biological marker for monitoring residual disease is the promyelocytic retinoic acid receptor alpha (PML-RARalpha) fusion transcript. Its detection by the reverse transcription-polymerase chain reaction (RT-PCR) during remission appears to represent a strong predictor of clinical relapse. One limitation of ATRA therapy is the rapid development of retinoid resistance. Arsenic trioxide and alternative retinoids (9-cis retinoic acid and Am-80) currently are being investigated to determine whether they might have a role in circumventing retinoid resistance and further improving long-term outcome in patients with APL.

Topics: Antineoplastic Agents; Humans; Leukemia, Promyelocytic, Acute; Tretinoin

A 41-year-old man was given a diagnosis with of acute promyelocytic leukemia (APL) in August 1994. A chromosome analysis showed 46, XY, t(15; 17) and 47, XY, idem, +8 at that time. Because initial induction chemotherapy (BHAC-DMP) has not been successful, the patient was given 45 mg/m2 of all-trans retinoic acid (ATRA) and achieved complete remission (CR) after 26 days on this regimen. Following intensified chemotherapy, he received an autologous peripheral blood stem cell transplant (PBSCT) with high-dose busulfan and cyclophosphamide in April 1995. Competitive RT-PCR for PML-RAR alpha mRNA did not find any of APL cells in the collected stem-cell fraction. Although the patient remained in CR without therapy, a myeloblastoma was found in his left external auditory canal in August 1996. Recurrence in bone marrow, moreover, was discovered the following month. A chromosome analysis of bone marrow cells showed 47, XY, t(15; 17), +8 at this time. Thus, the extramedullary relapse developed after autologous PBSCT. This case provides information linking ATRA to the development of extramedullary relapse in patients with APL.

Topics: Adult; Antineoplastic Agents; Combined Modality Therapy; Ear Canal; Ear Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Promyelocytic, Acute; Male; Recurrence; Tretinoin

Topics: Antineoplastic Agents; Artificial Gene Fusion; Chromosomes, Human, Pair 15; Chromosomes, Human, Pair 17; Humans; Leukemia, Promyelocytic, Acute; Prognosis; Receptors, Retinoic Acid; Retinoic Acid Receptor alpha; Translocation, Genetic; Tretinoin

All-trans retinoic acid (ATRA), a potent differentiating drug for acute promyelocytic leukemia (APL), induces a high incidence of complete remission (CR) in patients with APL and is now established as a first-line therapy. However, ATRA resistance has become a clinical problem. Patients who relapsed after ATRA-induced CR have had difficulty in obtaining a second CR with ATRA therapy. Although several mechanisms have been postulated, treatment strategies to overcome resistance have not been established. We used a new synthetic retinoid, Am-80, as reinduction therapy for APL relapse after from ATRA-induced CR. Am-80 was several times more potent than ATRA in inducing differentiation in vitro. At a 6 mg/m2 dose, there were 24 evaluable patients; 14 (58%) achieved CR between days 20 and 58 (median, 37 days). Clinical response correlated with the in vitro response to Am-80. Adverse effects included retinoic acid syndrome (n = 1), hyperleukocytosis (n = 1), xerosis (n = 9), cheilitis (n = 8), hypertriglyceridemia (n = 16), and hypercholesterolemia (n = 15). Am-80 is active in APL after relapse from ATRA-induced CR. Further clinical trials are needed to establish strategies to overcome ATRA resistance.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Arsenicals; Benzoates; Biomarkers, Tumor; Cheilitis; Cytarabine; Daunorubicin; Disease-Free Survival; Drug Resistance, Neoplasm; Female; Humans; Hypercholesterolemia; Hypertriglyceridemia; Leukemia, Promyelocytic, Acute; Leukocytosis; Male; Middle Aged; Neoplasm Proteins; Oncogene Proteins, Fusion; Pilot Projects; Recurrence; Remission Induction; Salvage Therapy; Tetrahydronaphthalenes; Treatment Outcome; Tretinoin; Tumor Cells, Cultured

Bleeding complications are often associated with acute promyelocytic leukemia (APL) they occur frequently at the onset of APL and become more serious during chemotherapy. The increased bleeding tendency of APL is caused by a massive proteolytic state, triggered by procoagulant substances, plasminogen activators and proteinases released into the circulation from leukemic cells. The introduction of all-trans-retinoic acid (ATRA) into the treatment of APL has reduced bleeding complications. However the mechanisms of the hemostatic defects in patients with APL and their modifications during ATRA with or without chemotherapy are still incompletely understood. Attempts at characterizing and monitoring these hemostatic abnormalities have been made by using several laboratory parameters. Among them we have studied the structural modifications of von Willebrand Factor (vWF). In APL, plasma vWF is massively degraded, with specific fragments produced by the action of plasmin and elastase. After ATRA therapy, proteolysis diminishes progressively in parallel with the improvement of other hemostatic measurements. We conclude that abnormalities of vWF structure and function might adversely affect hemostasis in APL and that their improvement after ATRA administration might explain in part the effectiveness of this drug in reducing hemorrhagic complications.

Topics: Antineoplastic Agents; Biopolymers; Blood Coagulation Tests; Cysteine Endopeptidases; Endopeptidases; Hemorrhagic Disorders; Humans; Leukemia, Promyelocytic, Acute; Macromolecular Substances; Models, Biological; Molecular Weight; Neoplasm Proteins; Pancreatic Elastase; Plasminogen Activators; Platelet Adhesiveness; Tretinoin; von Willebrand Factor

The discovery of the specific PML-RAR alpha gene rearrangement in acute promyelocytic leukemia (APL) and of the in vitro and in vivo differentiation of APL blasts by all transretinoic acid have allowed important advances in the pathophysiology and treatment APL. With a therapeutic strategy combining ATRA and anthracycline-AraC chemotherapy, about 70% of newly diagnosed APL cases can now be cured. ATRA syndrome--the major side effect of ATRA treatment--should, however, be prevented. Reverse transcription polymerase chain reaction of the PML-RAR alpha rearrangement is useful for the monitoring of minimal residual disease. Efforts are currently being made to treat patients that relapse and become resistant to ATRA.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cell Differentiation; Chromosomes, Human, Pair 15; Chromosomes, Human, Pair 17; Cytarabine; Daunorubicin; Humans; Leukemia, Promyelocytic, Acute; Neoplasm, Residual; Recurrence; Translocation, Genetic; Tretinoin

The vast majority of cases of APL are associated with t(15; 17) leading to the formation of PML-RAR alpha, RAR alpha-PML and aberrant PML fusion products. PML-RAR alpha is invariably transcribed and is believed to mediate leukaemogenesis. PML was initially considered to be a transcription factor. However, characterisation of other RING finger containing proteins shows no direct evidence for DNA binding. The RING, B-box, and coiled-coil domains are more likely to represent sites of protein-protein interaction and may be critical for the stability of the multiprotein nuclear domains of which PML is an integral part. In APL the nuclear bodies become disrupted, presumably as a consequence of the presence of PML-RAR alpha and aberrant PML proteins that might render the structure unstable. PML-RAR alpha is capable of binding RXR and sequestering it into the disrupted nuclear domains. Sequestration of RXR would be expected to limit high affinity binding of VDR, TR and residual RARs to DNA response elements and might account for the block in myeloid differentiation at the promyelocyte stage that characterizes APL. Recently PML has been found to have growth suppressor/anti-oncogenic activity. It is unclear whether this is a property of PML itself or reflects a nonspecific function of the PML-associated nuclear domains. Hence the PML/RAR alpha rearrangement alone may be sufficient to cause APL. Abnormal PML function may prevent its growth-suppressor activity, leading to leukaemic transformation; concomitant disruption of retinoid pathways due to sequestration of RXR and/or an abnormal repertoire and character of response element activation mediated by the fusion protein, causing the block in myeloid differentiation (Fig. 3). Disruption of RAR alpha would be expected to account for the similar leukaemic phenotype associated with the t(5;17) and t(11;17) APL cytogenetic variants. Further characterisation of NPM and PLZF at the structural and functional level will determine whether PML and other proteins disrupted in APL associated translocations play an active or purely permissive role in leukaemogenesis and will help dissect the events leading to transformation from those causing blockade of myeloid differentiation and mediating the response to ATRA.

Topics: Adult; Antineoplastic Agents; Cell Transformation, Neoplastic; Chromosomes, Human, Pair 15; Chromosomes, Human, Pair 17; Gene Expression Regulation, Leukemic; Humans; Leukemia, Promyelocytic, Acute; Middle Aged; Neoplasm Proteins; Nuclear Proteins; Oncogene Proteins, Fusion; Polymerase Chain Reaction; Promyelocytic Leukemia Protein; Receptors, Retinoic Acid; Retinoic Acid Receptor alpha; Signal Transduction; Transcription Factors; Translocation, Genetic; Tretinoin; Tumor Suppressor Proteins

The outlook for patients with acute promyelocytic leukaemia has improved vastly with the use of all-trans retinoic acid. The development of this therapeutic agent stemmed from the finding that an abnormality of the retinoic acid receptor is involved in this disease. In the search for other molecular abnormalities in the acute leukaemias that might serve as therapeutic targets, the chromosomal translocations associated with this group of disorders have been helpful in indicating where to look for potential cancer genes. Some common signal-transduction pathways through which different such genes act have been identified, and compounds that interfere with these pathways are already being screened for.

Topics: Acute Disease; Chronic Disease; Humans; Leukemia; Leukemia, Promyelocytic, Acute; Molecular Biology; Protein-Tyrosine Kinases; Translocation, Genetic; Tretinoin

Differentiation therapy with all-trans retinoic acid (ATRA, tretinoin) alone or in combination with chemotherapy induces around 90% complete remission in acute promyelocytic leukemia (APL). By giving non-cross resistant chemotherapy as postremission therapy, more than 50% of APL, especially more than 70% of APL patients of age less than 30, became curable. Since this active form of Vitamin A causes less toxicity and fewer complications compared with other cytotoxic drugs, the medical costs required are less. Therefore, ATRA therapy should be incorporated as a first-line therapy for APL.

Topics: Cell Differentiation; Drug Costs; Humans; Leukemia, Promyelocytic, Acute; Remission Induction; Tretinoin

Several adverse effects have been reported to occur after clinical application of all-trans retinoic acid (RA) in acute promyelocytic leukemia (APL). Except for severe side effects including retinoic acid syndrome, the mechanism of action of RA on adverse effects remains unclear. Here we describe some rare adverse effects and their management. We reviewed the English literature, and we added our cases of endocrine and metabolic adverse effects, such as hypercalcemia, male infertility, bone marrow necrosis, fibrosis and acute pancreatitis. We also described our cases of thromboembolic events, RA-dependent growth of pathologic cells including Sweet's syndrome, erythema nodosum, hyperhistaminemia, granulomatous proliferation, and mild cases of pulmonary complications. In addition, we reviewed the efficacy of RA administration for other types of leukemia or myelodysplastic syndrome. RA and chemotherapeutic agents might induce complete remission, but we obtained a response in only one case of M2 in the third relapse. During RA administration the patient should be monitored for these adverse effects, and early diagnosis and appropriate treatment are important.

Topics: Antineoplastic Agents; Humans; Leukemia, Promyelocytic, Acute; Male; Tretinoin

Recent studies have shown that a high proportion of patients with acute promyelocytic leukemia (APL) achieve complete remission after treatment with all-trans retinoic acid (RA). Nevertheless, despite an initial good response, most patients who received continuous treatment with all-trans RA relapsed and develop RA-resistant disease. The detailed mechanisms for this development of RA resistance by APL cells are still unclear. Several possible mechanisms have been considered to explain in vitro resistance to RA. One obvious explanation is the generation of new mutations in the retinoid receptors. However, UF-1 cells (the first permanent APL cell line with RA-resistant features) had no point mutations in the ligand-binding domain of the RAR-alpha gene. Another potential mechanism for clinical RA resistance is the pharmacologic alteration in the metabolism of all-trans RA. Continuous treatment with all-trans RA in APL is associated with a progressive reduction of the plasma concentrations of RA. Induction of cytochrome P-450, cellular RA-binding protein (CRABP) and P-glycoprotein resulted in lower plasma and cellular levels of active retinoids. Thus, acquired resistance to RA may be explained at least in part by drug metabolism in leukemic cells.

Topics: Antineoplastic Agents; Drug Resistance, Neoplasm; Humans; Leukemia, Promyelocytic, Acute; Tretinoin

Acute promyelocytic leukaemia (APL) is a distinct entity of acute myeloid leukaemia characterized by blast cell morphology, severe coagulopathy and t(15;17) translocation that fuses the PML gene on chromosome 15 to the retinoic acid receptor alpha (RAR alpha) gene on chromosome 17. Past experience indicated that APL is highly sensitive to anthracycline-based chemotherapy. GIMEMA experience reported a similar complete remission (CR) rate (77% versus 69%) in APL patients treated with idarubicin alone or idarubicin plus Ara-C, respectively. At present all-trans-retinoic-acid (ATRA) represents the mainstay of APL treatment. Current available clinical trials show that combination of ATRA and anthracycline induction therapy produces approximately 90% CR rate and seems to significantly improve disease-free survival. Furthermore ATRA combined therapy reduces induction death rate since ATRA syndrome has been managed with high-dose corticosteroids. However the development of ATRA resistance could limit the use of ATRA as post-remission treatment and therefore future efforts should be addressed to the search of new retinoids with comparable clinical activity, which can overcome ATRA resistance.

Topics: Antibiotics, Antineoplastic; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Disease-Free Survival; Humans; Idarubicin; Leukemia, Promyelocytic, Acute; Remission Induction; Treatment Outcome; Tretinoin

We report a female neonate delivered in week 32 of gestation by a mother who had acute promyelocytic leukemia (APL) treated by all-trans retinoic acid (ATRA). APL was diagnosed in week 29 of gestation and was treated with ATRA from week 30. Physical examination and laboratory tests showed no abnormalities at birth. The girl has since shown normal development, with no peripheral blood abnormalities at 2 years old. Hypersegmented neutrophils, which often appear during ATRA treatment, were seen in the peripheral blood of the mother and cord blood but not peripheral blood of the neonate on the day of birth. ATRA is known to cross the placenta, and has been revealed to be teratogenic in animal studies. There have been eight neonates born to the mothers with APL who were treated with ATRA during pregnancy. All infants, including this one, have shown normal growth without any complications.

Topics: Adult; Antineoplastic Agents; Female; Humans; Infant, Newborn; Leukemia, Promyelocytic, Acute; Pregnancy; Pregnancy Complications, Neoplastic; Pregnancy Outcome; Tretinoin

Acute promyelocytic leukemia (APL) is a subset of acute myeloid leukemia characterized by the morphology of the blast cells (M3 type in the FAB nomenclature), and a specific t(15; 17) translocation. APL was further characterized by a specific sensitivity to all-trans retinoic acid's differentiation effect and the production of a fusion gene altering the gene of RAR alpha and a gene called PML. In vivo differentiation therapy with retinoids in APL patients reduces the risk of relapse and increases the chance of long-term survival.

Topics: Cell Differentiation; Clinical Trials as Topic; Humans; Leukemia, Promyelocytic, Acute; Tretinoin

Topics: Antineoplastic Agents; Hematologic Neoplasms; Humans; Leukemia, Promyelocytic, Acute; Tretinoin

Topics: Animals; Arsenic; Artificial Gene Fusion; Cell Transformation, Neoplastic; Humans; Leukemia, Promyelocytic, Acute; Neoplasm Proteins; Nuclear Proteins; Promyelocytic Leukemia Protein; Receptors, Retinoic Acid; Retinoic Acid Receptor alpha; Transcription Factors; Translocation, Genetic; Tretinoin; Tumor Suppressor Proteins

Retinoic acid syndrome still remains as the most significant complication of the differentiation treatment of acute promyelocytic leukemia. Of unknown pathogenesis this syndrome is close but not absolutely related to hyperleukocytosis developed during treatment. It shares clinico-biological characteristics with three other known syndromes: adult respiratory distress syndrome, endotoxic shock and capillary leak syndrome. It can be hypothesized that as in these cases, the main target is the endothelial cell. Some observations contribute to support this hypothesis. An interleukin storm is probably triggered by retinoic acid treatment as well as an increase in adhesion molecules, both contributing to an autocatalytic injury in patients developing the retinoic acid syndrome.

Topics: Humans; Leukemia, Promyelocytic, Acute; Syndrome; Tretinoin

Topics: Cell Differentiation; Humans; Leukemia, Promyelocytic, Acute; Neoplasm Proteins; Nuclear Proteins; Promyelocytic Leukemia Protein; Prospective Studies; Receptors, Retinoic Acid; Retinoic Acid Receptor alpha; RNA, Neoplasm; Survival Analysis; Transcription Factors; Translocation, Genetic; Tretinoin; Tumor Suppressor Proteins

Induction therapy of promyelocytic leukemia with all-trans retinoic acid is a standard therapy despite significant side-effects. The most important, the "retinoic acid syndrome", consists of a hyperinflammatory reaction with capillary leakage (edema, pleural, and pericardial effusion), infiltration of myeloid cells into internal organs and systemic signs of inflammation. We describe here two cases of another hyperinflammatory reaction during all-trans retinoic acid therapy, the Sweet's syndrome, consisting of infiltrates of the skin and internal organs by neutrophilic granulocytes. Fever, painful erythematous cutaneous plaques, prominent musculoskeletal involvement (myositis, fasciitis), a sterile pulmonary infiltration and intercurrent proteinuria characterized the clinical course of all-trans retinoic acid-associated Sweet's syndrome. Treatment with glucocorticoids led to resolution of the syndrome within 48 h. Three other cases of all-trans retinoic acid-associated Sweet's syndrome without involvement of internal organs, prominent on our cases, were published previously. Recognition of ATRA-associated Sweet's syndrome is of practical importance.

Topics: Adult; Aged; Aged, 80 and over; Female; Fever; Humans; Leukemia, Promyelocytic, Acute; Middle Aged; Remission Induction; Sweet Syndrome; Tretinoin

The standard treatment of patients with acute myeloid leukemia (AML) has depended on the elimination of the leukemic clone with cytotoxic myeloablation. Differentiation therapy is receiving increasing attention due to the remarkable activity of a vitamin A derivative, all-trans retinoic acid (ATRA), in patients with acute promyelocytic leukemia (APL). The majority of patients treated have achieved complete remission and with rapid resolution of the life-threatening bleeding diathesis. Phase II studies with ATRA in APL indicate certain limitations in the therapeutic use of retinoic acid. Patients achieving complete remission with ATRA alone require postremission chemotherapy, once remission is achieved, to extend remission. The results of differentiating therapy in APL patients has encouraged the use of differentiating therapy in patients with non-M3 AML. A number of areas await research, such as the need to develop ways to overcome acquired retinoic resistance and the development of cytochrome P450 inhibitors. Other novel retinoids, such as 9-cis-retinoic acid, may be even more effective than ATRA in APL. Additional important areas of research involve studying combinations of retinoids and other putative differentiating agents, and identifying different selected treatments targeted at specific molecular defects.

Topics: Antineoplastic Agents; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Humans; Leukemia, Myeloid, Acute; Leukemia, Promyelocytic, Acute; Randomized Controlled Trials as Topic; Survival Rate; Tretinoin

Differentiating therapy is a new antineoplastic strategy which has received increasing attention due to the remarkable activity of the vitamin A derivative, all-trans retinoic acid (ATRA) in patients with acute promyelocytic leukemia (APL). Although it has been known for years that a variety of agents, including retinoids, could induce leukemic cells to differentiate in vitro, it was not until the initial report from Shanghai in 1988 that laboratory studies translated into clinical activity and benefit in patients. Since this initial report, a number of studies have confirmed that the majority of patients with both newly diagnosed and previously chemotherapy-treated patients with APL achieve complete remission (CR) with ATRA. In addition, the characteristic life-threatening coagulopathy resolves quickly. Several limitations to this approach have emerged, including the development of retinoid resistance, hyperleukocytosis and the retinoic acid syndrome, a constellation of findings including unexplained fever, fluid retention, pleuropericardial effusions and pulmonary infiltrates. Although ATRA is very effective in inducing CR, its benefits compared to conventional chemotherapy are only now being addressed. The first prospective randomized trial comparing ATRA plus chemotherapy to chemotherapy alone was terminated early because of an improved event-free survival for patients receiving ATRA. The benefit was attributable to a difference in relapse rate. A large, intergroup, prospective, randomized trial comparing conventional chemotherapy to ATRA for induction and ATRA to observation for maintenance has recently completed accrual and will provide insight into the emerging role of ATRA in patients with APL. ATRA represents the first example of a specific form of antileukemic therapy targeting a specific genetic abnormality and may serve as a paradigm for the development of differentiating therapy for patients with other hematologic malignancies.

Topics: Acute Disease; Cell Differentiation; Clinical Protocols; Clinical Trials, Phase II as Topic; Humans; Leukemia, Myeloid; Leukemia, Promyelocytic, Acute; Randomized Controlled Trials as Topic; Translocation, Genetic; Tretinoin

Topics: Hemorrhagic Disorders; Humans; Leukemia, Promyelocytic, Acute; Lymphocyte Subsets; Tretinoin

Differentiating therapy is a new antineoplastic strategy which has received increasing attention due to the remarkable activity of the vitamin A derivative, all-trans retinoic acid (ATRA) in patients with acute promyelocytic leukemia (APL). Although it has been known for years that a variety of agents, including retinoids, could induce leukemic cells to differentiate in vitro, it was not until the initial report from Shanghai in 1988 that laboratory studies translated into clinical activity and benefit in patients. Since this initial report, a number of studies have confirmed that the majority of patients with both newly diagnosed and previously chemotherapy-treated patients with APL achieve complete remission (CR) with ATRA. In addition, the characteristic life-threatening coagulopathy resolves quickly. Several limitations to this approach have emerged, including the development of retinoid resistance, hyperleukocytosis and the retinoic acid syndrome, a constellation of findings including unexplained fever, fluid retention, pleuropericardial effusions and pulmonary infiltrates. Although ATRA is very effective in inducing CR, its benefits compared to conventional chemotherapy are only now being addressed. The first prospective randomized trial comparing ATRA plus chemotherapy to chemotherapy alone was terminated early because of an improved event-free survival for patients receiving ATRA. The benefit was attributable to a difference in relapse rate. A large, intergroup, prospective, randomized trial comparing conventional chemotherapy to ATRA for induction and ATRA to observation for maintenance has recently completed accrual and will provide insight into the emerging role of ATRA in patients with APL. ATRA represents the first example of a specific form of antileukemic therapy targeting a specific genetic abnormality and may serve as a paradigm for the development of differentiating therapy for patients with other hematologic malignancies.

Topics: Antineoplastic Agents; Clinical Trials, Phase II as Topic; Controlled Clinical Trials as Topic; Drug Resistance, Neoplasm; Humans; Leukemia, Promyelocytic, Acute; Survival Rate; Tretinoin

Acute promyelocytic leukemia, formerly a highly lethal disease, was recently shown to be highly responsive to treatment with the natural retinoid, all-trans retinoic acid. This compound induces terminal differentiation of the malignant cells and produces complete remission in most patients with this disease. The clinical response is due in part to the presence of a chromosomal break that occurs in a gene that encodes a nuclear retinoic acid receptor.

Topics: Chromosome Aberrations; Humans; Leukemia, Promyelocytic, Acute; Receptors, Retinoic Acid; Remission Induction; Tretinoin

Retinoic acids (RAs) exert a broad range of physiologic actions during embryonic development and adult life. Two families of RA receptors, retinoic acid receptor (RAR) and retinoid X receptor (RXR), have been identified. The therapeutic effect of all-trans-RA (ATRA) in induction of remission for acute promyelocytic leukemia (APL) has largely been proved, and this has, over the past 10 years, greatly stimulated research on oncogenesis and RA-regulated differentiation pathways. In APL, one of the RAR genes, RARA, is fused to PML in the great majority of patients as a result of the chromosomal translocation t(15; 17). However, a small subset of APL patients have a different fusion gene, PLZF-RARA, resulting from the variant translocation t(11;17). A third translocation, t(5;17), in which the NPM gene is fused to RARA, has been described. Current data suggest that PML-RAR alpha and PLZF-RAR alpha fusion receptors may play an important role in the development of APL and that PML-RAR alpha could be the target of ATRA differentiation therapy. Characterization of the genes regulated by retinoic acid may open up new prospects for an understanding of the mechanisms of ATRA differentiation therapy for APL and may help to extend the concept of cancer-targeting treatment to other types of leukemias or solid tumors.

Topics: Adult; Antineoplastic Agents; Base Sequence; Chimera; Chromosome Mapping; Chromosomes, Human, Pair 11; Chromosomes, Human, Pair 15; Chromosomes, Human, Pair 17; Cloning, Molecular; Consensus Sequence; Embryonic and Fetal Development; Humans; Leukemia, Promyelocytic, Acute; Neoplasm Proteins; Neoplasms; Nuclear Proteins; Promyelocytic Leukemia Protein; Receptors, Retinoic Acid; Retinoid X Receptors; Transcription Factors; Translocation, Genetic; Tretinoin; Tumor Suppressor Proteins

Topics: Adult; Gingiva; Humans; Leukemia, Myeloid; Leukemia, Promyelocytic, Acute; Leukemic Infiltration; Male; Tretinoin

A review of recent information on the expression and the ATRA-driven modulation of cell surface adhesion molecules of acute myelogenous leukemia blast cells is presented. Cytofluorometric studies on fresh blast cells have demonstrated that CD11a, CD11b CD11c, CD15, CD45RO and CD54 expression is significantly lower in acute promyelocytic leukemia (APL) than is acute myeloid leukemia of other subtypes (AML). In vitro treatment with ATRA dramatically modifies the adhesion phenotype of APL blast cells, promoting a consistently striking up-regulation of CD11b, CD11c, CD15, CD65, CD54, and CD38. Which is in general, poorly demonstrable in AML. The behaviour of CD15s is variable and fully independent from CD15 and CD65 in induction experiments, suggesting a differential enzyme regulation within the selectin ligand system. ATRA is capable, in both APL and AML, of producing a switch from the high- (RA) to the low- (RO) molecular weight isoform of CD54, Moreover, treatment with this retinoid exerts a negative regulation of the membrane expression of CD49e, CD58 and CD11a in APL as well as in AML. Of particular interest is the fact that the negative effect on CD1 1a expression generates an asynchronous phenotype in APL (CD11a-, CD11b+, CD15+), undetectable on normal maturing myeloid cells. In the last part of this review the possible implications of adhesion molecule modulation in the pathogenesis of ATRA syndrome are discussed.

Topics: Acute Disease; Cell Adhesion Molecules; Humans; Leukemia, Myeloid; Leukemia, Promyelocytic, Acute; Tretinoin

Currently available clinical results show that the combination of ATRA and anthracycline-Ara-C chemotherapy can slightly increase the CR rate in newly diagnosed APL, from about 80% (with chemotherapy alone) to more than 90%, and patients presenting with high leukocyte counts seem to benefit particularly from this combined therapy. ATRA followed by chemotherapy also reduces the incidence of relapse (particularly of early relapse) as compared to chemotherapy alone. However, treatment with ATRA is still complicated by the risk of hyperleukocytosis and potentially fatal ATRA syndrome, whose best preventive approach (addition of chemotherapy and/or dexamethasone) is still debated. Because some patients still relapse after ATRA plus chemotherapy, prognostic factors for relapse need to be precisely determined. They certainly include persistence or re-appearance of PML-RAR transcript during follow-up. Allogeneic BMT should be considered in those patients. Most of the patients who are not cured by the combination of ATRA and chemotherapy or by subsequent allogeneic BMT still die from their disease. This is due to the acquisition by APL cells of progressive resistance to ATRA, that appears to depend on induction of increased ATRA catabolism in APL cells. Current efforts aimed at overcoming this resistance (including intermittent ATRA schedules, synthesis of new retinoid compounds, utilization of inhibitors of cytochrome P450) are being developed.

Topics: Antineoplastic Combined Chemotherapy Protocols; Controlled Clinical Trials as Topic; Drug Administration Schedule; Humans; Leukemia, Promyelocytic, Acute; Randomized Controlled Trials as Topic; Remission Induction; Syndrome; Tretinoin

Topics: Anticoagulants; Antifibrinolytic Agents; Blood Coagulation Disorders; Hemostasis; Humans; Leukemia, Promyelocytic, Acute; Tretinoin

Topics: Cell Differentiation; Humans; Leukemia, Promyelocytic, Acute; Receptors, Retinoic Acid; Retinoic Acid Receptor alpha; Tretinoin

Acute promyelocytic leukemia (APL) is a specific type of acute myeloid leukemia characterized by the morphology of the blast cells, a specific t(15;17) translocation, and risks of definite coagulopathy. Recently this leukemia was further characterized by an exquisite sensitivity to all-trans retinoic acid's differentiation effect and the production of a fusion gene altering the gene of RARalpha and a novel gene PML. In vivo differentiation therapy with retinoids in APL patients follows strict guidelines related both to the APL cell and the biodisposal of all-trans retinoic acid.

Topics: Antineoplastic Agents; Cell Differentiation; Drug Resistance; Humans; Isomerism; Leukemia, Promyelocytic, Acute; Neutrophils; Receptors, Retinoic Acid; Recurrence; Tretinoin

Recent progresses made in the biology of acute promyelocytic leukemia and therapeutic improvements obtained in acute promyelocytic leukemia since the advent of all-trans retinoic acid have continued to generate a large number of publications on this disease in the past 12 months, which concern both its biological and therapeutic aspects.

Topics: Bone Marrow Transplantation; Humans; Leukemia, Promyelocytic, Acute; Polymerase Chain Reaction; Tretinoin

Topics: Antineoplastic Agents; Clinical Trials as Topic; Drug Resistance, Neoplasm; Humans; Leukemia, Promyelocytic, Acute; Neoplasm Proteins; Nuclear Proteins; Oncogene Proteins, Fusion; Promyelocytic Leukemia Protein; Transcription Factors; Translocation, Genetic; Tretinoin; Tumor Suppressor Proteins

Topics: Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Cytochrome P-450 Enzyme System; Drug Resistance, Neoplasm; Humans; Leukemia, Promyelocytic, Acute; Point Mutation; Receptors, Retinoic Acid; Tretinoin; Tumor Cells, Cultured

Pseudotumor cerebri or idiopathic intracranial hypertension is a neurological syndrome characterized by signs and symptoms of intracranial hypertension without clinical and radiological evidence of infective or space occupying lesions. Iatrogenic factors are frequent; in particular, cases of Pseudotumor cerebri associated with all-trans-retinoic acid treatment in acute promyelocytic leukemia (APL) have been frequently described in pediatric patients. We review the literature and give diagnostic and therapeutic guidelines.

Topics: Humans; Leukemia, Promyelocytic, Acute; Pseudotumor Cerebri; Tretinoin

Acute promyelocytic leukemia (APL) is uniquely sensitive to treatment with all-trans retinoic acid (ATRA) which exerts its action via a well-documented cytodifferentiating mechanism. The combination of this retinoid with anthracyclines gives high percentages of complete remission and is now considered the optimal induction treatment for APL patients. Continuous treatment with ATRA, however, induces accelerated drug catabolism, with progressive decline in plasma drug concentrations potentially to below the levels required to maintain differentiation of leukemic cells. This process, which occurs rapidly and consistently has led to the hypothesis that the development of acquired clinical resistance to ATRA in APL has a pharmacologic basis. The rapid autoinduction of the hypercatabolic state precludes maintenance with continuous ATRA oral dosing, and is a limitation of better use of the drug both in APL and in other disorders in which it could be beneficial. Here we briefly review the pharmacologic alterations of ATRA metabolism induced by continuous oral administration, the clinical implications of this phenomenon, and the strategies currently under investigation to prevent or overcome the induced catabolism of this retinoid.

Topics: Administration, Oral; Drug Administration Schedule; Drug Resistance, Neoplasm; Humans; Leukemia, Promyelocytic, Acute; Liposomes; Tretinoin

Bleeding diathesis is a common complication of acute promyelocyctic leukaemia (APL). Multiple haemostatic defects are found in most patients with APL, which often worsen following cytoreductive chemotherapy. Besides thrombocytopenia, most patients develop disseminated intravascular coagulation, systemic fibrinolysis or both. A major aim in treating haemostatic defects of APL is to prevent death or disability from bleeding until chemotherapy clears the malignant promyelocytes from the blood and bone marrow. The therapeutic options are discussed in this review and practical guidelines for treatment are outlined.

Topics: Antineoplastic Agents; Blood Coagulation Disorders; Disseminated Intravascular Coagulation; Hemostasis; Humans; Leukemia, Promyelocytic, Acute; Tretinoin

Topics: Drug Resistance, Neoplasm; Humans; Leukemia, Promyelocytic, Acute; Receptors, Retinoic Acid; Remission Induction; Transcription, Genetic; Translocation, Genetic; Tretinoin

Significant advances have occurred in the diagnosis, treatment, and long-term outcome of patients with acute promyelocytic leukemia (APL). The purpose of this review is to describe the molecular genetics of this disease, the use of all-trans retinoic acid (ATRA) in clinical trials of APL, and the clinical and basic research questions for future investigation. Findings of clinical studies in mainland China using ATRA as induction therapy for patients with APL concurrent with laboratory characterization of the molecular changes in APL have led to worldwide clinical trials of ATRA in the treatment of patients with APL. Major advances in understanding the molecular biology and genetics of APL have occurred over the past 5 years. These findings have been translated into novel treatment strategies using all-trans retinoic acid as a differentiation agent in the induction phase of therapy resulting in improved long-term outcome, reduced morbidity, and lower costs for patients with APL. Advanced molecular techniques are being employed for diagnosis and for monitoring of patient response to treatment.

Topics: Child; Child, Preschool; Humans; Leukemia, Promyelocytic, Acute; Receptors, Retinoic Acid; Tretinoin

Topics: Adult; Aged; Bone Marrow Transplantation; Child; Chromosomes, Human, Pair 22; Chromosomes, Human, Pair 9; Cytarabine; Humans; Leukemia; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Promyelocytic, Acute; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Translocation, Genetic; Tretinoin

Topics: Humans; Leukemia, Promyelocytic, Acute; Myelodysplastic Syndromes; Tretinoin

Acute promyelocytic leukemia (APL) is a good model for studying the human malignancies in that up to 90% of APL patients can achieve complete remission (CR) with a differentiation inducer, all-trans retinoic acid (ATRA). APL is also associated with a specific chromosomal translocation t(15;17) which fuses the retinoic acid receptor alpha (RAR alpha) gene with a chromosome 15q locus, PML. Recently the RAR alpha and the PML gene structural alterations in t(15;17) have been characterized. The heterogeneity of the PML rearrangements juxtaposes different PML gene portions to the same set of RAR alpha exons, producing two major PML-RAR alpha fusion mRNA isoforms. A retrotranscriptase/polymerase chain reaction (RT-PCR) analysis of the fusion transcripts has been developed which allows the detection of minimal residual disease during the clinical remission of APL. Molecular study showed PML-RAR alpha can form heterodimers with wild-type PML and RXR. Recently, PML has been shown to be one of the components of a nuclear body, POD. In APL, the normal organization of POD is disrupted by PML-RAR alpha, whereas ATRA treatment in vivo and in vitro can induce a reorganization of this organelle. Cytogenetic and molecular study allowed a variant translocation t(11;17) being recently discovered in a small subset of APL. This time RAR alpha is fused to a new gene, PLZF, on chromosome 11q23. It has been shown that the PLZF-RAR alpha, like PML-RAR alpha, has a "dominant negative" effect on the wild-type RAR-RXR. Clinical data obtained from a group of t(11;17) APL patients showed that these respond poorly to ATRA and could be grouped in a special clinical syndrome within APL. The comparison of the biological activities mediated by PML-RAR alpha and PLZF-RAR alpha may give new insights into the pathogenesis as well as the mechanisms of ATRA-induced differentiation in APL.

Topics: Cell Differentiation; Chromosome Aberrations; Chromosome Disorders; Chromosomes, Human, Pair 11; Chromosomes, Human, Pair 15; Chromosomes, Human, Pair 17; DNA-Binding Proteins; DNA, Neoplasm; Humans; Kruppel-Like Transcription Factors; Leukemia, Promyelocytic, Acute; Neoplasm Proteins; Nuclear Proteins; Promyelocytic Leukemia Protein; Promyelocytic Leukemia Zinc Finger Protein; Receptors, Retinoic Acid; Transcription Factors; Translocation, Genetic; Tretinoin; Tumor Suppressor Proteins

Topics: Antineoplastic Combined Chemotherapy Protocols; Blood Coagulation Disorders; Bone Marrow Transplantation; Cell Differentiation; Drug Resistance; Humans; Leukemia, Promyelocytic, Acute; Neoplasm, Residual; Survival Analysis; Thrombosis; Tretinoin

All transretinoic acid (ATRA) gives complete remission (CR) rates of 80 to 90% in newly diagnosed acute promyelocytic leukemia (APL). However, it has two major drawbacks (1) a rapid rise in WBC in some patients, with potentially fatal ATRA syndrome (2) rapid relapse with maintenance therapy using ATRA alone or low dose chemotherapy. The French APL group therefore designed a treatment approach with ATRA followed by intensive chemotherapy. The latter was administered after CR achievement with ATRA, or was rapidly added to ATRA in case of rapid rise in leukocyte counts. This combined approach, in a pilot study and in a randomized trial, proved superior to intensive chemotherapy alone, by slightly increasing the CR rate but more importantly by reducing the relapse rate. These results were confirmed by the Chinese, Japanese and New York groups. Our group (and other European groups) are now testing in a new randomized trial the better timing of ATRA and chemotherapy administration (ATRA followed by chemotherapy or ATRA plus chemotherapy) and the role (after an intensive consolidation) of maintenance treatment with intermittent ATRA, continuous low dose chemotherapy or both.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Cell Differentiation; China; Combined Modality Therapy; Cytarabine; Daunorubicin; Disease-Free Survival; Etoposide; Europe; Humans; Immunologic Factors; Leukemia, Promyelocytic, Acute; Leukocytosis; Life Tables; Middle Aged; Mitoxantrone; New York; Pilot Projects; Remission Induction; Survival Rate; Treatment Outcome; Tretinoin

All-trans-retinoic acid (ATRA, tretinoin) is a natural metabolite of retinol and is normally found in plasma, at concentrations of approximately 0.5-1.5 ng/ml. The in vivo and in vitro studies has demonstrated that in pharmacological doses it can differentiate leukemic cells in acute promyelocytic leukemia (APL). ATRA has been shown to induce complete remission (CR) rates of approximately 90% in newly diagnosed and first relapsing APL. However, CR induced by ATRA alone are usually not sustained and intensive antileukemic consolidation therapy is required to prolong remission. ATRA followed by intensive chemotherapy has improved the outcome of newly diagnosed APL, by increasing the CR rate and by reducing the risk of relapse. The presence of the PML/retinoic acid receptor-alpha (PML/RAR-alpha) fusion gene is a marker for sensitivity to this agent. ATRA therapy is associated with the risk of rapidly rising leukocyte counts, leading to the retinoid acid syndrome which may be fatal if the increase in leukocytes is not reversed. A side effects from these complications ATRA therapy is generally well tolerated.

Topics: Animals; Antineoplastic Agents; Humans; In Vitro Techniques; Leukemia, Promyelocytic, Acute; Leukocytosis; Myelodysplastic Syndromes; Tretinoin

Acute promyelocytic leukemia (APL) results from a malignant process that leads to the accumulation in the blood and the bone marrow of myeloid precursor cells characterized by an abnormal behavior and a differentiation arrest. It aroused considerable interest well beyond the hematologic field during the last five years since APL has two unique features i) the remission of the disease obtained with all-trans retinoic acid (ATRA) treatment ii) the presence in APL blasts of an abnormal protein, the promyelocytic myeloid leukemia/retinoic acid receptor (PML/RAR alpha) protein. APL is characterized cytogenetically by a t(15;17) translocation which involves both the PML gene on chromosome 15 and the RAR alpha gene on chromosome 17 and gives rise to the PML/RAR alpha fusion protein.

Topics: Chromosome Aberrations; Chromosome Disorders; Clinical Trials as Topic; Drug Resistance; Humans; Leukemia, Promyelocytic, Acute; Receptors, Cytoplasmic and Nuclear; Remission Induction; Retinoids; Tretinoin

Topics: Animals; Cell Differentiation; Humans; Leukemia, Promyelocytic, Acute; Receptors, Retinoic Acid; Remission Induction; Tretinoin

Acute promyelocytic leukemia is a key model system in Cancer biology. Its ability to differentiate upon exposure to retinoic acid constitutes the first example of differentiation therapy. The molecular basis of leukemogenesis is the PML/RAR fusion resulting from the t(15, 17) translocation. The fusion protein likely acts through interference with the function of nuclear receptors (resulting in a differentiation block) and also through interference with PML which appear to be a growth suppressor. The exquisite sensitivity of this disease to retinoic acid represents the first example of a therapy directly targeted at a specific and causative genetic lesion.

Topics: Cell Differentiation; Humans; In Vitro Techniques; Keratolytic Agents; Leukemia, Promyelocytic, Acute; Recombinant Fusion Proteins; Translocation, Genetic; Tretinoin

Tretinoin (all-trans retinoic acid), a vitamin A derivative, induces cellular differentiation in several haematological precursor cell lines and cells from patients with acute promyelocytic leukaemia. Drug treatment with tretinoin is associated with morphological and functional maturation of leukaemic promyelocytes and a progressive reduction in the occurrence of the characteristic t(15;17) chromosomal translocation. Recent therapeutic trials indicate that tretinoin induces remission in 64 to 100% of patients with acute promyelocytic leukaemia. In newly diagnosed patients, remission induction treatment with tretinoin followed by intensive chemotherapy resulted in a significant reduction in relapse rate and prolongation of event-free and overall survival compared with chemotherapy alone in 1 comparative trial. Tretinoin alone does not totally eradicate the leukaemic clone and consolidation chemotherapy is recommended as follow-up. The use of reverse transcription polymerase chain reaction (RT-PCR) provides a sensitive and specific technique to assist in prediction and monitoring of a patient's response to treatment and to help detect the presence of residual or recurrent disease. The use of tretinoin is potentially limited by the rapid and almost universal development of drug resistance and occurrence of the often severe retinoic acid syndrome. Useful strategies have been described to manage these effects but current and future efforts must be directed at elucidating the mechanisms involved and determining the optimum therapeutic management. In summary, results to date indicate that the combination of tretinoin and intensive chemotherapy is more effective than chemotherapy alone and appears to improve the prognosis of newly diagnosed patients with acute promyelocytic leukaemia. Further information on the relative efficacy of various induction and post-remission strategies in subsets of patients will help determine optimum use of this promising agent in the management of acute promyelocytic leukaemia.

Topics: Animals; Antineoplastic Agents; Clinical Trials as Topic; Humans; Leukemia, Promyelocytic, Acute; Tretinoin

A 53-year-old man with acute promyelocytic leukemia (APL) treated with all-trans retinoic acid (ATRA) developed fever and small erythemas on his arms and legs when the peripheral blood neutrophil count had increased. Erythemas gradually enlarged and painful subcutaneous nodules appeared. Skin biopsy revealed dense neutrophil infiltration in the dermis without vasculitis. These findings were compatible with Sweet's syndrome. Treatment with ATRA for APL was continued and no other additional therapy for Sweet's syndrome was performed. The syndrome was spontaneously improved in parallel with improvement of APL. In addition to this case report, three previously reported cases were reviewed to clarify the clinical characteristics of Sweet's syndrome in patients with APL during treatment with ATRA.

Topics: Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Sweet Syndrome; Tretinoin

Acute promyelocytic leukemia (APL) is an uncommon form of acute myeloid leukemia usually associated with disseminated intravascular coagulation (DIC). Pregnancy in patients with APL requires special consideration to maximize the probability of survival of both mother and fetus.. A patient with APL diagnosed during pregnancy who developed DIC is described. Obstetric and oncologic management of this difficult patient is discussed, and a pertinent literature review of pregnancy in APL is presented.. Of 23 pregnancies in patients with APL reported in the literature (including the present patient), 19 yielded live births, including 8 of 12 who received chemotherapy during late pregnancy and all 3 patients who received all-trans-retinoic acid (ATRA) during late pregnancy. Chemotherapy or ATRA induced complete remission in 72% of treated patients.. Proper management of pregnant patients with APL usually results in a live birth and complete remission of the mother's leukemia, despite the potentially devastating consequences of DIC, which is present at diagnosis in most patients.

Topics: Adult; Antibiotics, Antineoplastic; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Disseminated Intravascular Coagulation; Female; Fetal Death; Humans; Leukemia, Promyelocytic, Acute; Pregnancy; Pregnancy Complications, Neoplastic; Pregnancy Outcome; Pregnancy Trimester, Second; Prenatal Care; Remission Induction; Tretinoin

Topics: Cell Cycle; Cell Differentiation; Cell Line; Dimethyl Sulfoxide; GMP Reductase; Humans; IMP Dehydrogenase; Leukemia, Promyelocytic, Acute; NADH, NADPH Oxidoreductases; Phenotype; Purines; Pyrimidines; Tetradecanoylphorbol Acetate; Thymidine; Tretinoin; Tumor Cells, Cultured

Acute promyelocytic leukemia (APL) is the first example among the human malignancies that responds to differentiation therapy, in that complete remission (CR) can be achieved in up to 90% of patients by using a differentiation inducer, all-trans retinoic acid (ATRA). The specific chromosomal translocation t(15;17) in APL has been shown to fuse the gene for the retinoic acid receptor alpha (RAR alpha) with a chromosome 15q locus, PML. Alterations to the RAR alpha and the PML gene structures in the t(15;17) have been characterized and used as specific molecular marker for diagnosis of the disease. PML/RAR alpha antagonizes wild-type PML and RXR and could block the differentiation pathways mediated by these two regulators. A variant translocation t(11;17) has also been discovered in a subset of APL which fuses RAR alpha to a new gene, PLZF on chromosome 11q23. Both PML/RAR alpha and PLZF/RAR alpha display the "dominant negative" effect on the wild-type RAR/RXR. However, t(11;17) APL patients differ from t(15;17) APL in that they respond poorly to ATRA. Morphologically defined APL cases which however do not have PML/RAR alpha generally show no response to ATRA. Recently it has been shown that PML/RAR alpha can be modulated directly by ATRA. All these data support the idea that PML/RAR alpha is a specific target of ATRA which can overcome the differentiation block imposed by PML/RAR alpha. The ATRA treatment of APL thus further reinforces the concept of differentiation therapy.

Topics: Gene Targeting; Humans; Leukemia, Promyelocytic, Acute; Models, Genetic; Neoplasms; Receptors, Retinoic Acid; Translocation, Genetic; Tretinoin

Topics: Drug Resistance; Humans; Leukemia, Promyelocytic, Acute; Recurrence; Tretinoin

Acute promyelocytic leukemia (APL) has been historically characterized by a high rate of early hemorrhagic death, particularly from intracranial bleeding. The hemorrhagic complications have been attributed to a combination of intravascular thrombin generation, excessive fibrinolysis and/or proteolytic activities released from blast cells. Before the era of all-trans retinoic acid (ATRA), the incidence of early fatal bleeding in recent series has ranged from 8 to 46%, and no anti-hemorrhagic treatment clearly appeared superior in abating this complication. This uncertainty is due to remain because of the lack of prospective studies. The increasing awareness of the need for prompt diagnosis and treatment of APL and the larger availability of supportive therapy has largely contributed to lessen the incidence of fatal bleeding, which can be reliably estimated around 10% in major centers. Groups pioneering the use of ATRA have reported a rapid improvement of the coagulopathy of APL, usually starting 48 h from the beginning of the treatment. However, the hemostatic changes during ATRA have been monitored only in a few patients and recent results suggest that hyperfibrinolysis/proteolysis is rapidly corrected by ATRA, whereas thrombin generation may persist longer. Moreover, although significantly less frequent, fatal bleeding may occur during ATRA and thrombotic events have also been reported so that hemostatic death rate is also approximately 10% in patients treated with ATRA. The combination of chemotherapy plus ATRA administration during induction has been suggested as a useful means of controlling hyperleukocytosis, and this could contribute in abating this unacceptably high rate of early death. On the other side, chemotherapy can dramatically exacerbate clotting abnormalities leading to catastrophic clinical outcomes. Thus, more detailed studies of the coagulopathy of APL and its changes during treatment with ATRA, or ATRA combined with chemotherapy, are required in order to offer the most appropriate treatment to these patients still at risk of severe bleeding and thrombotic complications.

Topics: Antineoplastic Combined Chemotherapy Protocols; Blood Coagulation; Hemorrhage; Humans; Leukemia, Promyelocytic, Acute; Syndrome; Thrombosis; Tretinoin

The current treatment of acute promyelocytic leukemia (APL, also called AML3 subtype) is focused on differentiating agents such as the vitamin A derivative all-trans retinoic acid (ATRA). This agent is a novel and very promising therapy for this disease characterized cytogenetically by a translocation t(15;17)(q21;q22) involving the alpha retinoic acid receptor on chromosome 17 and the PML gene on chromosome 15. Clinical trials have demonstrated that ATRA followed by or combined with conventional chemotherapy may be more beneficial than chemotherapy for inducing complete remission. Unfortunately, ATRA as a single agent, does not appear able to maintain patients in remission (median 5 months), and when relapse occurs resistance to a second induction of ATRA therapy is observed in almost all cases. Recently our laboratory investigated whether specific features of the AML3 cells at relapse could explain the in vivo resistance observed. We have demonstrated that AML3 patients' cells (from four patients) at relapse show high levels of CRABP, a cytosolic retinoic acid binding protein and this protein was not detected prior to ATRA therapy. Relapse-AML3 cells (n = 12) showed reduced differentiation induction when compared with 'virgin'-AML3 cells. Results from this study suggest that CRABP could modulate ATRA cellular concentrations reaching the nucleus. This induced ATRA hypercatabolytic state should be monitored during consolidation therapy and at relapse by evaluating CRABP and RA metabolite levels, in order to detect ATRA resistance in patients with AML3.

Topics: Clinical Trials as Topic; Drug Resistance; Humans; Leukemia, Promyelocytic, Acute; Receptors, Retinoic Acid; Recurrence; Remission Induction; Tretinoin; Tumor Cells, Cultured

A 61-year-old man with acute promyelocytic leukemia (APL) is described in whom some leukemic promyelocytes contained granules similar to those of basophils, and hyperhistaminemia developed after treatment with all-trans retinoic acid. The symptoms of hyperhistaminemia, mediated via H2 receptors, were prevented by the administration of an H2-blocker, famotidine, but wheezing due to bronchospasms, mediated via H1 receptors, developed and was improved by administration of chlorpheniramine. In APL, it is generally thought that the maturation of neutrophilic leukocytes is arrested at the level of abnormal promyelocytes. However, heterogeneity of leukemic promyelocytes has been described and in a few patients some leukemic promyelocytes have been known to show basophilic features. Marked basophilia and severe symptoms due to hyperhistaminemia have recently been reported after the treatment of APL with all-trans retinoic acid. Our case presented similar basophilic features, but indicated that the symptoms of hyperhistaminemia after administration of retinoic acid can be prevented with antihistaminic drugs and suggested that both H1- and H2-blockers should be administered to such APL patients with basophilia.

Topics: Basophils; Chlorpheniramine; Drug Therapy, Combination; Famotidine; Histamine; Humans; Karyotyping; Leukemia, Promyelocytic, Acute; Leukocyte Count; Male; Middle Aged; Tretinoin

Continuous daily treatment with all-trans-retinoic acid (ATRA) in patients with acute promyelocytic leukemia has been associated with a marked decline in the plasma drug concentration at the time of relapse. Recent pharmacologic studies have attempted to determine the reasons for the progressive reduction of plasma concentrations of the drug. A decrease in plasma concentrations over time may be attributed to either upregulation of metabolism or downregulation of absorption. The effect of intravenous ATRA was examined in Rhesus monkeys to help differentiate between these possibilities and to better establish the metabolism of ATRA. Findings were consistent with a capacity-limited (saturable) elimination process. A subsequent study with Rhesus monkeys demonstrated that this capacity-limited elimination process can be induced. Two potential ways of overcoming decreased plasma levels are suggested by the explanations for rapid elimination of ATRA: administration of a P-450 inhibitor such as ketoconazole to block oxidation of the drug, or use of an intermittent dosing schedule. Studies are currently under way to examine the effectiveness and tolerability of these methods.

Topics: Animals; Clinical Trials as Topic; Drug Administration Schedule; Humans; Ketoconazole; Leukemia, Promyelocytic, Acute; Macaca mulatta; Time Factors; Tretinoin

Retinoids, including retinoic acid (RA), are naturally occurring and synthetic analogs of vitamin A that inhibit cell growth and induce cell differentiation in many experimental tumor models. Differentiation of the human myelogenous leukemia cell line HL-60 by RA led to the finding that cells from patients with acute promyelocytic leukemia (APL) are terminally differentiated by RA. One mechanism for the activity of RA in a variety of cell types involves the RA nuclear receptors (RA receptors [RARs] and retinoid X receptors), which have specific high-affinity binding sites for RA and some of its metabolites. Other mechanisms may also be involved in RA-induced differentiation. Recent studies suggest that RA acylation (retinoylation) may be involved in the RA induction of differentiation in leukemia cells. Combinations of RA with cyclic adenosine monophosphate (cAMP)-elevating agents led to synergistically induced differentiation of HL-60 cells. The lower doses of RA needed in combination therapy are unlikely to lead to RA resistance, a major limitation of RA therapy in APL. In vitro studies suggest that combinations of RA with either PGE or the butyric acid (BA) prodrug tributyrin (TB) may be useful in differentiation therapy for APL and other malignancies. This is a US government work. There are no restrictions on its use.

Topics: Antineoplastic Combined Chemotherapy Protocols; Butyrates; Butyric Acid; Cell Differentiation; Child; Cyclic AMP; Humans; Leukemia; Leukemia, Promyelocytic, Acute; Prostaglandins E; Tretinoin

Several phase II clinical studies of all-trans-retinoic acid (ATRA) have been conducted in acute promyelocytic leukemia (APL), an uncommon subtype of acute myeloid leukemia (AML). ATRA has been shown to induce complete remission (CR) in 64% to 96% of patients with APL, and with rapid resolution of the coagulopathy, which is a major cause of early morbidity and mortality. Although CRs induced with ATRA alone are usually not sustained and intensive antileukemic consolidation therapy is required to prolong remission, these findings indicate that a new approach of differentiation therapy is effective in treating patients with APL and may potentially be effective in other malignancies. The presence of the PML/retinoic acid receptor-alpha (PML/RAR-alpha) fusion gene, produced as a result of the unique chromosomal translocation in APL, is a marker of sensitivity to ATRA. Aside from the complications of hyperleukocytosis and the retinoic acid syndrome, ATRA therapy is generally well tolerated. An international study (Intergroup 0129), headed by the Eastern Cooperative Oncology Group, is currently under way to determine further the role of ATRA in the treatment of patients with APL. Given its success in APL, studies of ATRA in other hematologic malignancies are also being conducted. A better understanding of how retinoids modulate carcinogenesis will help determine if the results in APL can be realized in other malignancies treated with ATRA or other retinoids.

Topics: Clinical Trials, Phase II as Topic; Disseminated Intravascular Coagulation; Forecasting; Hematologic Diseases; Humans; Leukemia, Promyelocytic, Acute; Remission Induction; Tretinoin

Acute promyelocytic leukemia (APL), is a homogeneous subgroup of acute myelogenous leukemias characterized by phenotypic and genetic markers. APL is associated with a reciprocal chromosomal translocation t(15,17) which has been shown to disrupt the retinoic acid receptor alpha (RAR alpha) gene. As a result, a portion of the RAR alpha gene becomes fused with a chromosome 15 locus termed PML (promyelocytic myeloid leukemia) from which chimeric PML/RAR alpha fusion mRNAs are expressed. The presence of these fusion transcripts in APL patients strongly support the hypothesis that both the t(15;17), and thus PML/RAR alpha, play a crucial role in the leukemogenesis of this disease. APL cells are specifically responsive to all-trans retinoic acid (ATRA) and this characteristic has allowed the first differentiation therapy with retinoic acid. However, failure or partial responses are observed and, though this has most frequently been reported in patients at second or third relapse. The molecular basis of the absence of ATRA response in these patients has not been determined.

Topics: Cell Differentiation; Cell Transformation, Neoplastic; Chromosomes, Human, Pair 15; Chromosomes, Human, Pair 17; Gene Expression Regulation, Leukemic; Humans; Leukemia, Promyelocytic, Acute; Multigene Family; Neoplasm Proteins; Neoplastic Stem Cells; Oncogene Proteins, Fusion; Receptors, Retinoic Acid; Translocation, Genetic; Tretinoin

Acute promyelocytic leukemia is characterized by a specific t(15;17) chromosomal translocation and a particular sensitivity to retinoic acid. The translocation fuses the PML gene to the retinoic acid receptor alpha (RAR alpha) gene resulting in the production of a PML-RAR alpha fusion protein. The hybrid molecule retains most of the functional domains of both native products, PML and RAR alpha, but it has novel features. Its cellular distribution is completely reorganized when compared to that of PML: the hybrid is found in multiple small nuclear substructures and upon retinoic acid treatment, it goes back to the normal PML localization, that is in typical well organized nuclear bodies. PML-RAR alpha also acquires novel transcriptional properties if compared to RAR alpha, it does so either by direct binding to target gene regulatory sequences or by protein interaction with cofactors. Expression of PML-RAR alpha in HL60 or U937 cell has been shown to block their maturation while it can force their differentiation at high doses of retinoic acid. Different mechanisms are proposed to explain how PML-RAR alpha blocks differentiation and how this may be reversed by retinoic acid. A likely hypothesis might be the delocalization of critical cofactors into the aberrant PML-RAR alpha substructures while the therapeutic effect of retinoic acid would be correlated to its capacity to restore a normal nuclear organization.

Topics: Cell Line; Cell Nucleus; Chromosomes, Human, Pair 15; Chromosomes, Human, Pair 17; Cloning, Molecular; Humans; Leukemia, Promyelocytic, Acute; Neoplasm Proteins; Nuclear Proteins; Oncogene Proteins, Fusion; Promyelocytic Leukemia Protein; Receptors, Retinoic Acid; Recombinant Fusion Proteins; Retinoic Acid Receptor alpha; Transcription Factors; Translocation, Genetic; Tretinoin; Tumor Suppressor Proteins

All-trans retinoic acid (RA) has proven a major advance in the treatment of acute promyelocytic leukemia (APL). However, the proper management of patients who present with or develop leukocytosis during remission induction with all-trans RA is not established, nor is there a clear relation between leukocytosis and the development of the retinoic acid syndrome. We reviewed the course of our patients who underwent induction with all-trans RA to identify potential factors that might predict for the development of this syndrome and to identify which patients, if any, might specifically benefit from additional treatment with cytotoxic chemotherapy. Seventy-eight courses of all-trans RA therapy were administered to patients with a molecular diagnosis of APL. Initial and peak leukocyte counts, their rate of rise, leukocyte count criteria developed in Europe, and cell surface marker expression were all analyzed relative to subsequent development of both the RA syndrome as well as all causes of early mortality. The outcome of patients who received specific treatment for retinoid-induced leukocytosis was also examined. No factor was found to consistently predict for the development of the RA syndrome. Although the occurrence of the syndrome was positively associated with the peak value of the peripheral blood leukocyte count (P = .001), neither the initial leukocyte count nor the rate of rise in leukocyte counts on days preceding onset of the syndrome were sufficiently well-correlated to be clinically useful (P = .21). The leukocyte count criteria developed in Europe had a sensitivity of 62%, a specificity of 69%, and a positive predictive value that ranged from only 44% to 72%. However, we unexpectedly found that basal expression of CD13 (aminopeptidase N), a cell surface enzyme previously linked to tumor cell invasion and an inferior outcome in patients with acute myeloid leukemia, was highly associated with both development of the syndrome (P < .05) as well as an elevated leukocyte count (P = .006). Neither low-dose chemotherapy nor leukapheresis prevented development of the syndrome nor ameliorated its effects. In fact, 9 of 11 patients who received these interventions sustained fatal or near-fatal events, most of which were due to hemorrhage. However, early treatment with a short-course of high-dose corticosteroids halted progression of the syndrome in most cases. Finally, we found that expression of the type "A" isoform of PML/RAR-alpha (also known as bcr3 or

Topics: Adrenal Cortex Hormones; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Cause of Death; CD13 Antigens; Cerebral Hemorrhage; Combined Modality Therapy; Gene Expression Regulation, Leukemic; Humans; Leukapheresis; Leukemia, Promyelocytic, Acute; Leukocytosis; Neoplasm Proteins; Pulmonary Edema; Receptors, Retinoic Acid; Remission Induction; Retinoic Acid Receptor alpha; Retrospective Studies; Survival Analysis; Syndrome; Treatment Outcome; Tretinoin

Topics: Blood Coagulation Disorders; Cell Differentiation; Clinical Trials as Topic; Humans; Leukemia, Promyelocytic, Acute; Tretinoin

Topics: Adult; Cholestasis, Intrahepatic; Disseminated Intravascular Coagulation; Humans; Leukemia, Promyelocytic, Acute; Male; Renal Insufficiency; Tretinoin

The clinical pharmacology of all-trans retinoic acid (RA) has distinct differences from that of its widely studied stereoisomer 13-cis retinoic acid (cRA). RA is much more rapidly cleared from plasma following oral administration; their respective half-lives are < 1 h and 13 h. There is extensive accumulation of the 4-oxo-cRA in plasma following repeated doses of cRA, while 4-oxo-RA is only a minor metabolite in plasma following RA administration. The extent of isomerization in vivo differs for the two retinoids. In contrast to cRA, where up to a 1:3 ratio of RA to cRA is observed in patient plasma following drug administration, cRA concentrations in excess of 10 ng/ml are rarely observed in plasma of patients receiving exogenous RA. RA administration produces autoinduction of its own oxidative catabolism; this effect does not occur with cRA. These pharmacokinetic differences have been observed in leukemia and solid tumor patients. Detailed analysis of the results of the population studied suggest that both constitutive and RA-induced hypercatabolism of RA occurs. Both of these hypercatabolic states can be modulated by concurrent administration of ketoconazole, an inhibitor of cytochrome P-450 and lipoxygenase-mediated oxidations.

Topics: Carcinoma, Non-Small-Cell Lung; Humans; Ketoconazole; Leukemia, Promyelocytic, Acute; Lung Neoplasms; Male; Metabolic Clearance Rate; Multiple Myeloma; Oxidation-Reduction; Prostatic Neoplasms; Tretinoin

Acute promyelocytic leukemia (M3) is a distinct subtype of AML considered to have better response to chemotherapy and a higher cure rate than other subtypes. We analyzed the outcome for 362 M3 patients transplanted in Europe from November 1979 to December 1992 and reported to the acute leukemia registry of the European Cooperative Group for Bone Marrow Transplantation (EMBT). Of these 362 patients, 187 received an autograft, 129 in first remission (CR1) and 58 in second remission (CR2), and 175 an allograft, 142 in CR1 and 33 in CR2. Patients autografted in CR1 had at 7 years a leukemia-free survival (LFS) of 48 +/- 5%, a relapse rate (RR) of 41 +/- 5% and a probability of transplant-related mortality (TRM) of 18 +/- 6%. Patients allografted in CR1 had a LFS of 42 +/- 6%, a RR of 28 +/- 5% and a TRM probability of 42 +/- 8%. For patients transplanted in CR2, the respective figures after auto and allotransplantation were: LFS: 31 +/- 7% and 22 +/- 8%, RR: 54 +/- 8% and 64 +/- 11%, TRM: 23 +/- 9% and 40 +/- 9%. These data, which do not permit comparison between autologous and allogeneic BMT, indicate that roughly 45% of M3 patients achieving CR1 may be cured by a marrow transplant. Since the recent use of transretinoic acid-containing induction regimens has increased early control for patients with AML M3, it will be important to find out how these results affect outcome following allogeneic or autologous BMT.

Topics: Adolescent; Adult; Bone Marrow Transplantation; Child; Child, Preschool; Disease-Free Survival; Europe; Female; Humans; Infant; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Registries; Tretinoin

Topics: Cell Differentiation; Humans; Leukemia, Promyelocytic, Acute; Receptors, Retinoic Acid; Tretinoin

The extramedullary collection of leukemic cells is an infrequent complication of myeloid leukemias, and extremely uncommon in acute promyelocytic leukemia (APL).. The case reports of two patients with APL who relapsed with extramedullary disease and a review of the literature are presented.. Two patients with cytogenetically and molecularly confirmed APL developed extramedullary relapse in skin and lymph nodes after prior treatment with all-trans retinoic acid. A review of the literature revealed only nine cases of APL complicated by extramedullary disease. However, only one of these previously reported patients was shown to have the cytogenetic abnormality characteristic of APL.. To the authors' knowledge, These two patients represent the first cases of cytogenetically confirmed APL treated with all-trans retinoic acid who developed extramedullary relapse. These events, which were reported infrequently in patients treated only with cytotoxic therapy, may be more common in patients receiving all-trans retinoic acid. In view of the differentiating activity of all-trans retinoic acid, which may increase the migratory capacity of these malignant cells, it is hypothesized that this agent may predispose some patients to unusual forms of relapse.

Topics: Adult; Antigens, CD; Chromosomes, Human, Pair 15; Chromosomes, Human, Pair 17; Ear Canal; Humans; Leukemia, Promyelocytic, Acute; Leukemic Infiltration; Male; Recurrence; Skin; Translocation, Genetic; Tretinoin

The characteristic balanced 15;17 translocation, t(15;17), of acute promyelocytic leukemia (APL) fuses the retinoic acid receptor alpha (RAR alpha) gene on chromosome 17 to PML, a recently described gene of unknown function, on chromosome 15. It is this fusion gene and consequent fusion protein that is thought to be responsible for both the block in normal myelocyte differentiation as well as the dramatic in vitro and in vivo response to the differentiating effects of all-trans retinoic acid (RA). The t(15;17) also provides a genetic marker for the presence of leukemic cells. PML/RAR alpha fusion mRNA's can be detected by a reverse transcription polymerase chain reaction (RT-PCR) assay. Using this assay, at least three distinct patterns, differing in the 3' region of the PML breakpoint, can be identified. The detection of abnormal mRNA's by the RT-PCR assay has proven to be an important aid in the diagnosis of APL as well as the best predictor of an initial clinical response to RA. The results of an ongoing, longitudinal evaluation of patients with APL show that the RT-PCR assay may also be a useful indicator of minimal residual disease (MRD). Negative RT-PCR assays following completion of all therapy are associated with prolonged disease free survival, whereas persistence or return of a positive test is highly correlated with subsequent relapse. Further studies will determine whether patients who test positive may benefit from the introduction of additional antileukemic therapy.

Topics: Humans; Leukemia, Promyelocytic, Acute; Neoplasm Proteins; Nuclear Proteins; Polymerase Chain Reaction; Promyelocytic Leukemia Protein; Receptors, Retinoic Acid; Transcription Factors; Translocation, Genetic; Tretinoin; Tumor Suppressor Proteins

All-trans retinoic acid (ATRA)-therapy against acute promyelocytic leukemia (APL) is epoch-making in the sense of the first success in both tumor-differentiation therapy and molecule-targeted therapy. Kouseishou APL-study group performed three clinical studies to refractory APL with ATRA from 1990 to 1993. Complete remission (CR) was obtained in 82%, 88% and 78% of 22, 41 and 46 patients, respectively. Molecular diagnosis of the t (15;17) translocation was possible using Southern blot analysis and reverse transcriptase polymerase chain reaction (RT-PCR).

Topics: Chromosomes, Human, Pair 15; Chromosomes, Human, Pair 17; Humans; Leukemia, Promyelocytic, Acute; Remission Induction; Translocation, Genetic; Tretinoin

Topics: Clinical Trials as Topic; Humans; Leukemia, Promyelocytic, Acute; Recurrence; Remission Induction; Tretinoin

The major cause of early death in acute promyelocytic leukemia (APL), the high risk of a bleeding diathesis is now successfully counteracted within a few days by differentiation therapy using ATRA. Moreover, no resistance to this drug has been recorded during induction when the usual presence of PML/RAR alpha was confirmed by molecular study (some M3 cases do lack rearrangement of PML/RAR alpha). Paradoxically, a hypercoagulable clotting tendency may occur in these patients during the first month of ATRA treatment. Leucocyte activation (retinoic acid syndrome), often secondary to hyperleukocytosis, is prevented by early addition of chemotherapy when WBCs exceed defined limits, and is successfully treated by high dose corticosteroids. Routine acquired progressive in vivo resistance to all trans retinoic acid (ATRA) requires consolidation of ATRA-induced complete remission (CR) with intensive chemotherapy. Prevention of relapses using maintenance therapy is questionable and has not been tested in randomized trials. Actually the event-free survival of APL patients treated by the combination of ATRA and chemotherapy is 80% at 1 year, and the cure of 50% of patients is within our reach.

Topics: Hemorrhage; Humans; Leukemia, Promyelocytic, Acute; Leukocytosis; Prognosis; Time Factors; Tretinoin

The current treatment of acute promyelocytic leukemia (APL, also called AML3 subtype) is focused on differentiating agents such as the vitamin A derivative all-trans retinoic acid (ATRA). This agent is a novel and very promising therapy for this disease characterized cytogenetically by a translocation t(15;17)(q21;q22) involving the alpha retinoic acid receptor on chromosome 17 and the PML gene on chromosome 15. Clinical trials have demonstrated that ATRA followed by or combined with conventional chemotherapy may be more beneficial than chemotherapy for inducing complete remission. Unfortunately, ATRA as a single agent, does not appear able to maintain patients in remission (median 5 months), and when relapse occurs resistance to a second induction of ATRA therapy is observed in almost all cases. Recently our laboratory investigated whether specific features of the AML3 cells at relapse could explain the in vivo resistance observed. We have demonstrated that AML3 patients' cells (from four patients) at relapse show high levels of CRABP, a cytosolic retinoic acid binding protein and this protein was not detected prior to ATRA therapy. Relapse-AML3 cells (n = 12) showed reduced differentiation induction when compared with 'virgin'-AML3 cells. Results from this study suggest that CRABP could modulate ATRA cellular concentrations reaching the nucleus. This induced ATRA hypercatabolytic state should be monitored during consolidation therapy and at relapse by evaluating CRABP and RA metabolite levels, in order to detect ATRA resistance in patients with AML3.

Topics: Drug Screening Assays, Antitumor; Humans; Leukemia, Promyelocytic, Acute; Receptors, Retinoic Acid; Remission Induction; Tretinoin

Topics: Cell Differentiation; Hematopoietic Stem Cells; Humans; Leukemia, Promyelocytic, Acute; Neoplasm Proteins; Nuclear Proteins; Promyelocytic Leukemia Protein; Receptors, Retinoic Acid; Transcription Factors; Translocation, Genetic; Tretinoin; Tumor Suppressor Proteins

Topics: Antineoplastic Combined Chemotherapy Protocols; Humans; Leukemia, Promyelocytic, Acute; Neoplastic Stem Cells; Retinoids; Tretinoin

Topics: Carrier Proteins; Cell Differentiation; Drug Resistance; Gene Rearrangement; Humans; Leukemia, Promyelocytic, Acute; Leukocytosis; Receptors, Retinoic Acid; Tretinoin; Tumor Cells, Cultured

Recently, a new therapeutic approach to leukemia has been developed by induction of differentiation of leukemic cells. To improve this therapy, various factors involved in in vivo induction of differentiation of leukemia cells should be clarified. Clinical studies showed that inducers of differentiation of leukemia cells including retinoic acid, hexamethylene bisacetamide and some chemotherapeutic drugs induced remission in patients with acute myelogenous leukemia. Clonal analysis of the matured granulocytes revealed that the effectiveness of these drugs was due to their ability to induce differentiation of the leukemic cells rather than their cytocidal activity. On the other hand, various types of agents have been found to induce in vitro differentiation of leukemia line cells and fresh human leukemic cells. To evaluate therapeutic efficacy of these differentiation-inducing agents, pre-clinical experiments using animal model and tests for in vivo inducibility of differentiation of the leukemia cells are essential. We are developing an experimental system to monitor in vivo induction of differentiation of murine leukemia cells inoculated into syngeneic mice.

Topics: Acetamides; Animals; Antineoplastic Agents; Cell Differentiation; DNA, Neoplasm; Flow Cytometry; Leukemia, Experimental; Leukemia, Promyelocytic, Acute; Mice; Polymorphism, Restriction Fragment Length; Translocation, Genetic; Tretinoin

Topics: Cloning, Molecular; Humans; Leukemia, Promyelocytic, Acute; Neoplasm Proteins; Nuclear Proteins; Oncogene Proteins, Fusion; Promyelocytic Leukemia Protein; Receptors, Retinoic Acid; Transcription Factors; Translocation, Genetic; Tretinoin; Tumor Suppressor Proteins

X-linked clonal analysis (XLCA) either using Glucose-6-phosphate dehydrogenase (G-6-P-D) polymorphisms or restriction fragment length polymorphisms (RFLP) and methylation analysis has provided considerable understanding of haematologic malignancy. Acute Promyelocytic Leukemia (APL) is characterized by a unique cytogenetic translocation t(15;17), frequent achievement of remission without a preceding phase of marrow hypocellularity after induction chemotherapy and a high rate of clinical response to all-trans retinoic acid (ATRA). In limited studies XLCA has provided insight into the pathogenesis and mechanism of drug action in this disease.

Topics: Humans; Leukemia, Promyelocytic, Acute; Tretinoin; Tumor Stem Cell Assay; X Chromosome

The modern treatment of acute myelogenous leukemia (AML), consists of a polychemotherapeutic induction treatment followed by a post-remission therapy of variable intensity and duration and acute promyelocytic leukemia (APL) does not differ from this behavior. However, differently from the other AML subtypes, APL shows a high response rate to induction monochemotherapies with anthracycline drugs. This high response rate to anthracycline monochemotherapies is very peculiar of APL. Moreover, it has been suggested that maintenance treatment regimens incorporating the drugs Methotrexate and 6-Mercaptopurine, two drugs generally not utilized in the post-remission treatment of other AML subtypes, may be effective in prolonging the leukemia-free survival of APL. Furthermore, the results firstly obtained by a Chinese group in 1988 by using the vitamin A derivative all-trans retinoic acid (ATRA) have been successively confirmed by several other groups in the world. Therefore, at present the all-trans retinoic acid appears to be the best CR inducer in APL. However, these CRs are short lasting when maintained with ATRA alone and eventually all patients relapse. As a consequence, patients achieving CR with ATRA still require intensive post-remission chemotherapy to maintain the CR. As for bone marrow transplantation procedures, it is our opinion that they do not represent the treatment of choice of APL in first CR considering the very good results obtained with standard pharmacological approaches. In conclusion, only future randomized prospective trials will clarify which, among the several proposed therapeutic approaches, should be preferred in this very peculiar subtype of AML.

Topics: Bone Marrow Transplantation; Humans; Leukemia, Promyelocytic, Acute; Tretinoin

Topics: Antineoplastic Combined Chemotherapy Protocols; Cell Differentiation; Combined Modality Therapy; Drug Evaluation; Drug Resistance; Humans; Immunologic Factors; Leukemia, Promyelocytic, Acute; Neoplasm Proteins; Neoplasm Recurrence, Local; Neoplastic Stem Cells; Nuclear Proteins; Oncogene Proteins, Fusion; Promyelocytic Leukemia Protein; Receptors, Retinoic Acid; Remission Induction; Transcription Factors; Translocation, Genetic; Tretinoin; Tumor Suppressor Proteins

Acute promyelocytic leukaemia (APL) is a rare acute myeloid leukaemia characterized by a distinctive coagulopathy, the differentiation of promyelocytes in response to all-trans retinoic acid and a reciprocal chromosomal translocation, t(15;17)(q22;q12-q21). Molecular analysis of the APL breakpoint has revealed the involvement of the retinoic acid receptor alpha (RARA) gene on chromosome 17 and the promyelocytic leukaemia (PML) gene on chromosome 15. Both reciprocal fusion products which arise as a result of the translocation, PML/RAR alpha and RAR alpha/PML, are expressed in many patients. PML/RAR alpha, is implicated in leukaemogenesis, and may block myeloid differentiation directly and/or interfere with the normal function(s) of PML and/or RAR alpha.

Topics: Amino Acid Sequence; Antineoplastic Combined Chemotherapy Protocols; Base Sequence; Cell Differentiation; Chromosomes, Human, Pair 15; Chromosomes, Human, Pair 17; Cloning, Molecular; Combined Modality Therapy; Gene Expression Regulation, Leukemic; Gene Rearrangement; Humans; Immunologic Factors; Leukemia, Promyelocytic, Acute; Molecular Sequence Data; Neoplasm Proteins; Nuclear Proteins; Oncogene Proteins, Fusion; Oncogenes; Polymerase Chain Reaction; Promyelocytic Leukemia Protein; Receptors, Retinoic Acid; Remission Induction; Retinoic Acid Receptor alpha; Transcription Factors; Translocation, Genetic; Tretinoin; Tumor Suppressor Proteins; Zinc Fingers

Topics: Genetic Therapy; Humans; Leukemia, Promyelocytic, Acute; Tretinoin

Patients with acute promyelocytic leukemia (APL) are at high risk for the development of life-threatening thrombotic and hemorrhagic complications, particularly during induction chemotherapy. This propensity has been attributed to the release of tissue factor (TF)-like procoagulants from the leukemic cells leading to disseminated intravascular coagulation (DIC). However, recent data suggest that the pathogenesis of the coagulopathy is more complicated and may involve activation of the generalized proteolytic cascade resulting in either clotting and/or excessive fibrinolysis. Furthermore, controversy exists regarding the mechanism(s) responsible for the activation of either clotting or fibrinolysis. The malignant promyelocyte may act directly to activate coagulation and/or fibrinolysis. Alternatively, reactive inflammatory cells, which express procoagulant and/or profibrinolytic activities may play an essential role. A third possibility may involve endothelial cell expression of mediators with procoagulant/profibrinolytic properties. Putative profibrinolytic mechanisms include the release of urokinase-type and tissue-type plasminogen activators, decreases in plasminogen activator inhibitor-1 and 2, and decreases in alpha-2 plasmin inhibitor. Putative procoagulant mechanisms include the release of tissue factor, Cancer Procoagulant, or cytokines such as interleukin-1, tumor necrosis factor and vascular permeability factor. Putative anticoagulant mediators include annexins, a group of proteins in human tissue which bind phospholipids and have anticoagulant activity, which have been reported in patients with APL. The current treatment of APL is rapidly evolving because of the efficacy of all-trans retinoic acid (ATRA). All-trans retinoic acid promotes terminal differentiation of leukemic promyelocytes leading to complete remission in the majority of patients with APL with rapid resolution of the coagulopathy. Although the mechanism by which this occurs has not been established, preliminary data suggest that ATRA blocks the downregulation of the thrombomodulin gene and the up-regulation of the tissue factor gene induced by tumor necrosis factor. Since APL is a relatively uncommon disorder, the collaboration of cooperative oncology groups will be important to study patients receiving ATRA or conventional chemotherapy to further elucidate the mechanism(s) of the coagulopathy.

Topics: Blood Coagulation; Blood Coagulation Disorders; Fibrinolysis; Humans; Leukemia, Promyelocytic, Acute; Tretinoin

Acute promyelocytic leukemia (APL) is a rare subtype of acute myelogenous leukemia. It is frequently associated with a life-threatening hemorrhagic diathesis, often aggravated by induction cytotoxic chemotherapy. Patients with APL have bone marrow infiltration by abnormal promyelocytes, usually with prominent cytoplasmic granulation. These patients have a unique cytogenetic abnormality, a balanced reciprocal translocation between the long arms of chromosomes 15 and 17. The nuclear retinoic acid receptor alpha gene, on chromosome 17, is translocated to the PML gene region, on chromosome 15, resulting in the synthesis of two fusion messenger ribonucleic acids, PML/RAR-alpha and RAR-alpha/PML, easily detected by the reverse transcriptase polymerase chain reaction. This assay is extremely useful in the diagnosis and detection of minimal residual disease in APL patients. All trans-retinoic acid (ATR) differentiates the malignant cell clone and corrects the coagulopathy associated with this disease. The most important adverse effect is a respiratory distress syndrome, treatable with steroids, if detected at its onset. ATR yields durable remissions in patients with APL, after consolidation with cytotoxic chemotherapy.

Topics: Adolescent; Adult; Humans; Leukemia, Promyelocytic, Acute; Middle Aged; Recurrence; Remission Induction; Tretinoin

Topics: Antineoplastic Agents; Blood Coagulation Disorders; Carrier Proteins; Gene Expression; Humans; Leukemia, Promyelocytic, Acute; Prognosis; Receptors, Retinoic Acid; Tretinoin

Topics: Carrier Proteins; Humans; Leukemia, Myeloid, Acute; Leukemia, Promyelocytic, Acute; Myelodysplastic Syndromes; Neoplasms; Receptors, Retinoic Acid; Retinoids; Teratogens; Tretinoin

Topics: Animals; Base Sequence; Carcinoma, Hepatocellular; Carrier Proteins; Chick Embryo; DNA; Gene Expression Regulation, Neoplastic; Leukemia, Promyelocytic, Acute; Mice; Molecular Sequence Data; Neoplasm Invasiveness; Neoplasm Proteins; Nuclear Proteins; Receptors, Cell Surface; Receptors, Retinoic Acid; Retinoid X Receptors; Retinol-Binding Proteins; Transcription Factors; Transcription, Genetic; Tretinoin

APL is a unique clinical example where a defined molecular genetic defect appears involved in both the pathogenesis and treatment of a human leukemia. The consistent finding that RA induces remissions in APL is especially notable, since treatment involves an oral formulation of RA. The clinical responses are linked to leukemic cell maturation, suggesting a noncytotoxic mechanism of RA action. This provides a rationale for combining cytotoxic and cytodifferentiation agents in future clinical trials. Despite high initial CR rates with continuous RA therapy, relapses frequently occur. Pharmacologic mechanisms of resistance to RA therapy are implicated in clinical resistance. Future work will explore if this resistance can be overcome and how genetic mechanisms contribute to clinical RA resistance in APL. The exciting convergence of clinical and basic information in PL has led to new insights into the molecular nature of this leukemia. The discovery that RAR-alpha is rearranged in the t(15,17) provides an opportunity to study how this rearrangement is involved in oncogenesis and treatment response in APL. The application of RT-PCR assays for this molecular rearrangement will be useful in the diagnosis and subsequent tailoring of postremission therapy in APL. Whether APL serves as a paradigm for cytodifferentiation therapy remains to be seen. However, it is encouraging that 13-cis-retinoic acid in combination with alpha interferon is an active therapy in squamous cell carcinomas of the cervix and skin. Although the mechanisms responsible for these clinical responses are unknown, they highlight the need to learn how RA works and when it should be used to treat cancer patients.

Topics: Base Sequence; Carrier Proteins; Gene Rearrangement; Humans; Leukemia, Promyelocytic, Acute; Molecular Sequence Data; Neoplasm Proteins; Receptors, Retinoic Acid; Tretinoin

The chromosome breakpoints of the acute promyelocytic leukemia (APL)-specific 15;17 translocation have recently been isolated. They are localized on a previously unknown gene, PML, on chromosome 15 and in the gene that encodes the alpha retinoic acid receptor (RAR alpha) on 17. The translocation, which is balanced and reciprocal, leads to the formation of two fusion genes, PML/RAR alpha and RAR alpha/PML. Both are expressed in APL. The PML/RAR alpha gene codes for two abnormal proteins: the PML/RAR alpha fusion protein and an abnormal PML protein, the RAR alpha/PML gene encodes the RAR alpha/PML fusion protein. Experiments to investigate the biological activity of the abnormal translocation products are in progress. Preliminary results suggest that the PML/RAR alpha fusion protein is responsible for two important properties of the APL phenotype: the differentiation block characteristic of the leukemic blasts and the high sensitivity of the blasts to the differentiative action of retinoic acid (RA) both in vivo and in vitro. The mechanism through which PML/RAR alpha exerts its biological function remains unknown. However, there is accumulating evidence that it acts by interfering with normal endogenous pathways of both RAR alpha and PML. The RAR alpha receptor is implicated in regulating the myeloid differentiation induced by RA. Although the physiological function of PML is not known, it is probably a transcription factor. Definition of the molecular architecture of the t(15;17) has furnished further tools for: (1) molecular diagnosis of APL and (2) highly sensitive evaluation of the neoplastic clone during antileukaemic therapy. The molecular identification of residual APL disease after anti-leukaemia therapy allows patients at risk of relapse to be identified.

Topics: Carrier Proteins; Cell Differentiation; Chromosomes, Human, Pair 15; Chromosomes, Human, Pair 17; Hematopoietic Stem Cells; Humans; Leukemia, Promyelocytic, Acute; Neoplasm Proteins; Nuclear Proteins; Polymerase Chain Reaction; Promyelocytic Leukemia Protein; Receptors, Retinoic Acid; Recombinant Fusion Proteins; Retrospective Studies; Transcription Factors; Translocation, Genetic; Tretinoin; Tumor Suppressor Proteins

Topics: Drug Resistance; Humans; Leukemia, Promyelocytic, Acute; Retinoids; Tretinoin; Tumor Cells, Cultured

To discuss acute promyelocytic leukemia (APL) and review the literature concerning differentiation treatment of APL with trans-retinoic acid (t-RA).. English-language articles concerning APL or its treatment with t-RA were identified with a MEDLINE search.. All studies available at the time of article preparation, which addressed t-RA treatment in APL, were selected.. Data extraction and assessment were performed subjectively by the authors. An extensive discussion of specific study details is included in the article.. APL is a unique subset of acute myelogenous leukemia and is typified by an accumulation of malignant promyelocytes in the bone marrow. Within the granulocyte cell cycle of a patient with APL, differentiation has been halted at the level of the promyelocyte, preventing formation of mature granulocytes. Upon treatment with traditional cytotoxic chemotherapy, complete remission rates of approximately 70 percent, with a five-year survival ranging from 25 to 40 percent have been achieved. In most patients with APL, a characteristic chromosomal t(15q+;17q-) translocation has been found, which may be responsible for the production of an aberrant retinoic acid receptor-alpha. Therefore, t-RA induction therapy has been investigated and has produced promising results. Administration of t-RA in dosages of 45-100 mg/m2/d has induced complete remissions. The apparent mechanism of t-RA is the induction of promyelocyte differentiation and maturation. The most common adverse effects noted have been dry skin, cheilitis, and headaches.. Upon consideration of the initial trials, t-RA appears to be a promising and unique treatment for APL.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Clinical Trials as Topic; Humans; Leukemia, Promyelocytic, Acute; Remission Induction; Tretinoin

The clinical and laboratory features of APL are distinct. APL has been effectively treated with anthracyclines. Postremission therapy and the addition of other cytotoxic agents in induction may be beneficial. Early deaths remain a problem despite improved management of coagulopathy. The cytogenetic marker, t(15;17), reflects a molecular defect that splices two transcription factors, PML and RARA, to produce chimeric mRNA and proteins. RA, the natural ligand for RARA, is able to induce CR by stimulating differentiation and maturation of the malignant cells. The addition of RA to the therapeutic armamentarium of the hematologic oncologist will allow further refinement of the management of these patients. Diagnosis is unambiguous because the molecular defect can be readily detected. Our understanding of the biology downstream of the affected genes is incomplete. Other retinoids may be more effective than all-trans RA and may avoid the fall in plasma levels seen in patients chronically treated with RA. Combination of retinoids with other cytokines or cytotoxic agents may decrease the immediate mortality and improve long-term DFS in APL.

Topics: Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Blood Coagulation Disorders; Cell Differentiation; Chromosomes, Human, Pair 15; Chromosomes, Human, Pair 17; Clinical Trials as Topic; Humans; Leukemia, Promyelocytic, Acute; Neoplastic Stem Cells; Remission Induction; Translocation, Genetic; Tretinoin

All-trans-retinoic acid (ATRA) has demonstrated in vivo and in vitro that it could differentiate leukemic cells in acute promyelocytic leukemia (APL). ATRA yields complete remission (CR) rates of approximately 90% in newly diagnosed and first relapsing APL, in APL resistant to one or two courses of chemotherapy, whereas patients in second and subsequent remissions often have only partial remissions. The use of ATRA in APL is associated with two major drawbacks: (1) the risk of rapidly rising leukocyte counts, leading to the 'retinoic acid syndrome' which may be fatal if the increase in leukocytes is not reversed and (2) almost universal relapse, if no intensive chemotherapy is administered after CR achievement. Preliminary results, however, suggest that ATRA followed by intensive chemotherapy has improved the outcome of newly diagnosed APL, by slightly increasing the CR rate but also by reducing the risk of relapse, as compared to chemotherapy alone.

Topics: Humans; Leukemia, Promyelocytic, Acute; Neoplasm Recurrence, Local; Polymerase Chain Reaction; Remission Induction; Tretinoin

Perhaps the most important advance in this field is not the specific actions of all-trans-retinoic acid in acute promyelocytic leukemia, but rather the conclusive documentation of differentiation as a practical and consistently effective method of treating human cancer. As a drug, all-trans-retinoic acid has certain undesirable pharmacologic properties that might be overcome by the use of alternative retinoids, such as 9-cis-retinoic acid, that are equally active against acute promyelocytic leukemia cells in vitro. In addition to retinoids that selectively activate RARs or RXRs, other ligands of the steroid-thyroid receptor superfamily, such as vitamin D3, glucocorticoids, and sex steroids also have cytodifferentiating actions in model systems. Numerous other agents can effect differentiation of neoplastic cells in such systems, including sodium butyrate, hexamethylene bisacetamide and its analogues, colony-stimulating factors, and interferons. Each of these compounds apparently acts through different pathways, and their activity may be greatly amplified when they are used in combination. Just as the practical usefulness of all-trans-retinoic acid in combination with conventional treatments continues to evolve, the use of differentiation agents in combination represents a novel and promising approach for oncologic therapy in the next decade. Although acute promyelocytic leukemia remains an "orphan" disease, its importance as a model for human neoplasia should not be minimized. The specific molecular lesion of acute promyelocytic leukemia is not shared by other cancers, but the physiologic actions of retinoids, their documented cytodifferentiating activity against a variety of human cancer cells in vitro, and their usefulness in cancer chemoprevention are clearly not mediated by identifiable mutations of retinoid receptors. The insights into transformation and leukemogenesis gained in acute promyelocytic leukemia may be a harbinger of further clinical applications and offer a glimpse into the next generation of cancer therapy.

Topics: Humans; Leukemia, Promyelocytic, Acute; Leukocytosis; Remission Induction; RNA, Neoplasm; Tretinoin

All-trans retinoic acid (ATRA) has recently been recognized as the first line therapeutic agent in the treatment of patients with acute promyelocytic leukemia (APL). The extraordinary high remission rate achieved by ATRA in comparison with other chemotherapeutic agents suggested that ATRA differentiation induction therapy seemed superior to conventional chemotherapy for APL patients. However, after the great excitement aroused after the initial successes, we have to take stock and examine in detail several problems which have emerged preventing us from improving the clinical outcome in APL. Maintenance in order to prolong remission and prevention of or retreatment for the relapse are the major subjects of concern at present. Efforts should be made either to keep ATRA effective for APL patients or to resensitize the relapsing patients for repeated ATRA therapy. The administration of ATRA should be carefully adapted in accordance with the individual patient's condition. From both conceptual and practical points of view, ATRA differentiation therapy should be combined with chemotherapy, bone marrow transplantation and biomodifier treatment. Thus, a more comprehensive strategy must be planned and developed in the near future. Using molecular biological techniques, the diagnosis of APL can be more precisely made and the course of the disease more closely monitored. The central dogma, still to be revealed, is the relationship between APL pathogenesis, the chromosome translocation present with the relevant molecular alterations and the response to ATRA treatment. Current studies in all these above fields have provided us with a deeper understanding of the pathogenesis of APL and the physiological function and curative action of ATRA.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Antineoplastic Combined Chemotherapy Protocols; Drug Evaluation; Edema; Fever; Humans; Leukemia, Promyelocytic, Acute; Leukocytosis; Lung Diseases; Remission Induction; Syndrome; Treatment Outcome; Tretinoin

All-trans-retinoic acid (ATRA), a vitamin A derivative, is a safe and effective drug in the obtention of complete remission in acute promyelocytic leukemia (APL). ATRA is able to activate the maturation of malignant cells from patients with APL either in vitro or in vivo. Complete remission was obtained without any feature of aplastic phase and the severe bleeding diathesis rapidly disappeared. The major adverse effect is the occurrence of hyperleukocytosis which is prevented by the addition of chemotherapy. A progressive acquired resistance appears during ATRA treatment and prolonged event free survival time is obtained after consolidation with cytotoxic drugs. In APL the retinoic acid receptor alpha gene is rearranged and fused with a novel gene called PML. The hybrid PML-RAR product could have a role in the leukemogenesis blocking the effect of the normal RAR on target genes. Retinoic acid exerts a differentiating effect either by the induction of a normal activity of the aberrant product in the presence of pharmacological concentration, or by an over-expression of the normal allele. The results obtained by cellular and molecular biology gave opportunities to confirm the diagnosis, to follow the assessment of the minimal residual disease and to understand the acquired resistance.

Topics: Carrier Proteins; Cell Differentiation; Gene Rearrangement; Humans; Leukemia, Promyelocytic, Acute; Receptors, Retinoic Acid; Tretinoin

Acute promyelocytic leukemia is a clonal expansion of malignant cells blocked at a specific stage of myeloid differentiation. The disease is associated with a specific translocation between chromosome 17 and chromosome 15 [t(15;17)] and with a bleeding diathesis previously attributed to disseminated intravascular coagulation, which has recently also been related to primary fibrinolysis. The high percentage of early deaths, about 20%, experienced by acute promyelocytic leukemia patients, is generally due to the hemorrhagic syndrome. A new finding is the high effectiveness of treatment with all-trans retinoic acid, a vitamin A derivative, for inducing complete remission. The induction of cellular maturation by this agent represents the first model of differentiation therapy. Furthermore, recent molecular studies revealed that the breakpoints of the t(15;17) translocation are clustered in the gene of retinoic acid receptor-alpha, generating a hybrid gene product. Gene transfection experiments disclosed the impairment of gene transactivation due to the hybrid gene products, opening new concepts for understanding leukemogenesis. Understanding the mechanisms of action of retinoic acid could extend differentiation therapy to other malignancies with aberrant gene transcription.

Topics: Carrier Proteins; Cell Differentiation; Gene Rearrangement; Humans; Leukemia, Promyelocytic, Acute; Models, Biological; Receptors, Retinoic Acid; Tretinoin

Topics: Carrier Proteins; Chromosome Mapping; Chromosomes, Human, Pair 15; Chromosomes, Human, Pair 17; DNA, Neoplasm; Genetic Markers; Humans; Leukemia, Promyelocytic, Acute; Receptors, Retinoic Acid; Translocation, Genetic; Tretinoin

All-trans retinoic acid can induce complete remissions in patients with acute promyelocytic leukemia. The balanced chromosomal translocation t(15;17)(q22;q12-21) of this malignancy is now known to involve the nuclear retinoic acid receptor-alpha (RAR-alpha) on the long arm of chromosome 17 and a novel gene on the long arm of chromosome 15, designated PML (previously called myl). A unique fusion mRNA, PML/RAR-alpha, is produced. Paradoxically, this rearrangement of RAR-alpha results in clinical sensitivity to retinoic acid. Despite its efficacy, retinoic acid therapy has side effect, including a syndrome of hyperleukocytosis and respiratory distress in some patients. Remissions induced and maintained by continuous all-trans-retinoic treatment are not durable in most of these patients. Retinoic acid therapy for acute promyelocytic leukemia represents a unique example where a molecular defect may be involved both in the pathogenesis and treatment of a malignancy.

Topics: Animals; Carrier Proteins; Clinical Trials as Topic; Humans; Leukemia, Promyelocytic, Acute; Mutation; Receptors, Retinoic Acid; Tretinoin

Acute promyelocytic leukaemia has two highly specific particularities: a t(15;17) chromosomal translocation and the ability of a differentiation inducer all-trans-RA, to revert the malignant phenotype both in vitro and in vivo. Molecular characterization of the t(15;17) translocation has shown that it fuses a previously unknown zinc finger encoding gene, PML, to the RAR alpha, suggesting a link between the molecular mechanism of transformation and of RA dependent differentiation. The PML/RAR alpha fusion receptor--which is functionally altered--may block RA target genes, impair RA mediated differentiation and lead to transformation. Alternatively, or in addition, the PML transduction pathway may also be affected. Although it is clear that RA treatment must relieve APL cells from differentiation arrest, so far no model can satisfactorily account for this effect.

Topics: Carrier Proteins; Cell Transformation, Neoplastic; Chromosomes, Human, Pair 15; Chromosomes, Human, Pair 17; Genes; Humans; Leukemia, Promyelocytic, Acute; Neoplasm Proteins; Nuclear Proteins; Promyelocytic Leukemia Protein; Receptors, Retinoic Acid; Transcription Factors; Translocation, Genetic; Tretinoin; Tumor Suppressor Proteins

The ability of vitamin A and its derivatives to induce differentiation in certain target tissues has been appreciated for nearly a century. Recently, oral all-trans retinoic acid (ATRA), a vitamin A metabolite, has been shown to induce terminal differentiation of leukemic cells in patients with acute promyelocytic leukemia (APL). Complete remissions are obtained and normal hematopoiesis is established in an outpatient setting with minimal side effects in the majority of cases. Although remissions are not durable, disseminated intravascular coagulation, a frequent complication of remission induction in APL, is avoided by oral ATRA prior to definitive chemotherapy. The molecular basis for the efficacy of ATRA in APL appears to be the involvement of the retinoic acid receptor alpha locus in the t(15;17) translocation breakpoint characteristic of APL.

Topics: Animals; Anticarcinogenic Agents; Antineoplastic Agents; Base Sequence; Binding Sites; Carrier Proteins; Cell Differentiation; Chromosomes, Human, Pair 15; Chromosomes, Human, Pair 17; DNA; Humans; Leukemia, Promyelocytic, Acute; Molecular Sequence Data; Neoplasms; Receptors, Cell Surface; Receptors, Retinoic Acid; Retinoid X Receptors; Retinoids; Transcription Factors; Translocation, Genetic; Tretinoin

Acute promyelocytic leukemia (APL) is characterized by a specific chromosome translocation t(15;17). Recently, using molecular biology techniques, a number of laboratories have demonstrated that the gene coding for the retinoic acid receptor alpha (RARA), normally located on chromosome 17, is disrupted by the t(15;17) and fused with the PML gene on chromosome 15. The chromosome 17 breaks were mapped consistently within the second intron of the RARA gene while the chromosome 15 breaks were clustered in two limited regions within the PML gene. Molecular cloning and sequence analysis of the PML gene demonstrated a complex splicing pattern and this gene may encode a transcription factor. Different isoforms of the PML-RARA fusion transcripts were discovered which are produced as a result of distinct PML gene rearrangements. Sequence analysis of the reciprocal products of the translocation t(15;17) in some APL cases suggested the implication of topoisomerase II in mediating the DNA recombination. The RT/PCR procedure has been established to characterize the expression patterns of the PML-RARA fusion gene and to detect minimal residual disease (MRD). The biological activity of the PML-RARA fusion gene and its isoforms should be further explored.

Topics: Carrier Proteins; Chromosomes, Human, Pair 15; Chromosomes, Human, Pair 17; Gene Expression Regulation, Leukemic; Genes; Humans; Introns; Leukemia, Promyelocytic, Acute; Neoplasm Proteins; Polymerase Chain Reaction; Receptors, Retinoic Acid; Translocation, Genetic; Tretinoin

APL (FAB M3) is a unique type of myeloid leukaemia characterized by specific clinical, morphological, cytogenetic and molecular features. An early and accurate diagnosis is necessary to initiate therapy and treat the life-threatening coagulopathy caused by release of procoagulants from the abundant promyelocytic granules. Cytogenetically the disease is characterized by a reciprocal translocation between the long arms of chromosomes 15 and 17, t(15;17)(q21;q22), which is seen in almost every patient with APL but in no other form of malignancy. The presence of this translocation, often as the only karyotypic change, suggests that potentially leukaemogenic sequences are located at the breakpoints and are activated by rearrangement. The recent cloning of the breakpoints by three groups has demonstrated that the retinoic acid receptor alpha gene (RARA) on chromosome 17 is fused to a previously undescribed transcription factor gene, PML, on chromosome 15. The DNA-binding motifs of both the RARA and PML proteins, together with the ligand-binding domain of RARA, are combined in a single fusion protein which may dysregulate either retinoic acid or PML-sensitive pathways. Identification of these dysregulated target genes has become the next molecular goal for research on APL. Intriguingly, some APLs not only express the PML-RARA fusion protein but also the reciprocal RARA-PML fusion protein, although the contribution of this product is unclear. The PML-RARA chimaeric protein is presumably the target during the striking differentiation therapy achieved with all-trans retinoic acid. This therapy induces the malignant promyelocytes to mature and die, rather than continue proliferating. Moreover, it represents the first direct connection between a genetic defect and clinical treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Amino Acid Sequence; Carrier Proteins; Child; Chromosomes, Human, Pair 15; Chromosomes, Human, Pair 17; Cloning, Molecular; Female; Humans; Leucine Zippers; Leukemia, Promyelocytic, Acute; Molecular Sequence Data; Neoplasm Proteins; Nuclear Proteins; Oncogene Proteins, Fusion; Oncogenes; Polymerase Chain Reaction; Promyelocytic Leukemia Protein; Receptors, Retinoic Acid; Transcription Factors; Translocation, Genetic; Tretinoin; Tumor Suppressor Proteins

In the past year, additional experimental data have expanded our understanding of the molecular mechanisms that underlie nuclear receptor control of regulatory programs. It is increasingly clear that steroid members (e.g. glucocorticoid and estrogen) and non-steroid members (e.g. retinoic acid, thyroid hormone, and vitamin D) of the nuclear receptor superfamily may utilize distinct strategies in achieving their complex control of gene regulation.

Topics: Animals; Carrier Proteins; Cell Nucleus; Chromosomes, Human, Pair 15; Chromosomes, Human, Pair 17; Gene Expression Regulation; Humans; Leukemia, Promyelocytic, Acute; Multigene Family; Receptors, Cell Surface; Receptors, Retinoic Acid; Retinoid X Receptors; Retinoids; Transcription Factors; Transcription, Genetic; Translocation, Genetic; Tretinoin

Human myeloid leukemia cells do not differentiate into functional end-cells but remain in the proliferation pool. Human cell lines can serve as model for hematopoietic cells arrested at different stages of myeloid differentiation and helps to dissect the cellular and molecular events involved in leukemogenesis. Furthermore, several agents have been identified as inducers of differentiation of leukemia cells. Exciting new clinical observation have shown that patients with APL respond well to the treatment with all-trans retinoic acid. RAR-alpha gene was proved to translocated from chromosome 17 to a locus PML on chromosome 15. This new chimeric gene, PML-RAR alpha is extremely important to understand the leukemogenesis of APL.

Topics: Calcitriol; Carrier Proteins; Cell Differentiation; Cell Division; Chimera; Cytokines; Humans; Interferons; Leukemia, Promyelocytic, Acute; Receptors, Retinoic Acid; Tretinoin; Tumor Cells, Cultured

Topics: Cell Differentiation; Humans; Leukemia, Promyelocytic, Acute; Tretinoin

Interest in retinoids as therapeutic agents has developed as a result of the observations of remission induction with all-trans retinoic acid (tRA) in patients with acute promyelocytic leukemia (APL), and of high objective response rates noted with the combination of cis-retinoic acid (cRA) with interferon-alpha in squamous cell carcinomas of skin and cervix. The therapeutic experience with RA in APL is discussed in this article from the perspectives of new information concerning retinoid biology, observations related to the development of the retinoid syndrome, complex pharmacology of this agent, and possible explanations for development of retinoid resistance. The current National Cancer Institute-supported drug development strategy for RA used alone or in combination with other differentiating agents, and the potential therapeutic uses in cancer for other retinoids are also discussed.

Topics: Animals; Antineoplastic Agents; Clinical Trials as Topic; Drugs, Investigational; Humans; Leukemia, Promyelocytic, Acute; Neoplasms; Retinoids; Tretinoin

All-trans retinoic acid (ATRA) is able to specifically differentiate acute promyelocytic leukemic cells (APL) in short-term culture. Patients with APL achieved complete remission within 1-3 months by a progressive maturation of leukemic cells. The advantages of this differentiation therapy are the rapid disappearance of the bleeding disorders and the absence of aplastic phase avoiding the early deaths occurring in 15-30% of patients with conventional chemotherapy. However, relapses occurred when ATRA alone was maintained. For this reason, a chemotherapy is added after complete remission obtained by ATRA. A pilot study on 27 patients was proposed with the sequential combination of ATRA and chemotherapy. A European trial randomizes conventional therapy to the sequential ATRA-chemotherapy protocol. Retinoic acid receptor (RAR alpha) is rearranged by the specific translocation t(15;17) of APL; a PCR technique was developed in order to ensure the diagnosis and to follow the minimal residual disease. Transfection experiment of the chimaeric gene inhibits the transactivation of the natural RAR. ATRA is able to revert the arrest of maturation perhaps through an increase of the expression of the normal allele of RAR, which could overpass the impairment induced by the chimaeric protein on target responsive elements. One of the steps of the repair is the modulation of programmed cell death (PCD). Bcl-2, a gene involved in the PCD, is modulated in in vitro studies, arguing for the engagement of the cell in the natural death. The beneficial effect of differentiation therapy is probably due to the induction of the natural death of the malignant cell.

Topics: Antineoplastic Agents; Carrier Proteins; Drug Therapy, Combination; Humans; Leukemia, Promyelocytic, Acute; Remission Induction; Tretinoin

Topics: Cell Differentiation; Disseminated Intravascular Coagulation; Humans; Leukemia, Promyelocytic, Acute; Tretinoin

Topics: Blood Coagulation Disorders; Disseminated Intravascular Coagulation; Hemostasis; Heparin; Humans; Leukemia, Promyelocytic, Acute; Tretinoin

Retinoic acid and its analogs, retinoids, have been shown to be useful in the treatment of several types of tumors. Retinoids elicit their biological activities by binding to their specific nuclear receptors, denoted as RAR-alpha, beta and gamma. RAR's have been established to be retinoid-dependent transcription factors which belong to the steroid/thyroid nuclear receptor superfamily. Recently, retinoic acid has been reported to be extremely effective in the treatment of acute promyelocytic leukemia (APL) giving more than 70% complete remission efficiency. APL has been characterized by the specific chromosomal translocation, t(15;17). Analysis of the t(15;17) breaking point revealed that (i) either RAR-alpha on chromosome 17 or the gene named myl on chromosome 15 is abnormal in APL cells, and (ii) the abnormal fused protein myl/RAR-alpha is expressed, which is suspected to cause the APL. Thus, RAR-alpha gene may be now regarded as one of tumor suppressor genes.

Topics: Animals; Chromosomes, Human, Pair 15; Humans; Leukemia, Promyelocytic, Acute; Receptors, Cell Surface; Transcription, Genetic; Translocation, Genetic; Tretinoin

Acute promyelocytic leukemia (APL) is a clonal expansion of malignant cells blocked at a specific stage of myeloid differentiation. The disease is associated with a specific translocation between chromosome 17 and chromosome 15 t (15; 17) and with a bleeding diathesis previously attributed to a disseminated intravascular coagulation which is recently also related to a primary fibrinolysis. The high percentage of early deaths, around 20% experienced by APL patients, is generally due to the haemorrhagic syndrome. A new feature is the highly effectiveness of all-trans retinoic acid treatment, a vitamin A derivative, for inducing complete remission in patients. The induction of cellular maturation by this agent represents the first model of differentiation therapy. Furthermore recent molecular studies revealed that the breakpoints of the t(15; 17) translocation are clustered in the gene of retinoic acid receptor a, generating a hybrid gene product. Gene transfection experiments disclosed the impairment of gene transactivation due to the hybrid gene products, opening new concepts for the leukemogenesis. The abnormal program made by the aberrant transcript might be overcome by pharmacological concentration of RA which induces an over expression of the normal allele and a normal activity of the aberrant product.

Topics: Carrier Proteins; Cell Differentiation; Gene Rearrangement; Humans; Leukemia, Promyelocytic, Acute; Neoplasm Proteins; Phenotype; Receptors, Retinoic Acid; Tretinoin

Topics: Animals; Hepatitis B virus; Humans; Leukemia, Promyelocytic, Acute; Oncogenes; Receptors, Cell Surface; Tretinoin

Topics: Cell Division; Cell Transformation, Neoplastic; Hemorrhagic Disorders; Humans; Leukemia, Promyelocytic, Acute; Prognosis; Risk Factors; Thrombosis; Tretinoin

Topics: Humans; Leukemia, Promyelocytic, Acute; Recurrence; Tretinoin

We have previously shown that all-trans retinoic acid therapy is an alternative therapy for acute promyelocytic leukemia (AML3) via differentiation of the leukemic cells. The t(15;17) translocation is specifically found in this leukemia. We and others have shown that through this translocation the RAR alpha gene is rearranged and its expression altered in AML3 cells. The gene is truncated and fused to a novel gene (PLM). This results in a fusion protein whose transactivating properties may be implicated in the leukemogenesis of this disease. Retinoic acid cytoplasmic binding proteins (CRABP and CRBP) are not detected by PAGE chromatography in normal or malignant hematopoietic cells. During all-trans RA therapy, a) all-trans RA plasma concentrations are within in vitro differentiating concentration (med. 0.4 microgram/ml); b) increased expression of the normal remaining RAR alpha allele is rapidly observed and may explain the paradoxical induction of RA differentiation in these cells; c) CRABPII is induced in the bone marrow cells of AML3 patients and remains detectable 1 month after withdrawal of RA. AML3 in relapse after RA therapy is always less sensitive to RA in vitro and in vivo. Our data suggest that modification of the metabolisation pathways of RA may be one of parameters linked to this resistance. It appears that the efficacy of all-trans RA is the resultant of multiple parameters (RA concentration, ratio of PML/RAR alpha transcripts to normal RAR alpha, CRABP) which need to be defined to efficiently monitor all-trans RA therapy in APL.

Topics: Drug Administration Schedule; Humans; Leukemia, Promyelocytic, Acute; Tretinoin

Acute promyelocytic leukemia (APL) is a particularly virulent subtype of acute myeloid leukemia that is associated with a specific chromosomal translocation, t(15;17). Patients with APL are currently being managed with cytolytic chemotherapy (usually an anthracycline in combination with arabinosylcytosine), a treatment that can induce complete remissions in 65% or more of patients and probably cure 15% or more. Exciting new clinical observations have shown that patients with APL also respond extremely well to treatment with all-trans retinoic acid, an agent which induces the leukemic promyelocytes to undergo maturation and lose their ability to proliferate. Retinoic acid by itself is not curative, but by combining it with cytolytic chemotherapy, it may be possible to cure the majority of patients with this previously fatal leukemia. Interestingly, independent molecular studies have recently revealed that the breakpoint of t(15;17) lies within the gene encoding the retinoic acid receptor-alpha (RAR-alpha) on chromosome 17q21, and that patients with APL express aberrant forms of the RAR-alpha transcript. This convergence of clinical and molecular observations, though fortuitous, is extremely important because it represents the first example of a selective form of treatment for a human leukemia that is related to a specific genetic abnormality.

Topics: Humans; Leukemia, Promyelocytic, Acute; Tretinoin

The aim of differentiation therapy is to induce a maturation of the leukemic clone. Various approaches have been used: suppression of proliferation by low dose Ara-C in acute myeloid leukemia (AML); enhancement of differentiation by retinoic acid derivatives in acute promyelocytic leukemia (APL) or by differentiation-inducing factors; modulation of cell metabolism by breaking an autocrine loop in hairy cell leukemia (HCL). In all cases the treatment is given continuously at small doses over a long period of time. The very significant clinical results which have been obtained mainly in APL with all-trans retinoic acid and in HCL with alpha-interferon are briefly discussed.

Topics: Cell Differentiation; Cytarabine; Humans; Interferon Type I; Leukemia; Leukemia, Hairy Cell; Leukemia, Myeloid, Acute; Leukemia, Promyelocytic, Acute; Myelodysplastic Syndromes; Tretinoin

Differentiation therapies try to change the malignant cell in order to acquire a more mature or normal phenotype. Various ways were tested in leukemia: suppression the proliferative pressure by low dose Ara-C, enhancement of the differentiation by retinoic acid derivatives or by differentiation factors, and modulation of the cell metabolism interrupting an autocrine loop (a growth factor and its receptor). The treatment is given continuously at small doses, during a long period of time. In all these cases it seems necessary to tailor the differentiation therapy to each category of leukemia.

Topics: Cell Differentiation; Cell Division; Cytarabine; Humans; Interferon Type I; Leukemia; Leukemia, Hairy Cell; Leukemia, Myeloid, Acute; Leukemia, Promyelocytic, Acute; Myelodysplastic Syndromes; Tretinoin

Homoharringtonine (HHT) is commonly used for the treatment of Chinese adult AML, and all-trans retinoic acid (ATRA) has been verified in acute promyelocytic leukemia (APL). However, the efficacy and safety of HHT-based induction therapy have not been confirmed for childhood AML, and ATRA-based treatment has not been evaluated among patients with non-APL AML.. This open-label, multicenter, randomized Chinese Children's Leukemia Group-AML 2015 study was performed across 35 centers in China. Patients with newly diagnosed childhood AML were first randomly assigned to receive an HHT-based (H arm) or etoposide-based (E arm) induction regimen and then randomly allocated to receive cytarabine-based (AC arm) or ATRA-based (AT arm) maintenance therapy. The primary end points were the complete remission (CR) rate after induction therapy, and the secondary end points were the overall survival (OS) and event-free survival (EFS) at 3 years.. We enrolled 1,258 patients, of whom 1,253 were included in the intent-to-treat analysis. The overall CR rate was significantly higher in the H arm than in the E arm (79.9%. HHT is an alternative combination regimen for childhood AML. The effects of ATRA-based maintenance are comparable with those of cytarabine-based maintenance therapy.

Topics: Antineoplastic Combined Chemotherapy Protocols; Child; Cytarabine; East Asian People; Homoharringtonine; Humans; Leukemia, Promyelocytic, Acute; Multicenter Studies as Topic; Remission Induction; Survival Rate; Treatment Outcome; Tretinoin

Realgar-Indigo naturalis formula (RIF), an oral traditional Chinese medicine mainly containing Realgar (As

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Arsenic; Arsenic Trioxide; Arsenicals; Child; Humans; Leukemia, Promyelocytic, Acute; Oxides; Treatment Outcome; Tretinoin

All-trans retinoic acid (ATRA) and arsenic trioxide therapy without the use of maintenance therapy has been found to be beneficial for the treatment of adults with standard-risk acute promyelocytic leukemia (APL). However, it is unclear whether similar regimens are safe and beneficial for the treatment of high-risk APL or pediatric patients with standard-risk APL.. To assess whether treatment with an ATRA and arsenic trioxide-based regimen is safe and allows for the elimination or substantial reduction of chemotherapy use among pediatric patients with standard-risk or high-risk APL, respectively.. The Children's Oncology Group AAML1331 study is a nonrandomized, noninferiority trial that examined survival outcomes among 154 pediatric patients with APL compared with a historical control group of patients with APL from the AAML0631 study. Patients aged 1 to 21 years were enrolled at 85 pediatric oncology centers (members of the Children's Oncology Group) in Australia, Canada, and the US from June 29, 2015, to May 7, 2019, with follow-up until October 31, 2020. All patients had newly diagnosed APL and were stratified into standard-risk APL (white blood cell count <10 000/μL) and high-risk APL (white blood cell count ≥10 000/μL) cohorts.. All patients received ATRA and arsenic trioxide continuously during induction therapy and intermittently during 4 consolidation cycles. Patients with high-risk APL received 4 doses of idarubicin during induction therapy only. The duration of therapy was approximately 9 months, and no maintenance therapy was administered.. Event-free survival (EFS) at 2 years after diagnosis.. Among 154 patients (median age, 14.4 years [range, 1.1-21.7 years]; 81 male participants [52.6%]) included in the analysis, 98 patients (63.6%) had standard-risk APL, and 56 patients (36.4%) had high-risk APL. The median follow-up duration was 24.7 months (range, 0-49.5 months) for patients with standard-risk APL and 22.8 months (range, 0-47.7 months) for patients with high-risk APL. Patients with standard-risk APL had a 2-year EFS rate of 98.0% and an overall survival rate of 99.0%; adverse events included 1 early death during induction therapy and 1 relapse. Patients with high-risk APL had a 2-year EFS rate of 96.4% and an overall survival rate of 100%; adverse events included 2 relapses and 0 deaths. These outcomes met predefined noninferiority criteria (noninferiority margin of 10% among those with standard-risk APL and 14.5% among those with high-risk APL).. In this nonrandomized, noninferiority trial, pediatric patients with standard-risk APL who received treatment with a chemotherapy-free ATRA and arsenic trioxide regimen experienced positive outcomes. Patients with high-risk APL also had positive outcomes when treated with a novel ATRA and arsenic trioxide-based regimen that included 4 doses of idarubicin during induction therapy only and no maintenance therapy. The 2-year EFS estimates were noninferior to the historical comparator group, and advantages of the regimen included shorter treatment duration, lower exposure to anthracycline and intrathecal chemotherapy, and fewer days hospitalized.. ClinicalTrials.gov Identifier: NCT02339740.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Child; Child, Preschool; Disease-Free Survival; Humans; Infant; Leukemia, Promyelocytic, Acute; Male; Tretinoin; Young Adult

Topics: Antineoplastic Agents; Arsenic; Arsenic Trioxide; Arsenicals; Child; Drugs, Chinese Herbal; Humans; Leukemia, Promyelocytic, Acute; Tretinoin

The combination of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) has been demonstrated to have comparable effectiveness or better to ATRA and chemotherapy (CHT) in non-high-risk acute promyelocytic leukemia (APL). However, the efficacy of ATRA-ATO compared to ATRA-ATO plus CHT in high-risk APL remains unknown. Here we performed a randomized multi-center non-inferiority phase III study to compare the efficacy of ATRA-ATO and ATRA-ATO plus CHT in newly diagnosed all-risk APL to address this question. Patients were assigned to receive ATRA-ATO for induction, consolidation, and maintenance or ATRA-ATO plus CHT for induction followed by three cycles of consolidation therapy, and maintenance therapy with ATRA-ATO. In the non-CHT group, hydroxyurea was used to control leukocytosis. A total of 128 patients were treated. The complete remission rate was 97% in both groups. The 2-year disease-free, event-free survival rates in the non-CHT group and CHT group in all-risk patients were 98% vs 97%, and 95% vs 92%, respectively (P = 0.62 and P = 0.39, respectively). And they were 94% vs 87%, and 85% vs 78% in the high-risk patients (P = 0.52 and P = 0.44, respectively). This study demonstrated that ATRA-ATO had the same efficacy as the ATRA-ATO plus CHT in the treatment of patients with all-risk APL.

Topics: Arsenic Trioxide; Arsenicals; Humans; Leukemia, Promyelocytic, Acute; Oxides; Treatment Outcome; Tretinoin

Arsenic combined with all-trans retinoic acid (ATRA) is the standard of care for adult acute promyelocytic leukemia (APL). However, the safety and effectiveness of this treatment in pediatric patients with APL have not been reported on the basis of larger sample sizes.. We conducted a multicenter trial at 38 hospitals in China. Patients with newly diagnosed APL were stratified into two risk groups according to baseline WBC count and. Arsenic combined with ATRA is effective and safe in pediatric patients with APL, although long-term follow-up is still needed.

Topics: Adolescent; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Child; Child, Preschool; China; Female; Humans; Infant; Leukemia, Promyelocytic, Acute; Male; Progression-Free Survival; Time Factors; Tretinoin

Despite the high cure probability for acute promyelocytic leukaemia (APL), a minority of patients will relapse and the risk factors for relapse are unclear. We retrospectively analysed 212 patients who were diagnosed with non-high-risk APL and received all-trans retinoic acid (ATRA) plus arsenic as front-line therapy at Peking University Institute of Hematology from February 2014 to December 2018. A total of 176 patients (83%) received oral arsenic (realgar-indigo naturalis formula) plus ATRA, 36 patients (17%) received arsenic trioxide plus ATRA and 203 patients were evaluable for relapse. After a median (range) follow-up of 53·6 (24·3-85·4) months, two patients had molecular relapse and eight had haematological relapse. A promyelocytic leukaemia/retinoic acid receptor alpha (PML-RARA) transcript level of ≥6·5% at the end of induction therapy was associated with relapse (P = 0·031). The 5-year cumulative incidence of relapse, event-free survival and overall survival were 5·5%, 92·3% and 96·3% respectively. In conclusion, the present long-term follow-up study further confirmed the high cure probability of ATRA plus oral arsenic as front-line therapy for non-high-risk APL and showed that the PML-RARA transcript level at the end of induction therapy was associated with relapse.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Arsenic Trioxide; Female; Humans; Induction Chemotherapy; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Oncogene Proteins, Fusion; Prognosis; Retrospective Studies; Tretinoin; Young Adult

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Female; Follow-Up Studies; Germany; Humans; Italy; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Prospective Studies; Treatment Outcome; Tretinoin; Young Adult

The objective of this study was to conduct the first systematic evaluation of the long-term economic impact of arsenic trioxide (ATO) plus all-trans retinoic acid (ATRA) for the treatment of patients with newly diagnosed acute promyelocytic leukemia (APL) from the perspective of the Chinese health care system.. On the basis of clinical data from a randomized phase 3 trial, a time-dependent Markov model with 4 health states (complete remission, relapse or treatment failure, post-treatment failure, and death) was used to evaluate the incremental costs per quality-adjusted life-year (QALY) gained from the ATO plus ATRA regimen compared with the ATRA plus chemotherapy (CT) regimen over a 30-year period. All costs were adjusted to 2018 levels based on the Chinese Consumer Price Index. Both costs and health outcomes were discounted by 3% annually. One-way sensitivity analysis and probability sensitivity analysis were performed.. Compared with the ATRA plus CT strategy, the ATO plus ATRA strategy was associated with 1.38 additional QALYs gained and $392.05 (estimated in 2018 US dollars) in incremental costs per patient over 30 years. Consequently, the incremental cost-effectiveness ratio was $284.02 per QALY gained, which was far below the Chinese willingness-to-pay threshold of $29,306 per QALY gained. Sensitivity analyses demonstrated the robustness of these results.. From the perspective of the Chinese health care system, the ATO plus ATRA strategy is cost-effective for patients with newly diagnosed APL compared with the ATRA plus CT strategy. Therefore, the authors strongly suggest that China's health authorities choose the former strategy for these patients, whether for the elderly or for young people.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; China; Cost-Benefit Analysis; Disease-Free Survival; Drug Costs; Female; Hospitalization; Humans; Kaplan-Meier Estimate; Leukemia, Promyelocytic, Acute; Male; Markov Chains; Middle Aged; Neoplasm Recurrence, Local; Quality-Adjusted Life Years; Remission Induction; Treatment Failure; Tretinoin

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Disease-Free Survival; Female; Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Retrospective Studies; Risk Factors; Survival Rate; Tretinoin

High-risk acute promyelocytic leukemia (APL) remains a therapeutic challenge, with higher associated rates of early mortality and relapse than standard-risk APL. All-trans retinoic acid (ATRA) plus arsenic trioxide (ATO) is a well-established treatment for patients with standard-risk APL, but it is not well defined for those with high-risk APL. In a prior study of patients with high-risk APL, the addition of gemtuzumab ozogamicin (GO) to ATO plus ATRA suggested benefit. The SWOG Cancer Research Network conducted a phase 2 study to confirm the efficacy and safety of the combination of ATRA plus ATO plus GO in treating high-risk APL patients. The primary end points were 3-year event-free survival (EFS) and early (6-week) death rates associated with this combination. Seventy patients were treated. With a median follow-up of 3.4 years, the 3-year EFS and overall survival estimates were 78% (95% confidence interval [CI], 67%-86%) and 86% (95% CI, 75%-92%), respectively. Overall, 86% of patients achieved complete response. The 6-week mortality rate was 11%. The most common treatment-emergent toxicities during the induction phase included febrile neutropenia, aspartate aminotransferase/alanine aminotransferase elevation, hyperglycemia, hypoxia, headache, and prolonged QT interval corrected for heart rate. Retinoic acid syndrome occurred in 9% of patients. Approximately 37% of patients did not complete all planned courses of postremission therapy. The combination of ATRA plus ATO plus GO in high-risk APL patients was effective and generally well tolerated, suggesting an opportunity to offer a chemotherapy-free induction platform for patients with this disease. This trial was registered at www.clinicaltrials.gov as #NCT00551460.

Topics: Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Gemtuzumab; Humans; Leukemia, Promyelocytic, Acute; Tretinoin

Topics: Adolescent; Adult; Age Factors; Aged; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Child; Child, Preschool; Cognition; Female; Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Tretinoin

Topics: Administration, Oral; Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Arsenicals; Female; Follow-Up Studies; Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Oncogene Proteins, Fusion; Retrospective Studies; Tretinoin

All-trans retinoic acid (ATRA) in combination with chemotherapies had been the standard therapy for newly diagnosed acute promyelocytic leukemia (APL). In Japan, APL204 study using ATRA+chemotherapy showed favorable outcomes, in which 7-year event-free and overall survival rates were 79% and 87%, respectively. Recently, a combination of ATRA and arsenic trioxide (ATO) has emerged as a promising therapy for newly diagnosed APL. Specifically, for patients with standard-risk APL with an initial white blood cell count (WBC) of <10,000/µl, two randomized controlled trials showed superior outcomes using ATRA+ATO to ATRA+chemotherapy, with long-term survival rates above 90%. Now ATRA+ATO is considered as an established standard therapy for newly diagnosed patients with standard-risk APL. Some prospective studies have also showed the efficacies of ATRA+ATO in patients with high-risk APL with an initial WBC of >10,000/µl although the administration of gemtuzumab ozogamicin or idarubicin was required in addition to ATRA+ATO during induction therapy. This review briefly summarizes the findings of ATRA+chemotherapy, focusing on the APL204 study, and introduces trials of ATRA+ATO for newly diagnosed APL. Furthermore, it describes the management of complications, including disseminated coagulation and differentiation syndrome.

Topics: Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Humans; Japan; Leukemia, Promyelocytic, Acute; Oxides; Prospective Studies; Treatment Outcome; Tretinoin

Acute promyelocytic leukemia (APL) is a unique leukemia subtype requiring specialized treatment including all-trans retinoic acid (ATRA). A prior report demonstrated worse outcome among young children <5 years old compared with older children.. We evaluated outcomes for pediatric patients (<18 years old; N = 83) with APL treated on North American intergroup study CALGB 9710 at Children's Oncology Group sites. Induction and consolidation included ATRA, cytarabine, and anthracyclines. Patients ≥15 years old were randomized to addition of arsenic trioxide (ATO) consolidation. All patients were randomized to ATRA maintenance with versus without oral chemotherapy.. The estimated 5-year overall survival (OS) rate was 82%, and the event-free survival (EFS) rate was 54%. Seven patients (8.4%) died during induction due to coagulopathy. Maintenance randomization demonstrated that addition of oral chemotherapy to ATRA significantly reduced relapse rate, but difference in EFS did not reach statistical significance (P = 0.12; 5-year rates [95% CI]: 41% [17%-64%] ATRA only vs 72% [56%-88%] ATRA plus chemotherapy). There was no difference (P = 0.93) in EFS for age <5 years versus 5-12.99 years versus 13-17.99 years (5-year rates: 56%, 47%, and 45%, respectively). Among adolescents 15-17.99 years old in the ATO randomization, there was a significantly lower relapse risk at 5 years for those receiving ATO (0% ATO vs 44% no ATO; P = 0.02).. Our data demonstrate that intensified ATRA, cytarabine, and anthracycline chemotherapy is effective for pediatric APL including very young patients, but early deaths and relapses remain barriers to cure. Further improvements are likely with incorporation of ATO into pediatric APL regimens.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Cytarabine; Daunorubicin; Female; Follow-Up Studies; Humans; Infant; Infant, Newborn; Leukemia, Promyelocytic, Acute; Male; Prognosis; Survival Rate; Tretinoin

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Arsenic; Arsenic Trioxide; Disease-Free Survival; Female; Follow-Up Studies; Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Models, Biological; Survival Rate; Tretinoin

Randomized comparison of two treatment strategies in frontline therapy of acute promyelocytic leukemia (APL): all-trans retinoic acid (ATRA) and double induction intensified by high-dose cytosine arabinoside (HD ara-C) (German AMLCG) and therapy with ATRA and anthracyclines (Spanish PETHEMA, LPA99).. Eighty of 87 adult patients with genetically confirmed APL of all risk groups were eligible. The outcome of both arms was similar: AMLCG vs PETHEMA: hematological complete remission 87% vs 83%, early death 13% vs 17% (P = .76), overall survival, event-free survival, leukemia-free survival, cumulative incidence of relapse at 6 years 75% vs 78% (P = .92); 75% vs 68% (P = .29); 86% vs 81% (P = .28); and 0% vs 12% (P = .04, no relapse vs four relapses), respectively. The median time to achieve molecular remission (RT-PCR negativity of PML-RARA) was 60 days in both arms (P = .12). The AMLCG regimen was associated with a longer duration of neutropenia (P = .02) and a higher rate of WHO grade ≥3 infections.. The small number of patients limits the reliability of conclusions. With these restrictions, the outcomes of both approaches were similar and show the limitations of ATRA and chemotherapy. The HD ara-C-containing regimen was associated with a lower relapse rate in high-risk APL.

Topics: Adult; Aged; Aged, 80 and over; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Biomarkers; Consolidation Chemotherapy; Cytarabine; Cytogenetic Analysis; Female; Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Neoplasm, Residual; Recurrence; Remission Induction; Survival Analysis; Treatment Outcome; Tretinoin; Young Adult

The aim of our study was to evaluate the impact of oral arsenic (the realgar-indigo naturalis formula, RIF) and all-trans retinoic acid (ATRA) on coagulopathy in acute promyelocytic leukemia (APL) compared with intravenous arsenic trioxide (ATO) and ATRA during induction. Mitoxantrone was added to all the patients at a dose of 1.4mg/m

Topics: Administration, Oral; Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Blood Transfusion; Disseminated Intravascular Coagulation; Drugs, Chinese Herbal; Female; Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Mitoxantrone; Platelet Transfusion; Retrospective Studies; Tretinoin; Young Adult

Acute promyelocytic leukemia (APL) is a curable form of acute myeloid leukemia; in recent years, the use of new treatment strategies, such as combination therapy, have led to improved APL outcomes. Here, outcomes of patients treated with a combination of arsenic trioxide (ATO) and all-trans-retinoic acid (ATRA) are compared against patients treated with single ATO therapy.. All patients except one in the ATO group and all patients in the ATO plus ATRA group were alive after a median follow-up of 18 and 17 months, respectively; 2.5-year overall survival in the ATO group was 86% (p-value = .32). Five patients in the ATO group experienced relapse, and 2.5-year leukemia-free survival in this group was 60%. No relapse occurred in the ATO plus ATRA group (p-value = .01). Differences in the mean of white blood cell (p-value = .67), platelet (p-value = .15), liver (p-value = .37), and renal (p-value = .95) dysfunctions were not significant.. Although ATO has been considered a first-line therapy in patients with APL, several studies have reported improved outcomes with a combination of ATO plus ATRA. This study demonstrated a significant decrease in relapse with this combination compared with single ATO therapy and supported the importance of ATRA in APL treatment.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Disease-Free Survival; Female; Follow-Up Studies; Humans; Induction Chemotherapy; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Survival Rate; Tretinoin

The combination of all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) has been suggested to be safe and effective for adult acute promyelocytic leukaemia (APL). As of 2010, the role of cytarabine (Ara-C) in APL was controversial. The aim of this study was to test the efficacy and safety of ATRA and ATO in paediatric APL patients. Also, we assessed whether Ara-C could be omitted in ATO and ATRA- based trials in children.. We performed a randomized controlled trial in paediatric APL patients (≤14 years of age) in our hospital from May 2010 to December 2016. All of the patients were assigned to receive ATRA plus ATO for induction followed by one course of idarubicin (IDA) and ATO (28 days). The patients were then randomly assigned to receive two courses of daunorubicin (DNR, no- Ara-C group) or DNR + Ara-C (Ara-C group). All of the patients were followed with maintenance therapy with oral ATRA, 6-mercaptopurine, and methotrexate for 1.5 years.. Among the 66 patients, 43 were male and 23 were female. All of the patients achieved complete remission (CR) with the exception of one who gave up the treatment. During induction therapy, all toxicity events were reversed after appropriate management. Thirty patients in the Ara-C group underwent 57 courses of treatment, and 35 patients in the no-Ara-C group underwent 73 courses of treatment. No significant differences in age, genders, white blood cell counts, haemoglobin levels, and platelet counts were found between the Ara-C and no-Ara-c groups. Greater myelosuppression and sepsis were observed in the Ara-C group during the consolidation courses. No patient died at consolidation, and only one patient relapsed. No differences were found in event-free survival, disease-free survival and overall survival between the two groups. Additionally, our analysis of the arsenic levels in the plasma, urine, hair and nails of the patients indicated that no significant accumulation of arsenic occurred after ATO was discontinued for 12 months.. Overall, ATO and ATRA are safe and effective for paediatric APL patients and Ara-C could be omitted when ATO is used for two courses.. ClinicalTrials.gov ( NCT01191541 , retrospectively registered on 18 August 2010).

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Biomarkers; Case-Control Studies; Child; Child, Preschool; Consolidation Chemotherapy; Cytarabine; Female; Humans; Induction Chemotherapy; Leukemia, Promyelocytic, Acute; Male; Treatment Outcome; Tretinoin

Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Female; Follow-Up Studies; Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Neoplasm Recurrence, Local; Survival Analysis; Tretinoin; Young Adult

Intravenous arsenic trioxide (ATO) has been adopted as the first-line treatment for acute promyelocytic leukemia (APL). Another arsenic compound named the Realgar-Indigo naturalis formula (RIF), an oral traditional Chinese medicine containing As

Topics: Adolescent; Arsenic Trioxide; Child; Child, Preschool; Disease-Free Survival; Drugs, Chinese Herbal; Humans; Infant; Length of Stay; Leukemia, Promyelocytic, Acute; Male; Treatment Outcome; Tretinoin

The treatment of acute promyelocytic leukemia (APL) has been revolutionized in the past two decades by the advent of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). It suggests that non-high-risk APL patients can be cured without chemotherapy. However, ATRA plus chemotherapy is still the standard therapy for the high-risk patients. Central nervous system (CNS) relapse remains a significant cause of treatment failure in high-risk patients. However, increasing the ATO concentration in cerebrospinal fluid (CSF) may reduce CNS relapse in high-risk patients. Mannitol can allow ATO to penetrate the blood-brain barrier (BBB) and reach therapeutically effective levels in the CSF. It is used for the treatment of CNS relapse in patients APL. We compare ATRA-ATO with ATRA-ATO plus chemotherapy in both high-risk and non-high-risk patients with APL.. This study was designed as a multicenter randomized controlled trial. Patients with APL were randomly assigned into two groups: the ATRA-ATO group (experimental group) and the ATRA-ATO plus chemotherapy group (control group). The experimental group receives therapy with ATRA-ATO for induction, consolidation and maintenance therapy. In the high-risk patients, mannitol will be used with ATO in the consolidation and maintenance therapy. Hydroxyurea will be used in patients who developed leukocytosis in the induction therapy. The control group receives therapy with ATRA-ATO plus chemotherapy for induction and consolidation therapy.. In this study, a randomized clinical trial design is described. It aims to compare the efficacy of ATRA-ATO versus ATRA-ATO plus chemotherapy in all-risk patients with APL.. Chinese Clinical Trials Registry, ID: ChiCTR-IPR- 15006821 . Registered on 27 July 2015.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; China; Female; Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Multicenter Studies as Topic; Randomized Controlled Trials as Topic; Risk Assessment; Risk Factors; Time Factors; Treatment Outcome; Tretinoin; Young Adult

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Female; Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Oxides; Prospective Studies; Risk Factors; Treatment Outcome; Tretinoin; Young Adult

To compare the efficacy and toxicities of combining homoharringtonine (HHT)±daunorubicin (DNR) with all-trans-retinoic acid (ATRA) based therapy and DNR plus ATRA based therapy in newly diagnosed low/intermediate risk acute promyelocytic leukemia (APL).. A total of 96 newly diagnosed patients with APL were randomized to HHT group, DNR group and HHT+ DNR group prospectively. The complete remission (CR) rate, the overall survival (OS) and event-free survival (EFS) of three groups were analyzed.. There were 31 patients in HHT group, 33 patients in DNR group and 32 patients in HHT+ DNR group. The baseline characteristics of three groups were similar. No patient died during induction therapy. The morphologic CR rate was 100.0%. The median time to peak WBC counts in HHT+DNR group (4 days, range: 1-23 days) was significantly shorter than that in HHT group (9 days, range: 1-27 days) (P=0.008) and DNR group (7 days, range: 1-27 days) (P=0.240). There was no difference among three groups about the incidence of differentiation syndrome, the median interval to achieve CR, peak WBC counts and transfusions (P >0.05). All patients achieved complete molecular remission (CMR) during consolidation therapy. The interval to achieve CMR was no significantly difference among three groups (P >0.05). The 3-year OS rates for HHT group, DNR group and HHT+DNR group were 95.0%, 100.0% and 91.0%, respectively (P=0.595). The 3-year EFS rates for three groups were 93.0%, 90.0% and 85.0% (P=0.382). No difference was found in the incidence of adverse events among three groups (P >0.05).. Similar to DNR plus ATRA based therapy, HHT plus ATRA based induction and consolidation therapy should be one of highly-efficient treatment options for newly diagnosed APL. Clinical trial registration Chinese Clinical Trial Registry, ChiCTR-TRC-12002628.

Topics: Antineoplastic Combined Chemotherapy Protocols; Blood Transfusion; Daunorubicin; Disease-Free Survival; Harringtonines; Homoharringtonine; Humans; Incidence; Leukemia, Promyelocytic, Acute; Leukocyte Count; Neoadjuvant Therapy; Platelet Transfusion; Prospective Studies; Remission Induction; Survival Rate; Treatment Outcome; Tretinoin

The APL0406 study showed that arsenic trioxide (ATO) and all-trans retinoic acid (ATRA) are not inferior to standard ATRA and chemotherapy (CHT) in newly diagnosed, low-intermediaterisk acute promyelocytic leukaemia (APL). We analysed the kinetics of promyelocytic leukaemia-retinoic acid receptor-α (PML-RARα) transcripts by real-time quantitative PCR (RQ-PCR) in bone marrow samples from 184 patients and assessed the prognostic impact of fms-related tyrosine kinase 3-internal tandem duplication (FLT3-ITD) in 159 patients enrolled in this trial in Italy. After induction therapy, the reduction of PML-RARα transcripts was significantly greater in patients receiving ATRA-CHT as compared with those treated with ATRA-ATO (3.4 vs 2.9 logs; P=0.0182). Conversely, at the end of consolidation, a greater log reduction of PML-RARα transcripts was detected in the ATRA-ATO as compared with the ATRA-CHT group (6.3 vs 5.3 logs; P=0.0024). FLT3-ITD mutations had no significant impact on either event-free survival (EFS) or cumulative incidence of relapse in patients receiving ATRA-ATO, whereas a trend for inferior EFS was observed in FLT3-ITD-positive patients receiving ATRA-CHT. Our study shows at the molecular level that ATRA-ATO exerts at least equal and probably superior antileukaemic efficacy compared with ATRA-CHT in low-intermediaterisk APL. The data also suggest that ATRA-ATO may abrogate the negative prognostic impact of FLT3-ITD.

Topics: Adolescent; Adult; Aged; Arsenic Trioxide; Arsenicals; Disease-Free Survival; Female; fms-Like Tyrosine Kinase 3; Humans; Induction Chemotherapy; Italy; Kinetics; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Mutation; Oncogene Proteins, Fusion; Oxides; Prognosis; Tretinoin; Young Adult

Topics: Adult; Arsenic; Female; Follow-Up Studies; Humans; Leukemia, Promyelocytic, Acute; Male; Remission Induction; Survival Analysis; Tretinoin

The clinical characteristics, treatment options and outcomes in patients with acute promyelocytic leukaemia (APL) and hyperleucocytosis remain poorly defined. This study reviewed 242 consecutive patients with APL; 29 patients (12%) had a white blood cell count (WBC) ≥ 50 × 10(9) /l at presentation (median WBC 85·5 × 10(9) /l). Patients with hyperleucocytosis had inferior complete remission (CR) rates (69% vs. 88%; P = 0·004) and higher 4-week mortality (24% vs. 9%; P = 0·018) compared to patients without hyperleucocytosis. We noted a trend towards inferior 3-year disease-free survival (DFS) (69% vs. 80%; P = 0·057) and inferior 3-year overall survival (OS) (74% vs. 92%; P = 0·2) for patients with hyperleucocytosis. Leukapheresis was performed in 11 (38%) of the 29 patients with hyperleucocytosis. CR rate and 3-year OS were not significantly improved in patients who received leukapheresis. CR rate and 3-year OS for the 15 patients with hyperleucocytosis treated with all-trans retinoic acid (ATRA) plus arsenic trioxide (ATO) plus cytotoxic therapy (idarubicin or gemtuzumab ozogamicin) combinations were 100% and 100% vs. 57% and 35% for the 14 patients treated with non-ATRA/ATO combinations (P = 0·004 and P = 0·002). Leukapheresis does not improve the outcomes in patients with APL presenting with hyperleucocytosis. ATRA/ATO-based combinations are superior to other regimens in these patients.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Disease-Free Survival; Female; Follow-Up Studies; Humans; Leukapheresis; Leukemia, Promyelocytic, Acute; Leukocyte Count; Leukocytosis; Male; Middle Aged; Oxides; Retrospective Studies; Survival Rate; Tretinoin

The combination of all-trans retinoic acid (ATRA) and idarubicin (AIDA) for induction therapy followed by three cycles of risk-adapted consolidation cycles is considered standard of care for patients with acute promyelocytic leukemia (APL). We report the outcome of 141 patients (median age 51 years; range, 19-82, 31 % ≥60 years) enrolled into the prospective Study Alliance Leukemia (SAL)-AIDA2000 trial, which comprised AIDA-based induction followed by only two courses of risk-adapted consolidation (daunorubicin or mitoxantrone ± cytarabine) followed by 2-year maintenance treatment. The early death rate was 7 % (median age 66 years), and additional 9 % stopped further treatment after induction. The estimated 6-year disease-free survival (DFS) was 80 % in all patients, 84 % in patients ≤60 and 72 % in patients >60 years (p = 0.140). No significant survival differences were observed between the high-risk and the non-high-risk patients (6-year OS 78 vs. 81 %, p = 0.625). Our results confirm the efficacy of a risk-adapted approach in APL patients. Furthermore, long-term outcomes are comparable to the results obtained with three cycles of consolidation. A modification of the number and intensity of conventional consolidation treatment may be a less toxic but equally effective approach and should be considered for further evaluation in randomized clinical trials in APL.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Consolidation Chemotherapy; Drug Administration Schedule; Female; Humans; Idarubicin; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Precision Medicine; Risk; Survival Analysis; Tretinoin; Young Adult

Front-line treatment of acute promyelocytic leukaemia (APL) consists of all-trans retinoic acid (ATRA) and anthracycline-based chemotherapy. In this setting, a comparison of idarubicin and daunorubicin has never been carried out. Two similar clinical trials using ATRA and chemotherapy for newly diagnosed APL were compared using matched-pair analysis. One was conducted by the PETHEMA/HOVON group with idarubicin and the other by the International Consortium on APL (IC-APL) using daunorubicin. Three hundred and fifty patients from the PETHEMA/HOVON cohort were matched with 175 patients in the IC-APL cohort, adjusting for the significantly unbalanced presenting features of the two entire cohorts. Complete remission (CR) rate was significantly higher in the PETHEMA/HOVON (94 %) than in the IC-APL cohort (85 %) (P = 0.002). The distribution of causes of induction failure and the time to achieve CR were similar in both cohorts. Patients who achieved CR had comparable cumulative incidence of relapse and disease-free survival rates, but lower overall and event-free survivals were observed in the IC-APL cohort, which was mainly due to a higher death rate during induction therapy. A higher death rate during consolidation therapy was also observed in the IC-APL. These results show that daunorubicin and idarubicin have similar antileukaemic efficacy in terms of primary resistance, molecular persistence, as well as molecular and haematological relapse rates when combined with ATRA in treatment of APL. However, a higher toxic death rate during induction and consolidation therapy was observed in the IC-APL cohort. This trial was registered at www.clinicaltrials.gov as #NCT00408278 [ClinicalTrials.gov].

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Daunorubicin; Disease-Free Survival; Female; Humans; Idarubicin; Leukemia, Promyelocytic, Acute; Male; Matched-Pair Analysis; Middle Aged; Risk Factors; Treatment Outcome; Tretinoin; Young Adult

Treatment of acute promyelocytic leukaemia (APL) with arsenic trioxide (ATO) and all-trans retinoic acid (ATRA) is highly effective first-line therapy, although approximately 5-10% of patients relapse. Tamibarotene is a synthetic retinoid with activity in APL patients who relapse after chemotherapy and ATRA, but has not been studied in relapse after treatment with ATO and ATRA. We report on a phase II study of tamibarotene in adult patients with relapsed or refractory APL after treatment with ATRA and ATO (n = 14). Participants were treated with tamibarotene (6 mg/m(2) /d) during induction and for up to six cycles of consolidation. The overall response rate was 64% (n = 9), the rate of complete cytogenetic response was 43% (n = 6) and the rate of complete molecular response was 21% (n = 3). Relapse was frequent with 7 of 9 responders relapsing after a median of 4·6 months (range 1·6-26·8 months). The median event-free survival (EFS) was 3·5 months [95% confidence interval (CI) 0-8·6 months] and the median overall survival (OS) was 9·5 months (95% CI 5·9-13·1 months). These results demonstrate that tamibarotene has activity in relapsed APL after treatment with ATO and ATRA and further studies using tamibarotene as initial therapy and in combination with ATO are warranted.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Benzoates; Biomarkers, Tumor; Cardiovascular Diseases; Cell Differentiation; Combined Modality Therapy; Consolidation Chemotherapy; Disease-Free Survival; Drug Resistance, Neoplasm; Febrile Neutropenia; Female; Hematopoietic Stem Cell Transplantation; Humans; Kaplan-Meier Estimate; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Oncogene Proteins, Fusion; Oxides; Recurrence; Remission Induction; Salvage Therapy; Tetrahydronaphthalenes; Tretinoin

To explore the clinical value of arsenious acid (H3AsO3) for treating patients with acute promyelocytic leukemia (APL).. A total of 86 patients with APL were randomly divided into experimental group (43 cases) and control group (43 cases). The control group was treated by all trans retinoic acid combined with chemotherapy, the experimental group were treated by arsenous acid on the basis of the control group.. The overall response rate (ORR) in experimental group (100.00%) was significantly higher than that in control group (88.37%) (P < 0.05). The time of returm to complete remission in experimental group (30.86 ± 4.34) was better than that in control group (42.42 ± 7.10) d (P < 0.05). The time of return to normal levels of peripheral WBC count (20.86 ± 9.28) × 10⁹/L, hemoglobin count (68.62 ± 14.97) g/L and thrombocyte count in experimental group obviously less than that in control group (P < 0.05). The rates of high white blood syndrome (HWBS), disseminated intravascular coagulation (DIC) in experimental group were lower than that in control group (P < 0.05). The survival rates of 2 and 3 years in experimental group were higher than that in control group (P < 0.05). The recurrence rate after treatment in experimental group was lower than that in control group (P < 0.05). The application of arsenious acid was main factor for patients survival (P < 0.05).. Arsenious acid can improve the clinical efficacy for the patients with acute promyelocytic leukemia, and reduce the complication, therefore it is worthy of application in clinic.

Topics: Arsenites; Disseminated Intravascular Coagulation; Humans; Leukemia, Promyelocytic, Acute; Leukocyte Count; Platelet Count; Recurrence; Remission Induction; Survival Rate; Tretinoin

Acute promyelocytic leukaemia is a chemotherapy-sensitive subgroup of acute myeloid leukaemia characterised by the presence of the PML-RARA fusion transcript. The present standard of care, chemotherapy and all-trans retinoic acid (ATRA), results in a high proportion of patients being cured. In this study, we compare a chemotherapy-free ATRA and arsenic trioxide treatment regimen with the standard chemotherapy-based regimen (ATRA and idarubicin) in both high-risk and low-risk patients with acute promyelocytic leukaemia.. In the randomised, controlled, multicentre, AML17 trial, eligible patients (aged ≥16 years) with acute promyelocytic leukaemia, confirmed by the presence of the PML-RARA transcript and without significant cardiac or pulmonary comorbidities or active malignancy, and who were not pregnant or breastfeeding, were enrolled from 81 UK hospitals and randomised 1:1 to receive treatment with ATRA and arsenic trioxide or ATRA and idarubicin. ATRA was given to participants in both groups in a daily divided oral dose of 45 mg/m(2) until remission, or until day 60, and then in a 2 weeks on-2 weeks off schedule. In the ATRA and idarubicin group, idarubicin was given intravenously at 12 mg/m(2) on days 2, 4, 6, and 8 of course 1, and then at 5 mg/m(2) on days 1-4 of course 2; mitoxantrone at 10 mg/m(2) on days 1-4 of course 3, and idarubicin at 12 mg/m(2) on day 1 of the final (fourth) course. In the ATRA and arsenic trioxide group, arsenic trioxide was given intravenously at 0·3 mg/kg on days 1-5 of each course, and at 0·25 mg/kg twice weekly in weeks 2-8 of course 1 and weeks 2-4 of courses 2-5. High-risk patients (those presenting with a white blood cell count >10 × 10(9) cells per L) could receive an initial dose of the immunoconjugate gemtuzumab ozogamicin (6 mg/m(2) intravenously). Neither maintenance treatment nor CNS prophylaxis was given to patients in either group. All patients were monitored by real-time quantitative PCR. Allocation was by central computer minimisation, stratified by age, performance status, and de-novo versus secondary disease. The primary endpoint was quality of life on the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 global health status. All analyses are by intention to treat. This trial is registered with the ISRCTN registry, number ISRCTN55675535.. Between May 8, 2009, and Oct 3, 2013, 235 patients were enrolled and randomly assigned to ATRA and idarubicin (n=119) or ATRA and arsenic trioxide (n=116). Participants had a median age of 47 years (range 16-77; IQR 33-58) and included 57 high-risk patients. Quality of life did not differ significantly between the treatment groups (EORTC QLQ-C30 global functioning effect size 2·17 [95% CI -2·79 to 7·12; p=0·39]). Overall, 57 patients in the ATRA and idarubicin group and 40 patients in the ATRA and arsenic trioxide group reported grade 3-4 toxicities. After course 1 of treatment, grade 3-4 alopecia was reported in 23 (23%) of 98 patients in the ATRA and idarubicin group versus 5 (5%) of 95 in the ATRA and arsenic trioxide group, raised liver alanine transaminase in 11 (10%) of 108 versus 27 (25%) of 109, oral toxicity in 22 (19%) of 115 versus one (1%) of 109. After course 2 of treatment, grade 3-4 alopecia was reported in 25 (28%) of 89 patients in the ATRA and idarubicin group versus 2 (3%) of 77 in the ATRA and arsenic trioxide group; no other toxicities reached the 10% level. Patients in the ATRA and arsenic trioxide group had significantly less requirement for most aspects of supportive care than did those in the ATRA and idarubicin group.. ATRA and arsenic trioxide is a feasible treatment in low-risk and high-risk patients with acute promyelocytic leukaemia, with a high cure rate and less relapse than, and survival not different to, ATRA and idarubicin, with a low incidence of liver toxicity. However, no improvement in quality of life was seen.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Biomarkers, Tumor; Denmark; Female; Humans; Idarubicin; Intention to Treat Analysis; Kaplan-Meier Estimate; Leukemia, Promyelocytic, Acute; Leukocyte Count; Male; Middle Aged; New Zealand; Oncogene Proteins, Fusion; Oxides; Quality of Life; Real-Time Polymerase Chain Reaction; Time Factors; Treatment Outcome; Tretinoin; United Kingdom; Young Adult

To investigate the efficacy of arsenic trioxide combined with all trans retinoic acid (ATRA) for patients with acute promyelocytic leukemia (APL).. A total of 159 cases of APL were selected from January 2011 to December 2014 in our hospital, among them 75 cases were treated by As₂O₃combined with ATRA, 43 cases were treated with As₂O₃alone, 41 cases were treated with ATRA alone. The cardiac enzymes level, lever function index change, death rate, complate remission (CR) rate, time of reaching CR and complicatiens were compared in 3 groups.. After treatment of 8 courses, ALT and AST levels in As₂O₃+ ATRA group were significantly higher than those in As₂O₃and ATRA alone groups; the CK-MB and TnI-UI index increased in As₂O₃group (P < 0.05); as compared with As₂O₃group, the mortality and CR rate in As₂O₃+ ATRA group were no significant different, but the time of reaching CR was significantly shortened. For relapsed patients, the CR rate in As₂O₃+ ATRA group was no significantly different from that in As₂O₃group, while was significantly higher than that in ATRA group. The ratio of liver function damage in As₂O₃+ ATRA group was increased, moreover the incidence of leukocytosis and headache in ATRA group was significantly higher than that in As₂O₃+ ATRA and As₂O₃group (P < 0.05).. The efficacy of As₂O₃conbined with ATRA for inducing remission is better than that of single drug treatment, moreover the adverse reactions occur less.

Topics: Arsenic Trioxide; Arsenicals; Drug Therapy, Combination; Humans; Leukemia, Promyelocytic, Acute; Oxides; Remission Induction; Tretinoin

Expression of CD56 has recently been introduced as one of the adverse prognostic factors in acute promyelocytic leukemia (APL). However, the clinical significance of CD56 antigen in APL has not been well elucidated. We assessed the clinical significance of CD56 antigen in 239 APL patients prospectively treated with all-trans retinoic acid and chemotherapy according to the Japan Adult Leukemia Study Group APL97 protocol. All patients were prospectively treated by the Japan Adult Leukemia Study Group APL97 protocol. The median follow-up period was 8.5 years. Positive CD56 expression was found in 23 APL patients (9.6%). Expression of CD56 was significantly associated with lower platelet count (P = 0.04), severe disseminated intravascular coagulation (P = 0.04), and coexpression of CD2 (P = 0.03), CD7 (P = 0.04), CD34 (P < 0.01) and/or human leukocyte antigen-DR (P < 0.01). Complete remission rate and overall survival were not different between the two groups. However, cumulative incidence of relapse and event-free survival (EFS) showed an inferior trend in CD56(+) APL (P = 0.08 and P = 0.08, respectively). Among patients with initial white blood cell counts of 3.0 × 10(9)/L or more, EFS and cumulative incidence of relapse in CD56(+) APL were significantly worse (30.8% vs 63.6%, P = 0.008, and 53.8% vs 28.9%, P = 0.03, respectively), and in multivariate analysis, CD56 expression was an unfavorable prognostic factor for EFS (P = 0.04). In conclusion, for APL with higher initial white blood cell counts, CD56 expression should be regarded as an unfavorable prognostic factor.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; CD56 Antigen; Cytarabine; Disease-Free Survival; Female; Humans; Idarubicin; Leukemia, Promyelocytic, Acute; Leukocyte Count; Male; Middle Aged; Neoplasm Recurrence, Local; Platelet Count; Prognosis; Prospective Studies; Remission Induction; Treatment Outcome; Tretinoin; Young Adult

Aa total of 105 patients (age ≥18 years) with newly diagnosed low or intermediate risk acute promyelocytic leukaemia (APL) were treated with a standard induction and consolidation regimen including arsenic trioxide (ATO). Sixty-eight patients who were polymerase chain reaction (PCR) negative for PML-RARA post-consolidation were randomized to either 1 year of maintenance with tretinoin, mercaptopurine and methotrexate, or observation. Enrollment in this non-inferiority trial was stopped prematurely due to slow accrual. With a median follow up of 36·1 months, the overall survival of the 105 patients was 93%, and there have been no relapses in the patients randomized to maintenance or observation. These results demonstrate that cures can be expected in >90% of patients with low and intermediate risk APL and suggest that maintenance therapy may not be needed if patients are treated with an intensive post-remission regimen including ATO. This trial was registered at clinicaltrials.gov as #NCT00492856.

Topics: Adult; Aged; Aminoglycosides; Animals; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Biomarkers, Tumor; Consolidation Chemotherapy; Cytarabine; Daunorubicin; Disease-Free Survival; Dogs; Female; Gemtuzumab; Humans; Leukemia, Promyelocytic, Acute; Maintenance Chemotherapy; Male; Mercaptopurine; Methotrexate; Middle Aged; Oncogene Proteins, Fusion; Oxides; Platelet Count; Remission Induction; Risk; Treatment Outcome; Tretinoin; Young Adult

A randomized clinical trial compared efficacy and toxicity of standard all-trans-retinoic acid (ATRA) plus chemotherapy versus ATRA plus arsenic trioxide in patients with newly diagnosed, low- or intermediate-risk acute promyelocytic leukemia (APL). Here, we report health-related quality-of-life (HRQOL) results.. HRQOL was a secondary end point of this trial. The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 was used to assess HRQOL at end of induction and after consolidation therapy. All analyses were based on 156 patients who received at least one dose of treatment, with groups defined according to randomly assigned treatment. Primary analysis was performed, estimating mean HRQOL score over time and differences between treatment arms using a linear mixed model.. Overall, 162 patients age 18 to 70 years were enrolled. Of these, 150 and 142 patients were evaluable for HRQOL after induction therapy and third consolidation course, respectively. Overall compliance with HRQOL forms was 80.1%. The largest difference, favoring patients treated with ATRA plus arsenic trioxide, was found for fatigue severity (mean score difference, -9.3; 95% CI, -17.8 to -0.7; P = .034) at end of induction therapy. This difference was also clinically relevant. HRQOL differences between treatment arms at end of consolidation showed that for several scales, differences between treatment arms were marginal.. Overall, current HRQOL findings further support the use of ATRA plus arsenic trioxide as preferred first-line treatment in patients with low- or intermediate-risk APL.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Humans; Leukemia, Promyelocytic, Acute; Oxides; Prospective Studies; Quality of Life; Tretinoin

Topics: Administration, Oral; Adult; Antineoplastic Combined Chemotherapy Protocols; Arsenic; Female; Humans; Induction Chemotherapy; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Pilot Projects; Tretinoin; Young Adult

We report a long-term follow-up (median 11.8 years) of the First North American Intergroup Study. 379 patients were randomized to induction with ATRA or to chemotherapy. All complete responders (CR) received consolidation chemotherapy, then randomized to 1 year ATRA or observation. 245 patients received ATRA sometime during the study: 195 (80%) achieved a CR. Nine (4.6%) relapsed late (>3 years from CR), the last occurred after 4.6 years; 7 of them were still alive after 5.5-15 years. In APL patients, late relapses are uncommon, and those who sustain CR >5 years can be considered cured.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Child; Child, Preschool; Female; Follow-Up Studies; Humans; Infant; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Neoplasm Recurrence, Local; Prognosis; Survival Rate; Time Factors; Tretinoin; Young Adult

All-trans retinoic acid (ATRA) combined to anthracycline-based chemotherapy is the reference treatment of acute promyelocytic leukemia (APL). Whereas, in high-risk patients, cytarabine (AraC) is often considered useful in combination with anthracycline to prevent relapse, its usefulness in standard-risk APL is uncertain. In APL 2000 trial, patients with standard-risk APL [i.e., with baseline white blood cell (WBC) count <10,000/mm(3) ] were randomized between treatment with ATRA with Daunorubicin (DNR) and AraC (AraC group) and ATRA with DNR but without AraC (no AraC group). All patients subsequently received combined maintenance treatment. The trial had been prematurely terminated due to significantly more relapses in the no AraC group (J Clin Oncol, (24) 2006, 5703-10), but follow-up was still relatively short. With long-term follow-up (median 103 months), the 7-year cumulative incidence of relapses was 28.6% in the no AraC group, compared to 12.9% in the AraC group (P = 0.0065). In standard-risk APL, at least when the anthracycline used is DNR, avoiding AraC may lead to an increased risk of relapse suggesting that the need for AraC is regimen-dependent.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Early Termination of Clinical Trials; Female; Follow-Up Studies; Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Recurrence; Risk Factors; Treatment Outcome; Tretinoin

To study the clinical outcome, adverse effect and treatment cost of homoharringtonine (HHT) in combination with all-trans retinoic acid (ATRA) and arsenic trioxide (AS2O3) for newly diagnosed with patients acute promyelocytic leukemia (APL).. Clinical data of treatment of newly diagnosed patients with APL in experimental group (HHT + ATRA + AS2O3, n = 14) and control group \\[Idarubicin (IDA) + ATRA + AS2O3, n = 21\\] were analyzed retrospectively. The therapeutic effects, side effects and costs during induction therapy were compared between the two groups.. (1) The complete remission (CR) rate were 92.9% (13/14) and 95.2% (20/21) in experimental group and control group, respectively. The time to achieve CR were (28.1 ± 3.8) and (31.7 ± 4.2) days, respectively (P > 0.05). The negative rate of PML-RARα fusion gene at the time of CR were 76.9% (10/13) and 75.0% (15/20), respectively, and that in CR patient at the end of the first cycle treatment were 100.0% (13/13) and 95.0% (19/20), respectively (P > 0.05). (2) 5-year overall survival (OS) rate were (92.6 ± 0.6)% and (89.9 ± 0.5)%, respectively (P > 0.05), 5-year disease free survival (DFS) rate were 100.0% and (86.8 ± 0.6)%, respectively (P > 0.05). (3) During induction therapy, the incidence of infection in experimental and control group were 23.1% (3/13), 60.0% (12/20), respectively (P < 0.05). The amount of platelet transfusion were (54.7 ± 29.6) and (76.5 ± 25.6) units, respectively (P > 0.05), and that of fresh frozen plasma were (1157.1 ± 238.4) and (1423.5 ± 324.6) ml, respectively (P > 0.05). The total medical costs (excluding HHT and IDA) in experimental and control group were (36074.9 ± 1245.6) and (50564.5 ± 3658.4)CNY, respectively (P < 0.05).. HHT in combination with ATRA and AS2O3 regimen for newly diagnosed APL has a better efficacy, a higher long-term survival rate, and a lower costs, which is one of the reasonable choice.

Topics: Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Female; Harringtonines; Homoharringtonine; Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Oxides; Retrospective Studies; Treatment Outcome; Tretinoin

All-trans retinoic acid (ATRA) with chemotherapy is the standard of care for acute promyelocytic leukemia (APL), resulting in cure rates exceeding 80%. Pilot studies of treatment with arsenic trioxide with or without ATRA have shown high efficacy and reduced hematologic toxicity.. We conducted a phase 3, multicenter trial comparing ATRA plus chemotherapy with ATRA plus arsenic trioxide in patients with APL classified as low-to-intermediate risk (white-cell count, ≤10×10(9) per liter). Patients were randomly assigned to receive either ATRA plus arsenic trioxide for induction and consolidation therapy or standard ATRA-idarubicin induction therapy followed by three cycles of consolidation therapy with ATRA plus chemotherapy and maintenance therapy with low-dose chemotherapy and ATRA. The study was designed as a noninferiority trial to show that the difference between the rates of event-free survival at 2 years in the two groups was not greater than 5%.. Complete remission was achieved in all 77 patients in the ATRA-arsenic trioxide group who could be evaluated (100%) and in 75 of 79 patients in the ATRA-chemotherapy group (95%) (P=0.12). The median follow-up was 34.4 months. Two-year event-free survival rates were 97% in the ATRA-arsenic trioxide group and 86% in the ATRA-chemotherapy group (95% confidence interval for the difference, 2 to 22 percentage points; P<0.001 for noninferiority and P=0.02 for superiority of ATRA-arsenic trioxide). Overall survival was also better with ATRA-arsenic trioxide (P=0.02). As compared with ATRA-chemotherapy, ATRA-arsenic trioxide was associated with less hematologic toxicity and fewer infections but with more hepatic toxicity.. ATRA plus arsenic trioxide is at least not inferior and may be superior to ATRA plus chemotherapy in the treatment of patients with low-to-intermediate-risk APL. (Funded by Associazione Italiana contro le Leucemie and others; ClinicalTrials.gov number, NCT00482833.).

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Consolidation Chemotherapy; Disease-Free Survival; Female; Humans; Induction Chemotherapy; Leukemia, Promyelocytic, Acute; Maintenance Chemotherapy; Male; Middle Aged; Neutropenia; Oxides; Thrombocytopenia; Tretinoin; Young Adult

Currently, there are few studies that address the prognostic significance of baseline additional chromosomal abnormalities (ACAs) in newly diagnosed acute promyelocytic leukemia (APL) patients treated with arsenic trioxide (ATO) as the front-line therapy. A series of 271 consecutive APL patients has been cytogenetically investigated between 2004 and 2011 in our institution. The incidence of ACAs was 27% (46/172) in APL cases with t(15;17). Trisomy 8 was the most recurrent abnormality, accounting for 30% (14/46) of patients with ACAs, followed by +21 (7%, 3/46) and -7/7q (7%, 3/46). Nine cases (14.1%) were found to have additional balanced translocation aberrations, most of them are new and non-recurrent. Treatment protocols consisted of all-trans retinoic acid (ATRA) and chemotherapy with or without the ATO therapy. Overall, patients with and without ACAs had similar complete remission (CR) rates (94% and 98%, respectively, P=0.344). With a median follow-up of 41 months, univariate analysis showed that ACAs did not show any prognostic significance in relapse-free survival (RFS) and overall survival (OS). In addition, ATO treatment was an independent favorable predictor for RFS. Thus, this data provides insights into cytogenetic features of APL, and suggests that ATO-based combination therapy improved RFS in de novo APL patients, while ACAs had no impact on prognosis.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Biomarkers, Tumor; Chromosome Aberrations; Chromosomes, Human, Pair 15; Chromosomes, Human, Pair 17; Female; Follow-Up Studies; Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Oxides; Prognosis; Remission Induction; Retrospective Studies; Survival Rate; Translocation, Genetic; Tretinoin; Young Adult

This randomized, multicenter, phase III noninferiority trial was designed to test the efficacy and safety of an oral tetra-arsenic tetra-sulfide (As4S4) -containing formula named the Realgar-Indigo naturalis formula (RIF) compared with intravenous arsenic trioxide (ATO) as both induction and maintenance therapies for newly diagnosed acute promyelocytic leukemia (APL).. In all, 242 patients with APL were randomly assigned (1:1) to oral RIF (60 mg/kg) or ATO (0.16 mg/kg) combined with all-trans retinoic acid (ATRA; 25 mg/m(2)) during induction therapy. After achieving complete remission (CR), all patients received three courses of consolidation chemotherapy and maintenance treatment with sequential ATRA followed by either RIF or ATO for 2 years. The primary end point was the rate of disease-free survival (DFS) at 2 years, which was assessed for noninferiority with a 10% noninferiority margin.. The median follow-up time was 39 months. DFS at 2 years was 98.1% (106 of 108) in the RIF group and 95.5% (107 of 112) in the ATO group. The DFS difference was 2.6% (95% CI, -3.0% to 8.0%). The lower limit of the 95% CI of DFS difference was greater than the -10% noninferiority margin, confirming noninferiority (P < .001). No significant differences were noted between the RIF and ATO groups with regard to the CR rate (99.1% v 97.2%; P = .62) or the overall survival at 3 years (99.1% v 96.6%; P = .18). The rates of adverse events were similar in the two groups.. Oral RIF plus ATRA is not inferior to intravenous ATO plus ATRA as first-line treatment of APL and may be considered as a routine treatment option for appropriate patients.

Topics: Administration, Intravenous; Administration, Oral; Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Disease-Free Survival; Drugs, Chinese Herbal; Female; Fever; Follow-Up Studies; Humans; Induction Chemotherapy; Leukemia, Promyelocytic, Acute; Liver; Maintenance Chemotherapy; Male; Middle Aged; Oxides; Remission Induction; Sulfides; Treatment Outcome; Tretinoin; Young Adult

To give the results of an investigation conducted at the Hematology Research Center (HRC), Ministry of Health of the Russian Federation (MHRF), to treat adult patients with acute promyelocytic leukemia (APL) according to the AIDA protocol elaborated by Spanish investigators.. The investigation enrolled 33 patients diagnosed with APL verified by cytogenetic and molecular studies, who had been treated at the HRC, MHRF, in July 2009 to January 2012. The patients classified in the low-, intermediate-, and high-risk groups were 30, 46.7; and 23.3%, respectively. The analysis was made in January 2013.. The number of patients who achieved complete remission, as well as the mortality rates during remission induction were wholly comparable to those previously obtained when using the 7+3+ATRA protocol: 90.3 and 9.7%, respectively. One patient in remission died (3.6% mortality rate). The likelihood of recurrence in this investigation was high (21%), which was due to gross noncompliance with maintenance therapy. On examining the clearance of the malignant clone by FISH and polymerase chain reaction, a naturally chimeric transcript identified by a molecular study was statistically significantly more frequently revealed during postinduction therapy, which was associated with different sensitivity of the techniques. Comparison of changes in the disappearance of a chimeric marker for APL with the AIDA and 7+3+ARTA programs showed that the clearance of the malignant clone was much slower.. The AIDA program is a highly effective treatment protocol for patients with APL.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Biomarkers; Disease-Free Survival; Female; Humans; Idarubicin; Kaplan-Meier Estimate; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Oncogene Proteins, Fusion; Remission Induction; Severity of Illness Index; Treatment Outcome; Tretinoin; Young Adult

Initial therapy for patients with acute promyelocytic leukemia most often involves the combination of all-trans-retinoic acid with anthracycline-based chemotherapy. The role of non-anthracycline drugs in induction and consolidation is less well-established and varies widely between different cooperative group protocols.. In an attempt to minimize relapse and maximize survival for patients with newly diagnosed acute promyelocytic leukemia, the Australasian Leukaemia and Lymphoma Group utilized all-trans-retinoic acid and idarubicin as anti-leukemic therapy for both induction and consolidation. The protocol (known as APML3) was subsequently amended to incorporate maintenance with all-trans-retinoic acid, methotrexate and 6-mercaptopurine.. Eight (8%) of 101 patients died within 30 days, and 91 (90%) achieved complete remission. With a median estimated potential follow-up of 4.6 years, 4-year overall survival was 84%, and 71% of the patients remained in remission at 4 years. The cumulative incidence of all relapses was 28.1%, with 15 of the 25 relapses initially identified as an isolated molecular relapse. Both FLT3 mutations (internal tandem duplications and codon 835/836 kinase domain mutations) and increased white cell count at diagnosis were associated with inferior overall survival, but in multivariate analyses only FLT3 mutations remained significant (hazard ratio 6.647, P=0.005). Maintenance therapy was significantly associated with improved remission duration (hazard ratio 0.281, P<0.001) and disease-free survival (hazard ratio 0.290, P<0.001).. The combination of all-trans-retinoic acid and just two cycles of idarubicin followed by triple maintenance produced durable remissions in most patients, but patients with high-risk disease, especially those with FLT3 mutations, require additional agents or alternative treatment approaches. The significant reduction in relapse seen after the addition of maintenance to the protocol supports a role for maintenance in the context of relatively low chemotherapy exposure during consolidation. (actr.org.au identifier: ACTRN12607000410459).

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Consolidation Chemotherapy; Female; Follow-Up Studies; Humans; Idarubicin; Induction Chemotherapy; Leukemia, Promyelocytic, Acute; Male; Mercaptopurine; Middle Aged; Survival Rate; Tretinoin; Young Adult

The purpose of the study was to evaluate event-free survival (EFS), overall survival (OS) and safety for early addition of arsenic trioxide (As(2)O(3)) as frontline consolidation therapy compared to high-dose arabinoside (HiDAC) in adult patients with de novo acute promyelocytic leukemia (APL). 271 patients (aged 17-65 years) received consolidation therapy containing As(2)O(3) (two 21-day courses) or HiDAC regimen. EFS at 5 years was 75% versus 54% (P < 0.001), and OS at 5 years was 83% versus 71% (P = 0.002) in As(2)O(3) and HiDAC treatment arms. 139 patients treated with As(2)O(3), EFS at 5 years reached 79% versus 56% (P = 0.014), but OS at 5 years was 77% versus 84% (P = 0.32) in low-risk (WBC ≤ 10 × 10(9)/L) and high-risk (WBC > 10 × 10(9)/L) cohorts. Further, patients treated with As(2)O(3) rarely incurred agranulocytosis (1.4%, P < 0.001), or severe infection (0.7%, P < 0.001). It is still very well tolerated compared to HiDAC. We confirmed that As(2)O(3) as a first-line consolidation regimen provided significant benefits of OS to patients with APL. The As(2)O(3) regimen made low-risk patients gain more EFS benefits than high-risk group. The high-risk cohort receiving As(2)O(3) overcame the negative impact, yielding OS similar to that for with the low-risk patients treated with As(2)O(3).

Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Consolidation Chemotherapy; Cytarabine; Daunorubicin; Disease-Free Survival; Female; Humans; Kaplan-Meier Estimate; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Oxides; Tretinoin; Young Adult

Acute promyelocytic leukemia (APL) is rare in children. All-trans-retinoic acid (ATRA) combined with chemotherapy, the reference treatment of APL, is generally considered to produce similar results in children and adults. However, previously published childhood APL studies have generally analyzed all patients age < 18 years as a group, without further dividing according to age.. We compared disease characteristics and outcomes of children (age ≤ 12 years), adolescents (13 to 18 years), and adults (> 18 years) included in two multicenter APL clinical trials (APL 93 and 2000 trials).. Of the 833 patients age ≤ 60 years included in the two trials, 26 (3%), 58 (7%), and 749 (90%) were children, adolescents, and adults, respectively. Children had significantly higher baseline WBC counts (P < .001). The complete remission (CR) rate (92%, 100%, and 94.5%, respectively) and 5-year cumulative incidence of relapse (CIR; 28%, 20%, and 23%, respectively) did not differ between children, adolescents, and adults, whereas adolescents had significantly better overall survival (OS; 5-year OS, 93.6% v 80.4% in adults and 80.4% in children; P = .03). However, in children age ≤ 4 years, the 5-year CIR was 52%, compared with 17.6% in children age 5 to 12 years (P = .006), although most of the younger children who relapsed experienced durable salvage with autologous or allogeneic stem-cell transplantation.. Adolescents and children age > 4 years with APL treated with ATRA and chemotherapy have outcomes at least as favorable as those of adults. Younger children seem to experience more relapses and may require reinforcement of first-line treatment.

Topics: Adolescent; Adult; Age Factors; Antineoplastic Combined Chemotherapy Protocols; Cause of Death; Child; Child, Preschool; Disease-Free Survival; Dose-Response Relationship, Drug; Drug Administration Schedule; Europe; Female; Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Neoplasm Recurrence, Local; Prognosis; Risk Assessment; Survival Analysis; Time Factors; Treatment Outcome; Tretinoin

The role of allogeneic stem cell transplant in advanced acute promyelocytic leukemia patients who received standard first- and second-line therapy is still unknown. We report the outcome of 31 acute promyelocytic leukemia patients (median age 39 years) who underwent allogeneic transplant in second remission (n=15) or beyond (n=16). Sixteen patients were real-time polymerase chain reaction positive and 15 negative for PML/RARA pre-transplant. The 4-year overall survival was 62% and 31% for patients transplanted in second remission and beyond, respectively (P=0.05), and 64% and 27% for patients with pre-transplant negative and positive real-time polymerase chain reaction, respectively (P=0.03). The 4-year cumulative incidence of relapse was 32% and 44% for patients transplanted in second remission and beyond, respectively (P=0.37), and 30% and 47% for patients transplanted with negative and positive real-time polymerase chain reaction, respectively (P=0.30). Transplant-related mortality was 19.6%. In conclusion, allogeneic transplant is effective in advanced acute promyelocytic leukemia in the all-trans-retinoic acid and arsenic trioxide era, and should be considered once relapse is diagnosed.

Topics: Adolescent; Adult; Antineoplastic Agents; Arsenic Trioxide; Arsenicals; Disease-Free Survival; Female; Follow-Up Studies; Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Oncogene Proteins, Fusion; Oxides; Retrospective Studies; Stem Cell Transplantation; Survival Rate; Transplantation, Homologous; Tretinoin

The treatment of acute promyelocytic leukemia has improved considerably after recognition of the effectiveness of all-trans-retinoic acid (ATRA), anthracycline-based chemotherapy, and arsenic trioxide (ATO). Here we report the use of all 3 agents in combination in an APML4 phase 2 protocol. For induction, ATO was superimposed on an ATRA and idarubicin backbone, with scheduling designed to exploit antileukemic synergy while minimizing cardiotoxicity and the severity of differentiation syndrome. Consolidation comprised 2 cycles of ATRA and ATO without chemotherapy, followed by 2 years of maintenance with ATRA, oral methotrexate, and 6-mercaptopurine. Of 124 evaluable patients, there were 4 (3.2%) early deaths, 118 (95%) hematologic complete remissions, and all 112 patients who commenced consolidation attained molecular complete remission. The 2-year rate for freedom from relapse is 97.5%, failure-free survival 88.1%, and overall survival 93.2%. These outcomes were not influenced by FLT3 mutation status, whereas failure-free survival was correlated with Sanz risk stratification (P[trend] = .03). Compared with our previously reported ATRA/idarubicin-based protocol (APML3), APML4 patients had statistically significantly improved freedom from relapse (P = .006) and failure-free survival (P = .01). In conclusion, the use of ATO in both induction and consolidation achieved excellent outcomes despite a substantial reduction in anthracycline exposure. This trial was registered at the Australian New Zealand Clinical Trials Registry (www.anzctr.org.au) as ACTRN12605000070639.

Topics: Adolescent; Adult; Aged; Antibiotics, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Child; Child, Preschool; Female; Humans; Idarubicin; Induction Chemotherapy; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Oxides; Treatment Outcome; Tretinoin; Young Adult

We treated individuals for disseminated intravascular coagulation (DIC) caused by acute promyelocytic leukemia (APL) (n=9) using human soluble thrombomodulin (rTM) in combination with all-trans retinoic acid (ATRA) and chemotherapy, and compared the clinical outcomes with historical control patients (n=8) treated with ATRA and/or chemotherapy. Two control patients developed intracranial vascular incidents. On the other hand, no bleeding related mortality was noted in rTM-treated patients. Notably, treatment with rTM rescued patients from DIC earlier than historical controls (log rank test, p=0.019). These results suggest that administration of rTM should be considered for the treatment of individuals with DIC associated with APL.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Disseminated Intravascular Coagulation; Female; Humans; Kaplan-Meier Estimate; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Recombinant Proteins; Thrombomodulin; Tretinoin

To compare the difference in the long-term efficacy between all-trans retinoic acid (ATRA) combined Compound Huangdai Tablet and ATRA combined methotrexate (MTX) and 6-mercaptopurine (6MP) as the sequential maintenance treatment of acute promyelocytic leukemia (APL) patients.. Totally 83 APL patients in the molecular remission (PML/RARalpha negative) were randomly assigned to two groups, the treatment group (45 cases) and the control group (38 cases) after they were induced to the complete remission (CR) by ATRA combined chemotherapy, and treated by sequential chemotherapy as the consolidated treatment for 3 therapeutic courses. Those in the treatment group were sequentially treated with ATRA and Compound Huangdai Tablet as maintenance therapy, while those in the control group were treated with ATRA and MTX + 6MP as maintenance therapy. After a long-term follow-up (2003 -2011), the long-term therapeutic efficacy and adverse reactions were compared between the two therapeutic regimens.. The 5-year relapse-free survival (RFS) rate was 84.4% +/- 5.4% in the treatment group and 63.2% +/- 7.8% in the control group, showing statistical difference between the two groups (P < 0.05). The 5-year overall survival rate (OSR) was 86.7% +/- 5. 1% in the treatment group and 78.7% +/- 6.7% in the control group, showing no statistical difference between the two groups (P > 0.05). There was no statistical difference in the adverse reaction between the two groups (P > 0.05).. The application of ATRA and Compound Huangdai Tablet as maintenance therapy could elevate the long-term RFS rate of APL patients.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Drugs, Chinese Herbal; Female; Humans; Leukemia, Promyelocytic, Acute; Male; Mercaptopurine; Methotrexate; Middle Aged; Phytotherapy; Treatment Outcome; Tretinoin; Young Adult

Reports on childhood APL from developing countries are scarce. We treated 65 APL with two consecutive trials combining ATRA and chemotherapy. Twenty (30.7%) were aged less than 20 years including 11 girls and 9 boys, with a median age of 12 years. Fever at presentation (P=0.002) and variant APL (P=0.044) were more frequent in children, while there were no significant difference between children and adults for WBC count, Sanz's score distribution and additional cytogenetic abnormalities. The CR rate was 95% (19/20) in children and 80% (36/45) in adults (P=0.13). Differentiation syndrome (DS) was less often observed in children (1/20) than in adults (13/45) (P=0.031). Two children relapsed and died during salvage therapy, and 2 died in CR from infection and from cardiac failure attributed to anthracyclines, while other children remained alive in CR. With a median follow-up of 4 years, 4-year EFS was 75% in children and 71.1% in adults (P=0.57), while 4-year OS was 75% in children vs. 73.3% in adults (P=0.72). Our results suggest that, even in the absence of optimal socio-economic condition, ATRA combined with anthracycline-based chemotherapy gives adequate results in childhood APL, as in adults.

Topics: Adolescent; Adult; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Disease-Free Survival; Female; Humans; Kaplan-Meier Estimate; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Treatment Outcome; Tretinoin; Tunisia; Young Adult

In childhood acute promyelocytic leukaemia (APL), the efficacy of therapy combining cytarabine with all-trans retinoic acid (ATRA) and anthracyclines remains unclear in terms of long-term prognosis. Between August 1997 and March 2004, 58 children with APL (median age: 11 years) were enrolled into an acute myeloid leukaemia (AML) study (AML99-M3) and followed up for a median time of 86 months. The regimen included ATRA and anthracyclines combined with cytarabine in both induction and consolidation. In induction, two patients died of haemorrhage and four patients developed retinoic acid syndrome. Of 58 patients, 56 (96·6%) achieved complete remission, two of whom relapsed in the bone marrow after 15 and 19 months respectively. Sepsis was a major complication, with an incidence of 5·6-10·9% in the consolidation blocks, from which all but one of patients recovered. Consequently, 7-year overall and event-free survival rates were 93·1% and 91·4% respectively, and cumulative incidence of relapse plateaued at 3·6% after 2 years. Follow-up survey of 54 patients revealed no patients with late cardiotoxicity or secondary malignancy, except one with asymptomatic prolongation of QTc interval. This study suggests that the combination of cytarabine with ATRA and anthracycline-based therapy may have useful implications in the perspective of long-term prognosis and late adverse effects for childhood APL.

Topics: Adolescent; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Chromosome Aberrations; Cytarabine; Epidemiologic Methods; Female; Humans; Infant; Leukemia, Promyelocytic, Acute; Leukocyte Count; Male; Neoplasm, Residual; Neutropenia; Prognosis; Recurrence; Treatment Outcome; Tretinoin

The expression of CD56 antigen in acute promyelocytic leukemia (APL) blasts has been associated with short remission duration and extramedullary relapse. We investigated the clinical significance of CD56 expression in a large series of patients with APL treated with all-trans retinoic acid and anthracycline-based regimens. Between 1996 and 2009, 651 APL patients with available data on CD56 expression were included in 3 subsequent trials (PETHEMA LPA96 and LPA99 and PETHEMA/HOVON LPA2005). Seventy-two patients (11%) were CD56(+) (expression of CD56 in ≥ 20% leukemic promyelocytes). CD56(+) APL was significantly associated with high white blood cell counts; low albumin levels; BCR3 isoform; and the coexpression of CD2, CD34, CD7, HLA-DR, CD15, and CD117 antigens. For CD56(+) APL, the 5-year relapse rate was 22%, compared with a 10% relapse rate for CD56(-) APL (P = .006). In the multivariate analysis, CD56 expression retained the statistical significance together with the relapse-risk score. CD56(+) APL also showed a greater risk of extramedullary relapse (P < .001). In summary, CD56 expression is associated with the coexpression of immaturity-associated and T-cell antigens and is an independent adverse prognostic factor for relapse in patients with APL treated with all-trans-retinoic acid plus idarubicin-derived regimens. This marker may be considered for implementing risk-adapted therapeutic strategies in APL. The LPA2005 trial is registered at http://www.clinicaltrials.gov as NCT00408278.

Topics: Adolescent; Adult; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; CD56 Antigen; Female; Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Prognosis; Recurrence; Risk Factors; Tretinoin; Young Adult

To explore the efficacy of treatment for childhood acute promyelocytic leukemia (APL) with a combination of all-trans-retinoic acid (ATRA) and arsenic trioxide (As(2)O(3)) for remission induction, we reviewed the clinical course and outcome of 37 children with APL from January 1999 to December 2003. Among the 37 children (≤14 years) with newly diagnosed APL, we applied treatments that consisted of ATRA alone or in combination with As(2)O(3) in induction followed by consolidation and maintenance treatment. Overall, 35 (94.6%) of 37 children achieved complete remission (CR). Two patients died of intracerebral hemorrhage on days 1 and 2. The 5-year estimates of event-free survival (EFS), disease-free survival (DFS), and overall survival (OS) rates for the 37 patients were 79.2, 83.7, and 91.5%, respectively. There were 27 patients with white blood cell (WBC) count lower than 10 × 10(9)/L. In 27 patients with a WBC count <10 × 10(9)/L, 17 patients (group-I) were treated with ATRA alone and 10 patients (group-II) were treated with ATRA which was switched to As(2)O(3) due to the side effects of ATRA. Although the 5-year estimate of DFS between group-I and group-II showed no significant difference (P = 0.108), the DFS rate improved by 25% in group-II. Our results suggest that the combination of As(2)O(3) and ATRA might decrease the relapse rate compared with ATRA alone in induction therapy for childhood APL, at least in those with a WBC count less than 10 × 10(9)/L.

Topics: Adolescent; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Child; Child, Preschool; China; Cohort Studies; Female; Humans; Leukemia, Promyelocytic, Acute; Male; Oxides; Remission Induction; Survival Analysis; Tretinoin

All-trans-retinoic acid (ATRA) has greatly modified the prognosis of acute promyelocytic leukemia; however, the role of maintenance in patients in molecular complete remission after consolidation treatment is still debated. From July 1993 to May 2000, 807 genetically proven newly diagnosed acute promyelocytic leukemia patients received ATRA plus idarubicin as induction, followed by 3 intensive consolidation courses. Thereafter, patients reverse-transcribed polymerase chain reaction-negative for the PML-RARA fusion gene were randomized into 4 arms: oral 6-mercaptopurine and intramuscular methotrexate (arm 1); ATRA alone (arm 2); 3 months of arm1 alternating to 15 days of arm 2 (arm 3); and no further therapy (arm 4). Starting from February 1997, randomization was limited to ATRA-containing arms only (arms 2 and 3). Complete remission was achieved in 761 of 807 (94.3%) patients, and 681 completed the consolidation program. Of these, 664 (97.5%) were evaluated for the PML-RARA fusion gene, and 586 of 646 (90.7%) who tested reverse-transcribed polymerase chain reaction-negative were randomized to maintenance. The event-free survival estimate at 12 years was 68.9% (95% confidence interval, 66.4%-71.4%), and no differences in disease-free survival at 12 years were observed among the maintenance arms.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Clinical Protocols; Disease-Free Survival; Female; Humans; Idarubicin; Infant; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Oncogene Proteins, Fusion; Remission Induction; Tretinoin; Young Adult

To reduce toxicity in elderly patients with acute promyelocytic leukaemia, in 1997 the Gruppo Italiano Malattie Ematologiche Dell'Adulto (GIMEMA) started an amended protocol for patients aged >60years, with the same induction [all-trans retinoic acid (ATRA)+idarubicin] as in younger patients, followed by a single consolidation course (idarubicin+ cytarabine) and maintenance with intermittent ATRA. Among 60 enrolled patients, 54 (90%) achieved haematological remission and six died during induction. Four additional patients died in complete remission (CR) from haemorrhage (2) and infection (2) prior or during consolidation therapy. Eleven patients relapsed at a median time of 17·5months from CR. The 5-year overall survival (OS), disease-free survival (DFS) and cumulative incidence of relapse (CIR) rates were 76·1%, 64·6% and 27·4%, respectively. Univariate analysis identified a performance score (PS)=2 as the only significant adverse prognostic factor for both OS (P=0·017) and DFS (P=0·0003). Male sex had an unfavourable impact on DFS (P=0·021) and on CIR (P=0·019), but not on OS (P=0·234). In multivariate analysis for DFS, only PS=2 retained prognostic significance (HR=4·5, P=0·0083). In conclusion, the amended GIMEMA protocol is effective, with similar relapse rate and inferior toxicity compared to the original AIDA 0493. However, considering the recent availability of effective new agents, a less aggressive approach should be tested in this setting.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Hemorrhage; Humans; Idarubicin; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Opportunistic Infections; Prognosis; Remission Induction; Survival Analysis; Tretinoin

Combined treatment with all-trans-retinoic acid and chemotherapy is extremely efficient in patients with acute promyelocytic leukemia with t(15;17)/PML-RARA, but up to 15% of patients relapse.. To further clarify the prognostic impact of parameters such as FLT3 mutations, we comprehensively characterized the relation between genetic features and outcome in 147 patients (aged 19.7-86.3 years) with acute promyelocytic leukemia.. Internal tandem duplications of the FLT3 gene (FLT3-ITD) were detected in 47/147 (32.0%) and tyrosine kinase domain mutations (FLT3-TKD) in 19/147 (12.9%) patients. FLT3-ITD or FLT3-TKD mutation status did not have a significant prognostic impact, whereas FLT3-ITD mutation load, as defined by a mutation/wild-type ratio of less than 0.5 was associated with trends to a better 2-year overall survival rate (86.7% versus 72.7%; P=0.075) and 2-year event-free survival rate (84.5% versus 62.1%, P=0.023) compared to the survival rates of patients with a ratio of 0.5 or more. Besides the t(15;17), an additional chromosomal abnormality was detected in 57 of 147 cases and did not show a significant impact on survival. White blood cell counts of 10×10(9)/L or less versus more than 10×10(9)/L were associated with a better 2-year overall survival rate (88.3% versus 69.4%, respectively; P=0.015), as was male sex (P=0.040). In multivariate analysis, only higher age had a significant adverse impact.. Prospective trials should further investigate the clinical impact of the FLT3-ITD/wild-type mutation load aiming to evaluate whether this parameter might be included in risk stratification in patients with acute promyelocytic leukemia.

Topics: Adult; Aged; Antineoplastic Agents; Chromosomes, Human, Pair 15; Chromosomes, Human, Pair 17; Disease-Free Survival; Female; fms-Like Tyrosine Kinase 3; Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Oncogene Proteins, Fusion; Survival Rate; Translocation, Genetic; Tretinoin

Seventy-six patients with acute promyelocytic leukemia (APL) in first complete remission after induction and consolidation by daunorubicin and cytosine arabinoside received oral arsenic trioxide (As(2)O(3))-based maintenance. Three regimens were used: oral As(2)O(3) (10 mg/day, regimen A, n = 20), oral As(2)O(3) plus all-trans retinoic acid (ATRA, 45 mg/m(2) per day, regimen AA, n = 19), and oral As(2)O(3) plus ATRA plus ascorbic acid (1000 mg/day, regimen AAA, n = 37), each given for 2 weeks every 2 months for 2 years. Patients receiving A, AA, and AAA maintenance did not differ significantly in clinicopathologic features and risk factors. Headache, dyspepsia, reversible liver function derangement, and herpes zoster reactivation were adverse effects observed during maintenance. QTc prolongation and arrhythmias were not encountered. At a median follow-up of 24 months (range, 1-115 months), there were 8 relapses. The 3-year leukemia-free-survival, event-free-survival, and overall-survival were 87.7%, 83.7%, and 90.6%, respectively. Adverse prognostic factors included male gender for leukemia-free-survival, and unrelated cancers for overall survival. Age, presentation WBC count and platelet count, and the type of oral As(2)O(3) maintenance regimens had no impact on survivals. Prolonged oral As(2)O(3) maintenance was feasible and safe and resulted in favorable outcomes when used with a simple induction and consolidation regimen compared with other protocols composed of multiple chemotherapeutic agents.

Topics: Administration, Oral; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Ascorbic Acid; Cytarabine; Daunorubicin; Disease-Free Survival; Dyspepsia; Female; Follow-Up Studies; Headache; Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Oxides; Recurrence; Remission Induction; Time Factors; Treatment Outcome; Tretinoin

To explore an efficacious protocol for the patients with acute promyelocytic leukemia (APL) after a complete remission (CR) by all-trans retinoic acid (ATRA).. A total of 32 APL patients with an induction of CR by ATRA at our hospital from January 2000 to October 2007 received conventional standard chemotherapy as a consolidation regimen. Stratified according to age, those under 50 years old received an intermediate dose of cytarabine(IDAra-C)and over 50 years old non-IDAra-C regimen. Maintenance regimen: all patients received ATRA, arsenic trioxide (As2O3) and 6-mercaptopurine (6-MP) + methotrexate (MTX) alternately and sequentially for 3 years. The efficacy and side effects of these chemotherapies were observed.. The median follow-up was 72 (40 - 124) months. The 5-year disease-free survival (DFS) rates of under 50 years old and over 50 years old were 94.7% and 92.3% respectively. The difference was statistically insignificant (P > 0.05). One patient relapsed after a consolidation therapy and so did another on a maintenance regimen. Thirty patients achieved a constant CR. And 16 of 30 patients completed chemotherapy beyond 5 years and survived disease-free. The 5-year DFS rate of 32 patients was 93.8%.. After the achievement of CR with ATRA, all APL patients have a higher rate of DFS after stratification. The side effects are generally mild. Thus a stratification therapy is both feasible and efficacious.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Female; Follow-Up Studies; Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Treatment Outcome; Tretinoin; Young Adult

Acute promyelocytic leukemia (APL) is one of the most curable myeloid malignancies because of its great sensitivity to all-trans retinoic acid (ATRA) and response to anthracycline therapy. In an attempt to simplify post-remission therapy, deliver adequate dose of anthracycline and reduce treatment related toxicity, we entered 26 consecutively newly diagnosed, previously untreated APL patients in a pilot treatment program consisting of concurrent induction using idarubicin/ATRA followed by an exclusive outpatient post-remission therapy using single dose of idarubicin and intermittent ATRA, every 4 weeks. Of 25 evaluable patients, two (8%) died early during induction due to hemorrhagic complications, and 23 (92%) achieved complete remission. Overall survival at 4.2 years was 90% (CI 76.4-100), and 3.6 years disease-free survival was 78% (CI 60.6-95.4). The treatment outcome of this program is encouraging; however, the result of this study needs to be validated in larger cohort of patients and optimally in a randomized comparison with other current post-remission approaches.

Topics: Adolescent; Adult; Aged; Ambulatory Care; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Dexamethasone; Disease-Free Survival; Drug Administration Schedule; Factor VIII; Female; Fibrinogen; Hemorrhage; Humans; Idarubicin; Kaplan-Meier Estimate; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Pilot Projects; Remission Induction; Tretinoin; Young Adult

Increased BMI has been correlated to an increased incidence of APL, but not to the occurrence of differentiation syndrome (DS) in APL. We consecutively treated 39 APL patients with ATRA and idarubicin (according to PETHEMA regimen). Median age was 26 years. Forty-one percent patients were classified as intermediate risk, and 59% as high risk according to Sanz's score. Thirty-three patients (85%) reached CR. Eleven of the 36 patients evaluable for DS (30.5%) developed this syndrome (severe in 7 cases, moderate in 4, and fatal in 3 cases) within a median of 12 days (range 3-23) of ATRA onset. Six of the 9 (66.6%) patients with BMI>or=30 developed DS vs. 5 of 27 (18.5%) with BMI<30 (p=0.012). Other predictors of DS in univariate analysis were: age>or=40 year (p=0.033), baseline WBC>or=20 x 10(9)/l (p=0.003), and creatinine>1.4 mg/dl (p=0.009). In multivariate analysis, BMI>or=30 remained an independent predictor of DS in addition to baseline WBC>or=20 x 10(9)/l.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Body Mass Index; Child; Child, Preschool; Disease Progression; Female; Humans; Idarubicin; Leukemia, Promyelocytic, Acute; Leukocyte Count; Male; Middle Aged; Prognosis; Survival Analysis; Syndrome; Tretinoin; Young Adult

We investigated the benefit of adding all-trans retinoic acid (ATRA) to chemotherapy for younger patients with nonacute promyelocytic acute myeloid leukemia and high-risk myelodysplastic syndrome, and considered interactions between treatment and molecular markers. Overall, 1075 patients less than 60 years of age were randomized to receive or not receive ATRA in addition to daunorubicin/Ara-C/thioguanine chemotherapy with Ara-C at standard or double standard dose. There were data on FLT3 internal tandem duplications and NPM1 mutations (n = 592), CEBPA mutations (n = 423), and MN1 expression (n = 195). The complete remission rate was 68% with complete remission with incomplete count recovery in an additional 16%; 8-year overall survival was 32%. There was no significant treatment effect for any outcome, with no significant interactions between treatment and demographics, or cytarabine randomization. Importantly, there were no interactions by FLT3/internal tandem duplications, NPM1, or CEBPA mutation. There was a suggestion that ATRA reduced relapse in patients with lower MN1 levels, but no significant effect on overall survival. Results were consistent when restricted to patients with normal karyotype. ATRA has no overall effect on treatment outcomes in this group of patients. The study did not identify any subgroup of patients likely to derive a significant survival benefit from the addition of ATRA to chemotherapy.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; CCAAT-Enhancer-Binding Proteins; Child; Child, Preschool; Cytarabine; Daunorubicin; Female; fms-Like Tyrosine Kinase 3; Gene Expression Regulation, Leukemic; Genotype; Humans; Infant; Infant, Newborn; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Mutation; Nuclear Proteins; Nucleophosmin; Reverse Transcriptase Polymerase Chain Reaction; Thioguanine; Treatment Outcome; Tretinoin; Young Adult

Acute promyelocytic leukemia (APL) is highly curable with the combination of all-trans retinoic acid (ATRA) and anthracycline-based chemotherapy (CT), but very long-term results of this treatment, when CT should be added to ATRA and the role of maintenance treatment, remain uncertain. In our APL93 trial that included 576 newly diagnosed APL patients, with a median follow-up of 10 years, 10-year survival was 77%. Maintenance treatment significantly reduced 10-year cumulative incidence of relapses, from 43.2% to 33%, 23.4%, and 13.4% with no maintenance, maintenance using intermittent ATRA, continuous 6 mercaptopurine plus methotrexate, and both treatments, respectively (P < .001). Maintenance particularly benefited patients with white blood cell (WBC) count higher than 5 x 10(9)/L (5000/microL). Early addition of CT to ATRA significantly improved 10-year event-free survival (EFS), but without significant effect on overall survival (OS). The 10-year cumulative incidence of deaths in complete response (CR), resulting mainly from myelosuppression, was 5.7%, 15.4%, and 21.7% in patients younger than 55, 55 to 65, and older than 65 years, respectively, supporting the need for less myelosuppressive treatments, particularly for consolidation therapy. This study is registered at http://clinicaltrials.gov as NCT00599937.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Disease-Free Survival; Europe; Female; Follow-Up Studies; Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Time Factors; Treatment Outcome; Tretinoin

PURPOSE Event-free survival following all-trans-retinoic acid (ATRA) -based therapy for acute promyelocytic leukemia (APL) averages 70% at 5 years. While arsenic trioxide (ATO) can induce remissions in 95% of relapsed patients, few studies have addressed the integration of ATO into the primary management of APL. This study examines the efficacy of a single cycle of ATO-based consolidation therapy in a treatment regimen designed to decrease exposure to other cytotoxic agents. PATIENTS AND METHODS After induction with ATRA and daunorubicin (DRN), untreated patients with APL received 3 days of cytarabine and DRN followed by 30 doses of ATO beginning on day 8. Molecular remitters received 2 years of risk-based maintenance therapy. Results Forty-one of 45 patients receiving induction therapy achieved remission; four patients died (one before treatment was initiated). Thirty-seven patients received consolidation and maintenance; of these one patient relapsed (CNS) and one died in remission during maintenance therapy (hepatic sickle cell crisis). With a median follow-up of 2.7 years, estimated disease-free survival was 90%; overall survival for all patients was 88%. Despite a total anthracycline dose of only 360 mg/m(2), cardiac ejection fraction decreased by > or = 20% in 20% of patients. CONCLUSION These data, combined with other recent studies using ATO in the primary management of APL, demonstrate the important role that ATO can play in the primary management of this curable disease. Future studies should continue to focus on reducing the toxicity of treatment without increasing the relapse rate.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Child; Child, Preschool; Cytarabine; Daunorubicin; Female; Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Oxides; Prognosis; Remission Induction; Survival Rate; Treatment Outcome; Tretinoin; Young Adult

Acute promyelocytic leukaemia (APL) treatment often includes high cumulative doses of anthracyclines, which can cause long-term cardiotoxicity. Here, we report the favourable outcome in 81 paediatric APL patients treated according to the consecutive acute myeloid leukaemia-Berlin/Frankfurt/Muenster (AML-BFM) trials -93/-98/-2004 with an anthracycline-cytarabine regimen in combination with all-trans-retinoid acid (ATRA). Outcomes achieved by treatment with a reduced cumulative anthracycline dose (350 mg/m(2)) were comparable to those reported for studies with higher doses. Five-year overall survival of the total cohort was 89 +/- 4% and event-free survival (pEFS) was 73 +/- 6%. Overall survival was similar when comparing AML-BFM trial periods (trial 93: 88 +/- 8%, 98: 85 +/- 7% and 2004: 94 +/- 8%, P((logrank)) = 0.63). Seventy-five (93%) patients achieved complete remission. Most fatal events occurred during the first 6 weeks of treatment. Long-term cardiotoxicity was observed in one patient. Two patients suffered from secondary haematological malignancies. Salvage treatment was effective in 7/9 patients (78%) with relapsed APL, who now are long-term survivors after second line combination treatment with arsenic trioxide (4/7 patients) and stem cell transplantation (5/7 patients). Our results demonstrate that - combined with ATRA - a lower cumulative anthracycline dose can be used safely to maintain high cure rates and promote the reduction of long-term sequelae, such as cardiotoxicity in APL patients.

Topics: Adolescent; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Cardiomyopathies; Child; Child, Preschool; Cytarabine; Drug Administration Schedule; Female; Humans; Infant; Infant, Newborn; Leukemia, Promyelocytic, Acute; Male; Neoplasms, Second Primary; Recurrence; Survival Analysis; Treatment Outcome; Tretinoin

After the identification of discrete relapse-risk categories in patients with acute promyelocytic leukemia (APL) receiving all-trans retinoic and idarubicin (AIDA)-like therapies, the Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) designed a protocol for newly diagnosed APL (AIDA-2000) in which postremission treatment was risk-adapted. Patients with low/intermediate risk received remission at 3 anthracycline-based consolidation courses, whereas high-risk patients received the same schedule as in the previous, non-risk-adapted AIDA-0493 trial including cytarabine. In addition, all patients in the AIDA-2000 received all-trans retinoic acid (ATRA) for 15 days during each consolidation. After induction, 600 of 636 (94.3%) and 420 of 445 (94.4%) patients achieved complete remission in the AIDA-0493 and AIDA-2000, respectively. The 6-year overall survival and cumulative incidence of relapse (CIR) rates were 78.1% versus 87.4% (P = .001) and 27.7% versus 10.7% (P < .0001). Significantly lower CIR rates for patients in the AIDA-2000 were most evident in the high-risk group (49.7% vs 9.3%, respectively, P < .0001). Our data confirm that anthracycline-based consolidation is at least equally effective as cytarabine-containing regimens for low-/intermediate-risk patients and suggest that a risk-adapted strategy including ATRA for consolidation improves outcome in newly diagnosed APL. Furthermore, our results highlight the role of cytarabine coupled to anthracyclines and ATRA during consolidation in the high-risk group.

Topics: Adolescent; Adult; Anthracyclines; Antibiotics, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Humans; Idarubicin; Leukemia, Promyelocytic, Acute; Middle Aged; Remission Induction; Tretinoin; Young Adult

Acute promyelocytic leukemia (APL) has now become the most curable of all subtypes of acute myeloid leukemia. A cure rate of 75-80% can be anticipated with a combination of all-trans retinoic acid (ATRA) and anthracyclines. In Tunisia, the ATRA era began in 1998 with the use, consecutively, of two regimens of a combination of ATRA with anthracycline and cytarabine (APL93), and without cytarabine (LPA99). From 2004, 39 patients with confirmed APL either by t(15;17) or PML/RARA were treated by the PETHEMA LPA 99 trial. The rationale of this protocol by avoiding cytarabine is to reduce death in complete remission (CR) without increasing the incidence of relapse. Thirty-three patients achieved CR (84.6%). The remaining six patients were considered as failure due to early death: three caused by differentiation syndrome (DS) and three died from central nervous system hemorrhage. Baseline blood cell count (WBC) >10 x 10(9)/l (P=0.26) and creatinine >1.4 mg/dl (P=0.42) were not predictive of mortality. DS was observed in 11 patients (30.5%) with a median onset time of 12 days (range: 3-23 days) and median WBC of 29 x 10(9)/L (range: 1.2 x 10(9)-82.7 x 10(9)/l). DS was severe in seven cases, moderate in four, and fatal in three cases. Body mass index > or =30 (P=0.044) and baseline WBC > or =20 x 10(9)/l (P=0.025) are independent predictors of DS. The median follow-up of this study is 36 months. Thirty patients are alive in continuous complete remission; two patients died in CR from septic shock and secondary myelodysplastic syndrome respectively; one patient died 47 months after achieving two relapses. Event free survival from diagnosis was 80% and overall survival was 82%. Our results are quite acceptable and can be improved by reducing mortality rate.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Body Mass Index; Child; Child, Preschool; Creatinine; Female; Humans; Idarubicin; Leukemia, Promyelocytic, Acute; Leukocyte Count; Male; Middle Aged; Paraneoplastic Syndromes; Risk Factors; Severity of Illness Index; Survival Analysis; Tretinoin; Tunisia; Young Adult

Arsenic trioxide (As(2)O(3)) is a highly effective treatment for patients with relapsed acute promyelocytic leukemia (APL); its role as consolidation treatment for patients in first remission has not been defined. We randomized 481 patients (age ≥ 15 years) with untreated APL to either a standard induction regimen of tretinoin, cytarabine, and daunorubicin, followed by 2 courses of consolidation therapy with tretinoin plus daunorubicin, or to the same induction and consolidation regimen plus two 25-day courses of As(2)O(3) consolidation immediately after induction. After consolidation, patients were randomly assigned to one year of maintenance therapy with either tretinoin alone or in combination with methotrexate and mercaptopurine. Ninety percent of patients on each arm achieved remission and were eligible to receive their assigned consolidation therapy. Event-free survival, the primary end point, was significantly better for patients assigned to receive As(2)O(3) consolidation, 80% compared with 63% at 3 years (stratified log-rank test, P < .0001). Survival, a secondary end point, was better in the As(2)O(3) arm, 86% compared with 81% at 3 years (P = .059). Disease-free survival, a secondary end point, was significantly better in the As(2)O(3) arm, 90% compared with 70% at 3 years (P < .0001). The addition of As(2)O(3) consolidation to standard induction and consolidation therapy significantly improves event-free and disease-free survival in adults with newly diagnosed APL. This trial was registered at clinicaltrials.gov (NCT00003934).

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Cytarabine; Daunorubicin; Disease-Free Survival; Female; Humans; Leukemia, Promyelocytic, Acute; Male; Mercaptopurine; Methotrexate; Middle Aged; North America; Oxides; Survival Analysis; Treatment Outcome; Tretinoin; Young Adult

Few studies have examined the outcome of large numbers of patients with the microgranular variant (M3V) of acute promyelocytic leukemia (APL) in the all-trans retinoic acid era. Here, the outcome of 155 patients treated with all-trans retinoic acid-based therapy on 3 clinical trials, North American Intergroup protocol I0129 and Programa para el Estudio de la Terapéutica en Hemopatía Maligna protocols LPA96 and LPA99, are reported. The complete remission rate for all 155 patients was 82%, compared with 89% for 748 patients with classical M3 disease. The incidence of the APL differentiation syndrome was 26%, compared with 25% for classical M3 patients, and the early death rate was 13.6% compared with 8.4% for patients with classical M3 morphology. With a median follow-up time among survivors of 7.6 years (range 3.6-14.5), the 5-year overall survival, disease-free survival, and cumulative incidence of relapse for patients with M3V were 70%, 73%, and 24%, respectively. With a median follow-up time among survivors of 7.6 years (range 0.6-14.3), the 5-year overall survival, disease-free survival, and cumulative incidence of relapse among patients with classical M3 morphology were 80% (P = .006 compared with M3V), 81% (P = .07), and 15% (P = .005), respectively. When outcomes were adjusted for the white blood cell count or the relapse risk score, none of these outcomes were significantly different between patients with M3V and classical M3 APL.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Cytarabine; Daunorubicin; Female; Follow-Up Studies; Humans; Infant; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Neoplasm Recurrence, Local; Remission Induction; Survival Rate; Treatment Outcome; Tretinoin; Young Adult

Differentiation syndrome (DS) can be a life-threatening complication in patients with acute promyelocytic leukemia (APL) undergoing induction therapy with all-trans retinoic acid (ATRA). Detailed knowledge about DS has remained limited. We present an analysis of the incidence, characteristics, prognostic factors, and outcome of 739 APL patients treated with ATRA plus idarubicin in 2 consecutive trials (Programa Español de Tratamientos en Hematología [PETHEMA] LPA96 and LPA99). Overall, 183 patients (24.8%) experienced DS, 93 with a severe form (12.6%) and 90 with a moderate form (12.2%). Severe but not moderate DS was associated with an increase in mortality. A bimodal incidence of DS was observed, with peaks occurring in the first and third weeks after the start of ATRA therapy. A multivariate analysis indicated that a WBC count greater than 5 x 10(9)/L and an abnormal serum creatinine level correlated with an increased risk of developing severe DS. Patients receiving systematic prednisone prophylaxis (LPA99 trial) in contrast to those receiving selective prophylaxis with dexamethasone (LPA96 trial) had a lower incidence of severe DS. Patients developing severe DS showed a reduced 7-year relapse-free survival in the LPA96 trial (60% vs 85%, P = .003), but this difference was not apparent in the LPA99 trial (86% vs 88%).

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anthracyclines; Child; Child, Preschool; Disease-Free Survival; Drug Therapy, Combination; Female; Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Prognosis; Recurrence; Risk Factors; Syndrome; Time Factors; Tretinoin

In the present study, 90 patients with newly diagnosed acute promyelocytic leukemia (APL) were studied for all-trans retinoic acid (ATRA) and arsenic trioxide (As(2)O(3)) combination treatment in remission induction and postremission therapy. In addition, 20 APL patients who had achieved complete remission (CR) with an ATRA-based regimen received ATRA/As(2)O(3) combination for consolidation and maintenance were also enrolled. The results showed that ATRA/As(2)O(3) combination therapy yielded a high CR rate of 93.3% and a significantly shorter time to enter CR (median: 31 days; range: 18-59 days) compared to the ATRA-based regimen (n = 72; median: 39 days; range: 25-62 days). With the ATRA/As(2)O(3) combination for CR maintaining, regardless of the way by which CR was attained, the relapse-free survival was significantly better than with an ATRA plus cytotoxic chemotherapy regimen (92.9 +/- 3.2% vs. 72.4 +/- 7.6%, for the 3-year Kaplan-Meier estimate of relapse-free survival). The drug toxicity profile showed that with the use of As(2)O(3), the incidence of hepatotoxicity was obviously high during remission induction but decreased significantly during postremission treatment. We conclude that APL patients may benefit from the early use of the combination of ATRA and As(2)O(3), in either remission induction or consolidation/maintenance.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Disease-Free Survival; Female; Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Oxides; Remission Induction; Survival Rate; Time Factors; Tretinoin

The prevalence of and risk factors for central nervous system recurrence in patients with acute promyelocytic leukemia are not well established and remain a controversial matter.. Between 1996 and 2005, 739 patients with newly diagnosed acute promyelocytic leukemia enrolled in two consecutive trials (PETHEMA LPA96 and LPA99) received induction therapy with all-trans retinoic acid and idarubicin. Consolidation therapy comprised three courses of anthracycline monochemotherapy (LPA96), with all-trans retinoic acid and reinforced doses of idarubicin in patients with an intermediate or high risk of relapse (LPA99). Central nervous system prophylaxis was not given.. Central nervous system relapse was documented in 11 patients. The 5-year cumulative incidence of central nervous system relapse was 1.7% (LPA96 3.2% and LPA99 1.2%; p=0.09). The cumulative incidence was 0%, 0.8%, and 5.5% in low-, intermediate-, and high-risk patients, respectively. Relapse risk score (p=0.0001) and the occurrence of central nervous system hemorrhage during induction (5-year cumulative incidence 18.7%, p=0.006) were independent risk factors for central nervous system relapse.. This study shows a low incidence of central nervous system relapse in patients with acute promyelocytic leukemia following therapy with all-trans retinoic acid and anthracycline without specific central nervous system prophylaxis. Central nervous system relapse was significantly associated with high white blood cell counts and prior central nervous system hemorrhage, which emerged as independent prognostic factors.

Topics: Adolescent; Adult; Aged; Antibiotics, Antineoplastic; Central Nervous System Neoplasms; Female; Humans; Idarubicin; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Recurrence; Risk Factors; Tretinoin

The objective of this study for newly diagnosed acute promyelocytic leukemia (APL) was to evaluate the efficacy of an intensified double induction chemotherapy including high dose ara-C (HD) and all-trans retinoic acid (ATRA) followed by consolidation and 3 years maintenance therapy. In contrast to APL studies stratifying therapy according to pretreatment white blood cell (WBC) count < and > or =10 x 10(9)/l (low/intermediate and high risk according to the Sanz score), our patients received uniform therapy. From 1994 to 2005, 142 patients (age, 16-60 years) were enrolled. In the low/intermediate (n=105) vs high (n=37) WBC group, the rates of complete remission were 95.2 vs 83.8%, of induction death were 4.8 vs 16.2% (P=0.05) and of molecular remission were 87.5 vs 91.3% (P=1). Long-term overall survival was 84.4 vs 73.0% (P=0.12), event free survival was 78.3 vs 67.3% (P=0.11), relapse free survival was 82.1 vs 80.0% (P=0.83) and the cumulative incidence of relapse was 7.4 vs 11.4% (P=0.46). No relapse or death occurred after 4.7 years. ATRA and intensified chemotherapy including HD ara-C followed by prolonged maintenance therapy reduced the relapse risk in high risk patients. Pretreatment WBC count > or =10 x 10(9)/l count was no relevant prognostic factor for relapse.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Germany; Humans; Leukemia, Promyelocytic, Acute; Longitudinal Studies; Lymphocyte Count; Middle Aged; Prognosis; Remission Induction; Survival Analysis; Treatment Outcome; Tretinoin; Young Adult

This report focuses on the children enrolled on the first North American Intergroup study of APL (INT0129). This study was designed to compare the rates of CR, disease-free survival (DFS), overall survival (OS) and toxicity of therapy with all-trans-retinoic acid (ATRA) for remission induction and/or maintenance compared to conventional chemotherapy in patients with previously untreated APL.. Fifty-three patients who were documented to have the t(15;17) translocation were able to be evaluated for toxicity of treatment, outcome of induction, and survival.. The overall CR rate was 81%. The estimated 5-year DFS from time of CR was 41% for all patients. The estimated 5-year OS for all patients from entry into the study was 69%. The 5-year DFS from time of CR for patients who were randomized to ATRA for induction or maintenance or both was 48% compared to 0% for patients who never received ATRA (P < 0.0001).. The most important finding of our study is that a significant DFS advantage exists for children with APL who received ATRA during induction or maintenance or both compared to children who received no ATRA. Furthermore, remissions in these children appear durable as the OS rates are stable at 10 years.

Topics: Adolescent; Child; Child, Preschool; Cytarabine; Daunorubicin; Female; Humans; Infant; Leukemia, Promyelocytic, Acute; Male; Remission Induction; Survival Analysis; Treatment Outcome; Tretinoin

An understanding of the prognostic factors associated with the various forms of induction mortality in patients with acute promyelocytic leukemia (APL) has remained remarkably limited. This study reports the incidence, time of occurrence, and prognostic factors of the major categories of induction failure in a series of 732 patients of all ages (range, 2-83 years) with newly diagnosed APL who received all-trans retinoic acid (ATRA) plus idarubicin as induction therapy in 2 consecutive studies of the Programa de Estudio y Tratamiento de las Hemopatias Malignas (PETHEMA) Group. Complete remission was attained in 666 patients (91%). All the 66 induction failures were due to induction death. Hemorrhage was the most common cause of induction death (5%), followed by infection (2.3%) and differentiation syndrome (1.4%). Multivariate analysis identified specific and distinct pretreatment characteristics to correlate with an increased risk of death caused by hemorrhage (abnormal creatinine level, increased peripheral blast counts, and presence of coagulopathy), infection (age>60 years, male sex, and fever at presentation), and differentiation syndrome (Eastern Cooperative Oncology Group [ECOG] score>1 and low albumin levels), respectively. These data furnish clinically relevant information that might be useful for designing more appropriately risk-adapted treatment protocols aimed at reducing the considerable problem of induction mortality in APL.

Topics: Adolescent; Adult; Age Factors; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Blast Crisis; Child; Child, Preschool; Creatinine; Disease-Free Survival; Female; Hemorrhage; Humans; Idarubicin; Infections; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Remission Induction; Risk Factors; Sex Factors; Survival Rate; Syndrome; Treatment Failure; Tretinoin

Although the occurrence of thrombosis in acute promyelocytic leukemia (APL) has been reported during retinoic acid treatment, no studies carried out in large clinical cohorts have specifically addressed this issue. We analyzed 124 APL patients treated with the all-trans retinoic acid and idarubicin protocol and compared clinico-biologic characteristics of 11 patients who developed thrombosis with those of 113 patients who had no thrombosis. In seven patients, the events were recorded during induction, whereas in four patients deep vein thrombosis occurred in the post-induction phase. Comparison of clinico-biological characteristics of patients with and without thrombosis revealed in the former group higher median white blood cell (WBC) count (17 x 10(9)/l, range 1.2-56, P=0.002), prevalence of the bcr3 transcript type (72 vs 48%, P=0.01), of FLT3-ITD (64 vs 28%, P=0.02), CD2 (P=0.0001) and CD15 (P=0.01) expression. No correlation was found with sex, age, French-American-British subtype, all-trans-retinoic acid syndrome or with thrombophilic state that was investigated in 5/11 patients. Our findings suggest that, in APL patients consistent biologic features of leukemia cells may predict increased risk of developing thrombosis.

Topics: Adult; Aged; Antibiotics, Antineoplastic; Antineoplastic Agents; CD2 Antigens; Female; fms-Like Tyrosine Kinase 3; Humans; Idarubicin; Leukemia, Promyelocytic, Acute; Leukocyte Count; Lewis X Antigen; Male; Middle Aged; Mutation; Predictive Value of Tests; Risk Factors; Tandem Repeat Sequences; Thrombosis; Tretinoin

To determine prognosis of acute promyelocytic leukemia (APL) failing to front-line therapy with all-trans retinoic acid (ATRA) and anthracyclines, outcome of 52 patients (32 M/20 F; age: 37, 3-72) included in PETHEMA trials LPA96 and LPA99 who presented with either molecular failure (MOLrel, n=16) or hematological relapse (HEMrel, n=36) was analyzed. Salvage therapy consisted of ATRA and high-dose ara-C-based chemotherapy (HDAC) in most cases (83%), followed by stem-cell transplantation (autologous, 18; allogeneic, 10; syngeneic, 1). Fourteen patients with MOLrel (88%) achieved second molecular complete response (molCR), whereas 81% HEMrel patients responded to second-line treatment, with 58% molCR. After median follow-up of 45 months, four MOLrel and 18 HEMrel patients, respectively, experienced a second relapse. Outcome after MOLrel compared favorably to HEMrel, with longer survival (5-year survival: 64+/-14 vs 24+/-8%, P=0.01) and lower relapse risk (5-year relapse risk: 30+/-13 vs 64+/-9%; P=0.044). Additionally, age

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Child; Child, Preschool; Combined Modality Therapy; Cytarabine; Etoposide; Female; Hematopoietic Stem Cell Transplantation; Humans; Idarubicin; Kaplan-Meier Estimate; Leukemia, Promyelocytic, Acute; Liposomes; Male; Middle Aged; Mitoxantrone; Neoplasm, Residual; Oncogene Proteins, Fusion; Prognosis; Recurrence; Remission Induction; Salvage Therapy; Survival Analysis; Time Factors; Treatment Outcome; Tretinoin

To examine the efficacy of intensified maintenance chemotherapy, we conducted a prospective multicenter trial in adult patients with newly diagnosed acute promyelocytic leukemia treated with all-trans retinoic acid and chemotherapy. Of the 302 registered, 283 patients were assessable and 267 (94%) achieved complete remission. Predicted 6-year overall survival in all assessable patients and disease-free survival in patients who achieved complete remission were 83.9% and 68.5%, respectively. A total of 175 patients negative for PML-RARalpha at the end of consolidation were randomly assigned to receive either intensified maintenance chemotherapy (n = 89) or observation (n = 86). Predicted 6-year disease-free survival was 79.8% for the observation group and 63.1% for the chemotherapy group, showing no statistically significant difference between the 2 groups (P = .20). Predicted 6-year survival of patients assigned to the observation was 98.8%, which was significantly higher than 86.2% in those allocated to the intensified maintenance (P = .014). These results indicate that the intensified maintenance chemotherapy did not improve disease-free survival, but rather conferred a significantly poorer chance of survival in acute promyelocytic leukemia patients who have become negative for the PML-RARalpha fusion transcript after 3 courses of intensive consolidation therapy.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Japan; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Oncogene Proteins, Fusion; Remission Induction; RNA, Neoplasm; Survival Analysis; Treatment Outcome; Tretinoin

To compare the efficacy of all-trans retinoic acid (ATRA) combining chemotherapy and As4S4 with ATRA combining chemotherapy for the maintenance treatment of patients with acute promyelocytic leukemia (APL).. Sixty patients with APL induced to complete remission by ATRA and consolidated by chemotherapy were randomly divided into two groups. Thirty patients as As4S4 group received ATRA + As4S4 + chemotherapy, and another thirty patients as non-As4S4 group were treated only with ATRA + chemotherapy as maintenance therapy. The therapeutic effects, side effects and PML-RARalpha gene expression were analyzed.. The three-year continuous complete remission (CCR) rate was 90.0% for As4S4 group and 61.1% for non-As4S4 group, the difference being statistically significant. Significant difference was also found in the positive rate of PML-RARalpha fusion gene between the two groups. The side effects were mild.. APL patients in maintenance therapy with ATRA + 6-MP + MTX + As4S4 can obtain a higher CCR.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Arsenicals; Female; Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Remission Induction; Sulfides; Treatment Outcome; Tretinoin

We analyzed the incidence, presenting features, risk factors of extramedullary (EM) relapse occurring in acute promyelocytic leukemia (APL) treated with all-trans retinoic acid (ATRA) and chemotherapy by using a competing-risk method. In total, 740/ 806 (92%) patients included in three multicenter trials (APL91, APL93 trials and PETHEMA 96) achieved CR, of whom 169 (23%) relapsed, including 10 EM relapses. Nine relapses involved the central nervous system (CNS) and one the skin, of which two were isolated EM relapse. In patients with EM disease, median WBC count was 26950/mm3 (7700-162000). The 3-year cumulative incidence of EM disease at first relapse was 5.0%. Univariate analysis identified age <45 years (P=0.05), bcr3 PML-RARalpha isoform (P= 0.0003) and high WBC counts (> or = 10,000/ mm3) (P<0.0001) as risk factors for EM relapse. In multivariate analysis, only high WBC count remained significant (P= 0.001). Patients with EM relapse had a poorer outcome since median survival from EM relapse was 6.7 months as compared to 26.3 months for isolated BM relapse (P=0.04). In conclusion, EM relapse in APL occurs more frequently in patients with increased WBC counts (> or = 10,000/mm3) and carries a poor prognosis. Whether CNS prophylaxis should be systematically performed in patients with WBC > or = 10,000/mm3 at diagnosis remains to be established.

Topics: Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Follow-Up Studies; Humans; Leukemia, Promyelocytic, Acute; Prognosis; Recurrence; Risk Factors; Survival Rate; Treatment Outcome; Tretinoin

We examined whether combining all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) might be an alternative to ATRA plus chemotherapy in untreated acute promyelocytic leukemia (APL). Twenty-five low-risk patients (white blood cell [WBC] count less than 10 x 10(9)/L [10,000/microL]) received ATRA (45 mg/m(2) daily) and ATO (0.15 mg/kg daily, beginning day 10 of ATRA), and in complete remission (CR) received ATO plus ATRA, without chemotherapy, unless they were reverse transcriptase-polymerase chain reaction (RT-PCR)-positive 3 months from CR date or had molecular relapse. Nineteen high-risk patients were treated identically, but received chemotherapy, generally 9 mg/m(2) gemtuzumab ozogamycin (GO) on day 1 of induction. The CR rate was 39 of 44 (24 of 25 in low-risk, 15 of 19 in high-risk). Disease recurred at 9, 9, and 15 months, respectively, in 3 high-risk patients. The median follow-up time from CR date in the 36 patients alive in first CR is 16 months (15 months in low-risk, 20 months in high-risk), with 9 patients followed for at least 24 months. Each of the 36 patients was PCR-negative at last follow-up. Thus, none of the low-risk patients has received chemotherapy, and only 3 high-risk patients (the 3 with relapsed disease) have received chemotherapy past induction. ATRA plus ATO may serve as an alternative to chemotherapy in low-risk untreated APL (eg, in older patients) and, when combined with GO, may improve outcome in high-risk patients.

Topics: Aged; Aged, 80 and over; Aminoglycosides; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Arsenic Trioxide; Arsenicals; Female; Gemtuzumab; Humans; Leukemia, Promyelocytic, Acute; Leukocyte Count; Male; Middle Aged; Neoplasm Proteins; Oncogene Proteins, Fusion; Oxides; Polymerase Chain Reaction; Remission Induction; Tretinoin

Relapse of acute promyelocytic leukemia (APL) following all-trans retinoic acid (ATRA) therapy has been associated with the acquisition of mutations in the high-affinity ATRA binding site in PML-RARalpha, but little information is available about the selection dynamics of the mutation-harboring subclones. In this study, 6/18 patients treated with sequential ATRA and chemotherapy on protocol INT0129 relapsed with complete replacement of the nonmutant pretreatment APL cell population by a PML-RARalpha mutant subclone. Two patients relapsed in proximity of ATRA treatment; however, in four patients there was a 6-48 month hiatus between the last ATRA treatment and relapse. The mutant subclones were not detectable in samples tested > or = 3 months before relapse at > or = 1 in 10(2) (10(-2)) sensitivity. In one patient, a functionally weak mutation was detected at 10(-4) sensitivity before therapy but only limited pre-relapse enrichment of the mutant subclone was observed on subsequent ATRA therapy. These results indicate that proximate ATRA selection pressure is frequently not the main determinant for the emergence of strongly dominant PML-RARalpha mutant subclones and suggest that APL subclones harboring PML-RARalpha mutations are predisposed to the acquisition of secondary genetic/epigenetic alterations that result in a growth/survival advantage.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Binding Sites; Cell Lineage; Clone Cells; Drug Resistance, Neoplasm; Epigenesis, Genetic; Humans; Leukemia, Promyelocytic, Acute; Mutation; Neoplasm Proteins; Oncogene Proteins, Fusion; Recurrence; Remission Induction; Reverse Transcriptase Polymerase Chain Reaction; Sensitivity and Specificity; Structure-Activity Relationship; Tretinoin

The promotion of an operational network between hospitals and medical schools in Iraq and in Western countries is a primary humanitarian objective of international collaboration. As a consequence of a collaborative project between the Al Mansour Hospital for Pediatrics in Baghdad and the Pediatric Unit of Hematology of "La Sapienza" University, in Rome, in October 2003 a specific all-trans-retinoic acid-based protocol was designed in order to offer a modern therapeutic program for the management of Iraqi children with acute promyelocytic leukemia, adapted to the severe local difficulties. The preliminary encouraging results represent a substantial improvement over the earlier experience in childhood acute promyelocytic leukemia in Iraq.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Cooperative Behavior; Developing Countries; Humans; Infant; International Cooperation; Iraq; Italy; Leukemia, Promyelocytic, Acute; Prognosis; Remission Induction; Treatment Outcome; Tretinoin

Topics: Adult; Aged; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Combined Modality Therapy; Europe; Female; Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Oxides; Prognosis; Recurrence; Risk Factors; Treatment Outcome; Tretinoin

Seventy adults with acute promyelocytic leukemia were studied to clarify the significance of the level and kinetics of minimal residual disease (MRD) over their entire treatment course by realtime quantitative polymerase chain reaction. At a median follow-up of 44 months, nine relapses had occurred. The 5-year probabilities of relapse and disease-free survival were 17.3+/-5.4% and 81.5+/-5.4%, respectively. A MRD level of >10-3 after first consolidation was the most powerful predictor of relapse (85.7+/-13.2% versus 7.3+/-4.1%, p<0.001) and disease-free survival (14.3+/-13.2% versus 91.2%+/-4.3%, p<0.001). Prospective MRD monitoring may allow us to identify subgroups of patients at high risk of relapse earlier during treatment.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Disease Progression; Disease-Free Survival; Female; Humans; Idarubicin; Kinetics; Leukemia, Promyelocytic, Acute; Life Tables; Male; Mercaptopurine; Methotrexate; Middle Aged; Mitoxantrone; Neoplasm Proteins; Neoplasm, Residual; Oncogene Proteins, Fusion; Prognosis; Proportional Hazards Models; Prospective Studies; Remission Induction; Survival Analysis; Tretinoin

Several phase II studies have suggested that cytarabine (AraC) was not required in the treatment of newly diagnosed acute promyelocytic leukemia (APL) patients receiving all-trans-retinoic acid (ATRA), an anthracycline, and maintenance therapy, and we aimed at confirming this finding in a randomized trial.. Newly diagnosed APL patients younger than age 60 years with a WBC count of less than 10,000/microL were randomly assigned to receive either ATRA combined with and followed by three daunorubicin (DNR) plus AraC courses and a 2-year maintenance regimen (AraC group) or the same treatment but without AraC (no AraC group). Patients older than age 60 years and patients with initial WBC count of more than 10,000/microL were not randomly assigned but received risk-adapted treatment, with higher dose of AraC and CNS prophylaxis in patients with WBC counts more than 10,000/microL.. Overall, 328 (96.5%) of 340 patients achieved complete remission (CR). In the AraC and the no AraC groups, the CR rates were 99% and 94% (P = .12), the 2-year cumulative incidence of relapse (CIR) rates were 4.7% and 15.9% (P = .011), the event-free survival (EFS) rates were 93.3% and 77.2% (P = .0021), and survival rates were 97.9% and 89.6% (P = .0066), respectively. In patients younger than age 60 years with WBC counts more than 10,000/microL, the CR, 2-year CIR, EFS, and survival rates were 97.3%, 2.9%, 89%, and 91.9%, respectively.. These results support a role for AraC in addition to ATRA and anthracyclines in the treatment of newly diagnosed APL, at least using DNR at the cumulative dose we used and with the consolidation and maintenance regimens we used.

Topics: Adult; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Drug Administration Schedule; Female; Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Remission Induction; Survival Analysis; Tretinoin

We analyzed the outcome of patients aged more than 60 included in a multicenter trial in newly diagnosed acute promyelocytic leukemia (APL93 trial), which tested the role of early addition of chemotherapy to all trans retinoic acid (ATRA) and of maintenance with ATRA and/or low-dose chemotherapy. In total, 129/533 (24.2%) patients included in this trial were older than 60. The CR rate was 86% in patients older than 60 as compared to 94.5% in younger patients (P=0.0014), due to a higher incidence of early deaths in elderly patients. The 4-year incidence of relapse was 15.6% in adults older than 60 and 23.2% in younger adults although most elderly patients received less intensive consolidation chemotherapy. However, 18.6% of the patients older than 60 years who achieved CR died in CR, mainly from sepsis during consolidation course or maintenance treatment, as compared to 5.7% of younger adults (P<0.001). Thus, overall 4-year survival of elderly patients was 57.8% as compared to 78% in younger adults (P<0.0001). APL in elderly patients appears as sensitive to ATRA-Chemotherapy based regimen as in younger adults. Less favorable outcome is mainly due to an increase of early deaths and to toxicity of consolidation treatment, strongly suggesting a beneficial role for less intensive consolidation chemotherapy and possibly introduction of arsenic derivates in the treatment of APL in the elderly.

Topics: Adolescent; Adult; Age Factors; Aged; Antineoplastic Agents; Europe; Female; Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Recurrence; Survival Analysis; Treatment Outcome; Tretinoin

Topics: Antineoplastic Agents; Drug Carriers; Follow-Up Studies; Humans; Leukemia, Promyelocytic, Acute; Liposomes; Time Factors; Tretinoin

The role of all-trans retinoic acid (ATRA) in pediatric acute promyelocytic leukemia (APL) is the topic of several ongoing studies. The results of the Italian pediatric experience with the multicentric Gruppo Italiano per le Malattie Ematologiche dell'Adulto (GIMEMA)-Italian Pediatric Hematology and Oncology Group (AIEOP) "AIDA" (ATRA and idarubicin) trial are presented. Of the 983 patients with APL enrolled in this protocol between January 1993 and June 2000, 124 (13%) had younger than 18 years. Treatment consisted of ATRA and idarubicin induction followed by 3 polychemotherapy consolidation courses. Molecular response by reverse transcriptase-polymerase chain reaction (RT-PCR) was assessed after consolidation and patients who were PCR- were randomized for different maintenances. One hundred and seven children were eligible and evaluable for induction: 103 (96%) achieved a hematologically complete remission. Overt ATRA syndrome was observed in 2 patients and pseudotumor cerebri was observed in 10 patients. Ninety-four patients were evaluable for RT-PCR analysis at the end of consolidation: 91 (97%) proved PCR+ and 3 PCR-. The overall survival and event-free survival (EFS) are 89% (95% confidence interval [c.i.]: 83%-95%) and 76% (c.i.: 65%-85%), respectively, at more than 10 years. A white blood cell (WBC) count at diagnosis of greater than 10 x 10(9)/L had a significant impact on EFS (59% vs 83% at 10 years). These results highlight the efficacy and feasibility of the AIDA protocol in the pediatric APL population.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Clinical Protocols; Female; Humans; Idarubicin; Infant; Italy; Leukemia, Promyelocytic, Acute; Male; Neoplasm Proteins; Oncogene Proteins, Fusion; RNA, Messenger; RNA, Neoplasm; Tretinoin

The objective of our study was to evaluate high-dose cytarabine in consolidation therapy in patients with newly diagnosed acute promyelocytic leukemia (APL). Patients (age 16-60 years) received induction therapy according to the AIDA protocol (all-trans retinoic acid, idarubicin) followed by one cycle of ICE (idarubicin, cytarabine, etoposide) and two cycles of HAM (cytarabine 3 g/m(2) q12h, days 1-3; mitoxantrone 10 mg/m(2), days 2 and 3). From 1995 to 2003, 82 patients were enrolled. In total, 72 patients (88%) achieved a complete remission, and 10 patients (12%) died from early/hypoplastic death (ED/HD). A total of 71 patients received at least one cycle of HAM. Relapse-free survival (RFS) and overall survival (OS) after 46 months were 83 and 82%, respectively. White blood cell count above 10.0 x 10(9)/l at diagnosis and additional chromosomal aberrations were unfavorable prognostic markers for OS, whereas no prognostic markers for RFS were identified including FLT3 mutations. In conclusion, high-dose cytarabine in consolidation therapy for patients with newly diagnosed APL is an effective treatment approach.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Female; fms-Like Tyrosine Kinase 3; Humans; Idarubicin; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Mitoxantrone; Prognosis; Proto-Oncogene Proteins; Receptor Protein-Tyrosine Kinases; Remission Induction; Tretinoin

All-trans-retinoic acid (ATRA) increases the efficacy of chemotherapy when used for induction and maintenance treatment of acute promyelocytic leukemia (APL), but its role in consolidation is unknown. Since November 1996, 426 patients with newly diagnosed APL have received induction therapy with ATRA and idarubicin. Before November 1999 (LPA96 study), consolidation therapy consisted of 3 courses of anthracycline monochemotherapy. After November 1999 (LPA99 study), patients with intermediate and high risks of relapse received consolidation therapy with ATRA and increased doses of anthracyclines. Of the 384 patients who achieved complete remission (90%), 382 proceeded to consolidation therapy. Seven patients died in remission (1.8%). The 3-year cumulative incidence of relapse for patients in the LPA96 and LPA99 studies was 17.2% and 7.5%, respectively (P =.008). Patients treated with ATRA in consolidation therapy showed an overall reduction in the relapse rate from 20.1% to 8.7% (P =.004). In intermediate-risk patients the rate decreased from 14.0% to 2.5% (P =.006). This improved antileukemic efficacy also translated into significantly better disease-free and overall survival. A risk-adapted strategy combining anthracycline monochemotherapy and ATRA for induction and consolidation therapy of newly diagnosed APL results in improved antileukemic efficacy and a high degree of compliance.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antibiotics, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Idarubicin; Incidence; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Recurrence; Remission Induction; Risk Factors; Tretinoin

Both all-trans retinoic acid (ATRA) and arsenic trioxide (As(2)O(3)) have proven to be very effective in obtaining high clinical complete remission (CR) rates in acute promyelocytic leukemia (APL), but they had not been used jointly in an integrated treatment protocol for remission induction or maintenance among newly diagnosed APL patients. In this study, 61 newly diagnosed APL subjects were randomized into three treatment groups, namely by ATRA, As(2)O(3), and the combination of the two drugs. CR was determined by hematological analysis, tumor burden was examined with real-time quantitative RT-PCR of the PML-RAR alpha (promyelocytic leukemia-retinoic acid receptor alpha) fusion transcripts, and side effects were evaluated by means of clinical examinations. Mechanisms possibly involved were also investigated with cellular and molecular biology methods. Although CR rates in three groups were all high (> or =90%), the time to achieve CR differed significantly, with that of the combination group being the shortest one. Earlier recovery of platelet count was also found in this group. The disease burden as reflected by fold change of PML-RAR alpha transcripts at CR decreased more significantly in combined therapy as compared with ATRA or As(2)O(3) mono-therapy (P < 0.01). This difference persisted after consolidation (P < 0.05). Importantly, all 20 cases in the combination group remained in CR whereas 7 of 37 cases treated with mono-therapy relapsed (P < 0.05) after a follow-up of 8-30 months (median: 18 months). Synergism of ATRA and As(2)O(3) on apoptosis and degradation of PML-RAR alpha oncoprotein might provide a plausible explanation for superior efficacy of combination therapy in clinic. In conclusion, the ATRA/As(2)O(3) combination for remission/maintenance therapy of APL brings much better results than either of the two drugs used alone in terms of the quality of CR and the status of the disease-free survival.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Female; Humans; In Situ Nick-End Labeling; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Neoplasm Proteins; Oncogene Proteins, Fusion; Oxides; Prospective Studies; Remission Induction; Reverse Transcriptase Polymerase Chain Reaction; Treatment Outcome; Tretinoin; Tumor Cells, Cultured

To determine the results of treatment combining all-trans-retinoic acid (ATRA) and chemotherapy (CT) in childhood acute promyelocytic leukemia (APL).. Children (< 18 years) with newly diagnosed APL were included in the APL93 trial, treated by ATRA followed or combined with daunorubicin-cytarabine, and then randomly assigned between no maintenance, intermittent ATRA, continuous CT, or both.. Of the 576 patients included in APL93 trial, 31 (5%) were children, including 22 girls (71%) and nine boys (29%). Thirty of the children (97%) obtained complete remission (CR). ATRA syndrome occurred in four children (13%), who all achieved CR, and headaches occurred in 12 children (39%), with signs of pseudotumor cerebri in five children (16%). Seven patients (23%) relapsed. None of the eight patients who received both ATRA and CT for maintenance relapsed. All relapsing patients achieved a second CR. Twenty-two patients remained in first CR after 43+ to 96+ months, six remained in second CR after 17+ to 66+ months, and three patients had died. The 5-year event-free survival (EFS), relapse, and overall survival rates were 71%, 27%, and 90%, respectively. No difference between adults and children included in the APL93 trial was seen for CR rate, 5-year relapse rate, EFS, and overall survival, but significantly better survival was seen in children after adjustment on WBC counts (P =.02) and incidence of microgranular M3 variant (P =.04).. ATRA combined with CT for induction and also probably for maintenance provides as favorable results in children with APL as in adults and currently constitutes the reference first-line treatment in both age groups.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Cytarabine; Daunorubicin; Female; Humans; Infant; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Treatment Outcome; Tretinoin

Debate exists over the clinical relevance of molecular heterogeneity of acute promyelocytic leukemia (APL). Based on the genomic breakpoint in PML gene, three different PML/RARalpha isoforms are recognized: intron 3 [short (S)], intron 6 [long (L)] and exon 6 [variable (V)]. Studies on the prognostic significance of PML/RARalpha isoforms have reported contradictory results. This discrepancy may be related to differences in the treatment protocols, as some studies used ATRA alone during induction therapy. We analyzed the clinical course of 61 consecutive newly diagnosed patients with a genetically confirmed diagnosis of APL, treated with ATRA and chemotherapy at Princess Margaret Hospital from January 1994 to January 2002. The results of RT PCR at diagnosis were available on 48 patients. In this study, we report on clinico-biological features and prognostic significance of PML/RARalpha isoforms in these 48 patients. Of 48 patients, 19(40%) had the S isoform and 29 (60%) had the L/V isoform. Median white blood cell (WBC) count for patients with S isoform was 8.6 [interquartile range Q1-Q3 i.e. IQR 3.2-29] compared to 1.8 [IQR 1.0-4.9] for the L/V isoform group (P 0.001). No difference was seen in number of patients achieving of molecular remission after induction and consolidation treatment in the two-isoform groups. The patients with S isoform had significantly inferior relapse-free survival (RFS) at 3 years compared to L/V isoform patients [48% (95% C.I. 19 77) vs. 92% (95% C.I. 82-100), P0.006]. In a univariate analysis, S isoform status (P 0.006) and high WBC count ( > or = 5 x 10(9)+/l) (P 0.017) were significant prognostic factors for RFS. No difference in overall survival was seen between the two isoform groups (P 0.35). Our results suggest that based on molecular characterization, it may be possible to identify a subgroup of APL patients at higher-risk of relapse.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Female; Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Molecular Diagnostic Techniques; Neoplasm Proteins; Oncogene Proteins, Fusion; Prognosis; Protein Isoforms; Remission Induction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Neoplasm; Survival Analysis; Treatment Outcome; Tretinoin

Therapeutic results in elderly patients with acute promyelocytic leukemia (APL) have been generally reported as less effective than for younger patients. Patients 60 years or older with APL who were enrolled in 2 successive multicenter PETHEMA studies received induction therapy with all-trans retinoic acid (ATRA) and idarubicin, consolidation with 3 anthracycline monochemotherapy courses with or without ATRA, and maintenance with ATRA and low-dose chemotherapy. Eighty-seven of 104 patients achieved complete remission (84%). Eighty-six proceeded to consolidation therapy (2 withdrew after the first and second courses). Deaths in remission occurred during consolidation and maintenance therapy in 3 and 4 patients, respectively. One patient showed molecular persistence after consolidation and 5 had a relapse. The 6-year cumulative incidence of relapse, leukemia-free survival, and disease-free survival were 8.5%, 91%, and 79%, respectively. A significantly higher incidence of low-risk patients found among the elderly, as compared to younger patients, may partially account for the low relapse rate observed. This study confirms the high antileukemic efficacy, low toxicity, and high degree of compliance of protocols using ATRA and anthracycline monochemotherapy for induction and consolidation therapy in elderly patients.

Topics: Aged; Aged, 80 and over; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Idarubicin; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Patient Compliance; Recurrence; Remission Induction; Sex Factors; Survival Analysis; Tretinoin

To study efficacy of maintenance therapy of patients with acute promyelocytic leukemia (APL) in the APL treatment Russian multicenter trial.. The trial was made with participation of 18 hematological departments of clinics in Russia. A total of 68 APL patients entered the trial. The maintenance therapy consisted of 5-day courses of cytostatic drugs which alternated or did not alternate with 5-day courses of ATRA. Cytogenetic tests were made in 31 patients, t(15;17) was detected in 26 of them. Molecular examination conducted in 28 patients discovered chimeric transcript PML/RARa in 26 of them. Of 20 patients examined in Hematological Research Center, 7 (35%) had a bcr 1/2 variant of the transcript PML/RARa, 13 (65%)--bcr 3 variant.. 65 patients were eligible for assessment. A complete remission was achieved in 90% cases. No resistance was observed. In follow-up within 30 months the recurrence rate was similar on both treatments. The results of the induction therapy and survival in patients with different variants of the transcripts were also similar. Overall 2.5 year survival for all the patients was 77%, recurrence-free--80%. The survival analysis in patients with leukocytosis higher and lower 10 x 10(9)/l found no statistical differences by the survival. Patients with hyperleukocytosis had higher early lethality than patients with leukocytes under 10 x 10(9)/l (25% vs 5.3%, p = 0.03).. The APL 06.01 protocol showed high efficacy of the relevant maintenance which provides a complete molecular remission in the majority of patients with probable recurrence-free 2.5 year survival 80%.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Cytarabine; Daunorubicin; Disease-Free Survival; Drug Administration Schedule; Female; Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Neoplasm Proteins; Oncogene Proteins, Fusion; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcr; Remission Induction; Transcription, Genetic; Tretinoin

Treatment combining ATRA and chemotherapy (CT) has improved the outcome of APL patients, by comparison with CT alone. ATRA syndrome is a life-threatening complication of ATRA treatment whose prophylaxis remains somewhat controversial. In APL93 trial, newly diagnosed APL patients CT) and ATRA with early addition of CT, on day 3 of ATRA treatment (ATRA + CT). The incidence of ATRA syndrome in the ATRA --> CT arm was 18% (22/122) as compared to 9.2% (17/184) in the ATRA + CT arm (P = 0.035). In the ATRA --> CT arm, three (2.5%) patients died from ATRA syndrome, as compared to one (0.5%) in the ATRA + CT group. Early addition of chemotherapy to ATRA in newly diagnosed APL with low WBC counts significantly reduced the incidence of ATRA syndrome.

Topics: Adult; Age of Onset; Antineoplastic Agents; Female; Humans; Leukemia, Promyelocytic, Acute; Leukocyte Count; Leukopenia; Male; Middle Aged; Retrospective Studies; Syndrome; Treatment Outcome; Tretinoin

Due to severe side effects in virtually all children treated with a standard dose of 45 mg/m(2)/day all-trans-retinoic acid (ATRA) for acute promyelocytic leukemia (APL) the AML-BFM study group reduced the dosage to 25 mg/m(2)/day. For the lack of data on the use of ATRA at this dosage in children with APL, the study group further decided to evaluate the pharmacokinetics and metabolism of ATRA in children.. Twenty-three pharmacokinetic and metabolic profiles of ATRA were studied in 14 children (aged 0.9-18.4 years) with APL. Eleven plasma samples were collected over a period of 8 hr and analyzed for ATRA and its metabolites by high-performance liquid chromatography.. Peak plasma concentrations of ATRA were characterized by wide interpatient variability (range: 28.6-513.0 nM). Compared to adults the same metabolic pathways were observed in children. Even though peak plasma concentrations were in the lower range of those considered effective in vitro, ATRA side effects, notably neurotoxicity, still required dose reduction, treatment break, or drug withdrawal in eight patients. In this small number of patients, neurotoxicity could not be related to age or any specific level of ATRA or metabolites in the plasma. Plasma concentrations of vitamin A, however, were significantly higher in those patients, who developed signs of neurotoxicity (P = 0.03, Mann-Whitney Rank Sum test).. Considering the low plasma concentrations and the persistence of toxicity in spite of dose reduction intermittent dosing schedules might be considered as an alternative to further dose reduction of ATRA in the treatment of APL especially in children, who might be at risk of ATRA-induced neurotoxicity.

Topics: Adolescent; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Dose-Response Relationship, Drug; Female; Half-Life; Humans; Infant; Leukemia, Promyelocytic, Acute; Male; Neurotoxicity Syndromes; Retinoids; Statistics, Nonparametric; Tretinoin

In all, 134 elderly patients (median age 66 years, range 60-75 years) with newly diagnosed acute promyelocytic leukemia (APL) were enrolled in two successive protocols of the Italian multicenter group GIMEMA. All patients received an identical induction with all-trans retinoic acid and idarubicin; 116 (86%) entered complete remission (CR), two (2%) were resistant and 16 (12%) died during induction. After CR, 106 patients received further therapy whereas 10 did not, because of refusal (n=5) or toxicity (n=5). Consolidation consisted of three chemotherapy courses in the AIDA protocol (AIDA, 67 patients) or, since 1997, of an amended protocol including only the first cycle (amended AIDA, aAIDA, 39 patients). In the AIDA group, 43 patients (64%) completed consolidation, while seven (11%) and 17 (25%) patients were withdrawn after first and second courses, respectively; nine patients (13%) died in CR and 12 (18%) relapsed. In the aAIDA group, all patients received the assigned treatment; two patients (5%) died in CR and six (15%) relapsed. In the AIDA and aAIDA series, the 3-year overall and discase-free survival rates were 81 and 83% (P=NS), 73 and 72% (P=NS), respectively. We highlight here the frequency and severity of complications linked to intensive chemotherapy in this clinical setting and suggest that, in APL of the elderly, less intensive postremission therapy allows significant reduction of severe treatment-related toxicity and may be equally effective.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Idarubicin; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Neoplasm Proteins; Oncogene Proteins, Fusion; Remission Induction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; RNA, Neoplasm; Survival Rate; Treatment Outcome; Tretinoin

Arsenic trioxide (ATO) is capable of inducing a high hematologic response rate in patients with relapsed acute promyelocytic leukemia (APL). Preclinical observations have indicated that all-trans-retinoic acid (ATRA) may strongly enhance the response to ATO.. Between 1998 and 2001, we conducted a randomized study of ATO alone versus ATO plus ATRA in 20 patients with relapsed APL, all previously treated with ATRA-containing chemotherapy. The primary objective was to demonstrate a significant reduction in the time necessary to obtain a complete remission (CR) in the ATO/ATRA group compared with the ATO group. Secondary objectives were safety and molecular response.. The CR rate after one ATO with or without ATRA induction cycle was 80%. Clinical and pharmacokinetic observations indicated that the main mechanism of action of ATO in vivo was the induction of APL cell differentiation. Hematologic and molecular response, time necessary to reach CR, and outcome were comparable in both treatment groups. Of 16 CR patients, three patients who reached a molecular remission after one induction cycle had all received chemotherapy for a treatment-induced hyperleukocytosis. Three additional patients who received further additional ATO with or without ATRA cycles converted later to molecular negativity.. ATRA did not seem to significantly improve the response to ATO in patients relapsing from APL. Other potential combinations, including ATO plus chemotherapy, have to be tested.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Female; Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Oxides; Recurrence; Statistics, Nonparametric; Survival Rate; Treatment Outcome; Tretinoin

Topics: Administration, Oral; Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Female; Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Oxides; Remission Induction; Salvage Therapy; Treatment Outcome; Tretinoin

To define duration and schemes of maintenance therapy, to evaluate cytarabine demand while treatment of acute promyelocytic leukemia (APL) with an original program 5D + Ifa + AT RA.. The above treatment was conducted in 7 patients with APL (1 male, 6 females, 18-45 years, leukocytes 1.2-15.0 x 10(9)/l).. Induction by 5D program was performed in 5 patients. A complete remission was achieved in 4 of them, molecular--in 3. One woman died. 5D consolidation was performed in 6 patients. After the first course of consolidation all the patients achieved molecular remission. Maintenance of remission with Ifa + ATRA was made in 5 patients. In one female the remission came to the end. Mean time of the follow-up was 18 months. The remission lasted 5-36 months. Monitoring of molecular remission has not found marker PML/RARa.. Daunozom monotherapy leads to a complete remission after the first course in most of the patients. In the majority of them it was molecular. Maintenance with If + ATRA for 2 years maintains molecular remission for 5-36 months.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Daunorubicin; Drug Therapy, Combination; Female; Humans; Interferon-alpha; Leukemia, Promyelocytic, Acute; Liposomes; Male; Middle Aged; Neoplasm Proteins; Oncogene Proteins, Fusion; Pilot Projects; Polymerase Chain Reaction; Remission Induction; Tretinoin

We analyzed the clinicobiological features and treatment outcome of a series of acute promyelocytic leukemias (APLs) occurring as a second tumor (APL-st's, n = 51) and compared these with a large group of de novo APL cases (n = 641), both observed by the Italian cooperative group GIMEMA. In the APL-st group, 37 patients had received radiotherapy and/or chemotherapy for their primary malignancy (PM), while 14 had been treated by surgery alone. Compared with de novo APL patients, APL-st patients were characterized by a predominance of females (P <.003), higher median age (P <.05), and worse performance status (P <.005). The median time elapsed between PM and APL-st was 36 months, with a longer latency for patients treated with surgery alone. No significant differences were found with regard to karyotypic lesions or type of promyelocytic leukemia/retinoic acid receptor alpha (PML/RARalpha) fusion in the 2 cohorts. A high prevalence of PMs of the reproductive system was observed among the female APL-st population (24 [71%] of 34 patients in this group had suffered from breast, uterine, or ovarian cancer). Thirty-one APL-st and 641 de novo APL patients received homogeneous APL therapy according to the all-trans retinoic acid (ATRA) and idarubicin regimen (the AIDA regimen). The complete remission (CR), 4-year event-free survival (EFS), and 4-year overall survival (OS) rates were 97% and 93%, 65% and 68%, and 85% and 78% in the APL-st and de novo APL groups, respectively. In spite of important clinical differences (older age and poorer performance status), the APL-st group responded as well as the de novo APL group to upfront ATRA plus chemotherapy, probably reflecting genetic similarity.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Child; Child, Preschool; Female; Humans; Idarubicin; Incidence; Infant; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Neoplasms, Second Primary; Retrospective Studies; Risk Factors; Survival Analysis; Treatment Outcome; Tretinoin

We previously reported a benefit for all-trans retinoic acid (ATRA) in both induction and maintenance therapy in patients with acute promyelocytic leukemia (APL). To determine the durability of this benefit and identify important prognostic factors, long-term follow-up of the North American Intergroup APL trial is reported. A total of 350 patients with newly diagnosed APL were randomized to either daunorubicin and cytarabine (DA) or ATRA for induction and then either ATRA maintenance or observation following consolidation chemotherapy. The complete remission (CR) rates were not significantly different between the ATRA and DA groups (70% and 73%, respectively). However, the 5-year disease-free survival (DFS) and overall survival (OS) were longer with ATRA than with DA for induction (69% vs 29% and 69% vs 45%, respectively). Based on both induction and maintenance randomizations, the 5-year DFS was 16% for patients randomized to DA and observation, 47% for DA and ATRA, 55% for ATRA and observation, and 74% for ATRA and ATRA. There was no advantage of either induction regimen among any subgroups when CR alone was considered. However, female sex, classical M3 morphology (vs the microgranular variant [M3v]), and treatment-white blood cell count (WBC) interaction (ATRA/WBC below 2 x 10(9)/L [2000/microL] best, DA/WBC above 2 x 10(9)/L worst) were each significantly associated with improved DFS (P <.05). Treatment with ATRA, WBC below 2 x 10(9)/L, and absence of bleeding disorder were each significantly associated with improved OS. Age more than 15 years, female sex, and treatment-morphology interaction (DA/M3v worst, ATRA best regardless of morphology) were each significantly associated with improved DFS based on maintenance randomization. The improvement in outcome with ATRA in APL was maintained with long-term follow-up.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Cytarabine; Daunorubicin; Disease-Free Survival; Female; Follow-Up Studies; Humans; Infant; Leukemia, Promyelocytic, Acute; Leukocyte Count; Life Tables; Male; Middle Aged; Prognosis; Remission Induction; Survival Analysis; Treatment Outcome; Tretinoin

Topics: Antineoplastic Combined Chemotherapy Protocols; Cuba; Cytarabine; Daunorubicin; Follow-Up Studies; Humans; Leukemia, Promyelocytic, Acute; Remission Induction; Survival Rate; Treatment Outcome; Tretinoin

We administered gemtuzumab ozogamycin ("mylotarg"; 9 mg/m(2) day 1 or 5) and all-trans retinoic acid (ATRA) to 19 patients with untreated acute promyelocytic leukemia (APL). There were 3 patients who also received idarubicin because of a white blood cell (WBC) count of more than 30 000/microL. In complete remission (CR), patients were to receive 8 courses of mylotarg (9 mg/m(2) every 4 to 5 weeks) and ATRA; idarubicin was added only for persistent or recurrent polymerase chain reaction (PCR) positivity. The CR rate was 16/19 (84%). All 12 patients tested to date were PCR-negative 2 to 4 months from CR date; none of the 7 patients evaluated subsequently have reverted to PCR positivity (median follow-up in CR was 5 months, up to 14 months). Mylotarg was well tolerated. A median of 5 post-CR courses have been given to date with 3 patients having currently received 8 post-CR courses, and 4 patients receiving 7 post-CR courses. Mylotarg appears active in APL, and repeated administration is feasible.

Topics: Anti-Bacterial Agents; Antibodies, Monoclonal; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Confidence Intervals; Disease-Free Survival; Humans; Idarubicin; Leukemia, Promyelocytic, Acute; Polymerase Chain Reaction; Time Factors; Tretinoin

A novel intravenous liposomal formulation of all-trans retinoic acid (ATRA) was evaluated in 69 patients with acute promyelocytic leukemia (APL): 32 new diagnoses, 35 relapses, and 2 oral ATRA failures. Liposomal ATRA (90 mg/m(2)) was administered every other day until complete remission (CR) or a maximum of 56 days. Treatment following CR was liposomal ATRA with or without chemotherapy. In an intent-to-treat (ITT) analysis of all patients, CR rates were 62%, 70%, and 20% in newly diagnosed, group 1 first relapses (ATRA naive or off oral ATRA more than or equal to 1 year), or group 2 relapses (second or subsequent relapse or first relapses off oral ATRA less than 1 year), respectively. In 56 evaluable patients (receiving 4 or more doses), CR rates for the same groups were 87% (20 of 23), 78% (14 of 18), and 23% (3 of 13). Remission failure in newly diagnosed patients was not from resistant disease. Several patients in CR became polymerase chain reaction (PCR) negative for promyelocytic leukemia/retinoic acid receptor-alpha (PML/RARalpha) after liposomal ATRA alone. Toxicity was generally mild, most commonly headaches (67. 5%). Eighteen patients (26%) had ATRA syndrome develop during induction. One-year survival of ITT patients was 62%, 56%, and 20% for newly diagnosed, group 1, and group 2, respectively. The medium duration of CR has not yet been reached and was 18 and 5.5 months in the same groups. These results demonstrate that liposomal ATRA is effective in inducing CR in newly diagnosed or group 1 APL patients. It provides a reliable dosage of ATRA for patients with APL unable to swallow or absorb medications and can induce molecular remissions without chemotherapy.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Bone Marrow; Child; Child, Preschool; Disease-Free Survival; DNA; Drug Compounding; Female; Humans; Injections, Intravenous; Leukemia, Promyelocytic, Acute; Liposomes; Male; Middle Aged; Neoplasm Proteins; Oncogene Proteins, Fusion; Prospective Studies; Racial Groups; Recurrence; Remission Induction; Risk Factors; Treatment Outcome; Tretinoin

Of 167 newly diagnosed acute promyelocytic leukaemia patients, 83 patients were long (L)-form (50%), eight variable (V)-form (5%) and 76 short (S)-form (45%). The V-form and S-form groups presented a significantly higher percentage of patients with white blood cell counts > 10 x 10(9)/l (P < 0.05). The S-form cases displayed a significantly higher number of cases with M3v microgranular features (P = 0.005) and CD34 expression (P < 0.0001). There were no differences between the three isoforms in complete remission (CR) rate (overall CR 90%), but the 3-year disease-free survival was lower for V-form cases than it was for L- and S-form cases (62% vs. 94% and 89%, P = 0.056). We conclude that the V-form and S-form types are associated with some negative prognostic features at diagnosis. However, our data were only able to demonstrate an association with adverse prognosis in the V-form type and, moreover, as the number of cases was limited, needs to be confirmed in large, uniformly treated series.

Topics: Adolescent; Adult; Aged; Antigens, CD34; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Disease-Free Survival; Female; Humans; Infant; Infant, Newborn; Leukemia, Promyelocytic, Acute; Leukocyte Count; Male; Middle Aged; Neoplasm Proteins; Oncogene Proteins, Fusion; Polymerase Chain Reaction; Prognosis; Proportional Hazards Models; Protein Isoforms; Treatment Outcome; Tretinoin

To evaluate the efficiency of combination of interferon-alpha (INF) and all trans-retinoic acid (ATRA) as a treatment for maintaining remission in high risk group patients with acute myeloid leukemia (AML).. Three-day INF + ATRA course was administered every 3 months to 22 patients with AML from high risk group (impossibility of drug therapy during the first complete remission, resistant forms of AML, relapses, secondary AML, acute promyelocytic leukemia after attaining molecular remission).. INF + ATRA during remission maintained a long first complete remission (median 18 months) in patients with primary AML after small-volume drug therapy, led to long first and second complete remissions (median 12 months) in patients with resistant AML, and induced and maintained molecular remissions in patients with acute promyelocytic leukemia.

Topics: Acute Disease; Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Drug Therapy, Combination; Female; Humans; Interferon-alpha; Leukemia, Myeloid; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Recurrence; Remission Induction; Risk Factors; Time Factors; Tretinoin

All-trans-retinoic acid (ATRA) has been incorporated in front-line therapy for newly diagnosed acute promyelocytic leukemia (APL). We conducted a multicenter study of differentiation therapy with ATRA alone or in combination with chemotherapy followed by intensive postremission chemotherapy in patients with APL (the JALSG APL92 study), and analyzed prognostic factors to increase the cure rate in our subsequent trial. From 1992 to 1997, adult patients with newly diagnosed APL received oral ATRA 45 mg/m2 daily alone until complete remission (CR) if initial leukocyte counts were < 3.0x10(9)/l, and ATRA daily plus daunorubicin (DNR) 40 mg/m2x3 days plus enocitabine (BHAC) 200 mg/m2x5 days if leukocyte counts were > or =3.0 x 10(9)/l. If peripheral blasts exceeded 1.0x10(9)/l during therapy, DNRx3 days plus BHACx5 days was added. After CR was achieved, three courses of consolidation and six courses of maintenance/intensification chemotherapy were administered. Of 376 patients enrolled, 369 were evaluable (median age 46 years, range 15-86 years; median leukocyte counts 2.0x10(9)/l), and 333 (90%) achieved CR (94% of patients treated with ATRA alone, 88% with ATRA plus later chemotherapy, 89% with ATRA plus initial chemotherapy, and 86% with ATRA plus initial and later chemotherapy). At a median follow-up of 45 months, the predicted 6-year overall and event-free survival (EFS) rates for all patients were 65% and 52%, respectively. Favorable prognostic factors for CR were younger age, no or mild purpura, high serum total protein level, low lactate dehydrogenase level, and no or mild disseminated intravascular coagulation (DIC). Favorable prognostic factors for EFS were leukocyte counts < 10.0x10(9)/l, mild DIC, and no sepsis during induction therapy. In the JALSG APL97 study, we intensified chemotherapy for patients with leukocyte counts > or =3.0x10(9)/l, and are randomly testing whether further chemotherapy is required for APL patients with negative PCR for PML/retinoic acid receptor alpha in the maintenance phase.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cell Differentiation; Female; Follow-Up Studies; Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Multivariate Analysis; Prognosis; Survival Rate; Tretinoin

Recent reports of extramedullary disease (EMD) at recurrence in acute promyelocytic leukemia (APL) have raised increasing concern about a possible role of retinoic acid (RA) therapy.. We analyzed the risk of developing EMD localization at relapse in APL patients enrolled onto two consecutive studies of the Gruppo Italiano Malattie Ematologiche dell'Adulto. The studies investigated chemotherapy alone (LAP0389) versus RA plus chemotherapy (AIDA).. When all relapse types were taken into account, 94 (51%) of 184 patients and 131 (18%) of 740 patients who attained hematologic remission underwent relapse in the LAP0389 and AIDA studies, respectively (P < .0001). EMD localization was documented in five (5%) of 94 and 16 (12%) of 131 patients (P = .08). Hematologic and/or molecular relapse was diagnosed concomitantly in all but two patients with EMD in the AIDA study. For patients in the LAP0389 and AIDA series, the probability of EMD localization of any type at relapse was 3% and 4.5%, respectively (P = .79), while the probability of CNS involvement was 0.6% and 2% (P = .28). No significant differences were found with regard to mean WBC count and promyelocytic leukemia/retinoic acid receptor-alpha junction type in comparisons of patients with EMD and hematologic relapse.. APL patients receiving all-trans retinoic acid in addition to chemotherapy have no increased risk of developing EMD at relapse as compared with those treated with chemotherapy alone.

Topics: Adult; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Female; Hematopoiesis, Extramedullary; Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Receptors, Retinoic Acid; Recurrence; Retinoic Acid Receptor alpha; Reverse Transcriptase Polymerase Chain Reaction; Risk Factors; RNA; Tretinoin

All-trans retinoic acid (ATRA), alone or combined with chemotherapy (CHT) is widely used to induce complete remission (CR) in newly diagnosed acute promyelocytic leukemia (APL). If used alone, ATRA results in a substantial proportion of CRs. To maintain remission further, ATRA is commonly used with cycles of CHT, frequently followed by autologous (auto) or allogeneic (allo) stem cell transplantation (SCT), as early reports have shown that the continuous administration of ATRA as single therapy almost invariably leads to relapse in a short period of time (months). Pharmacokinetic studies have shown that induced resistance to ATRA is frequently suppressed by the intermittent use of the drug. In this study we applied an intermittent therapeutic protocol with ATRA in five APL patients who were either molecularly refractory after combined ATRA/CHT treatment, or relapsed, or at diagnosis, but not eligible for the combination treatment because of previous toxicity. They were treated with ATRA (45 mg/m2/day) for 21 days. The treatment was then prolonged continuously for 1 week every 2 weeks. Molecular analysis was performed by qualitative and quantitative reverse transcription-polymerase chain reaction (RT-PCR). All patients obtained molecular remission, as assessed by qualitative RT-PCR, in a median of 3 months (range 1-15). Quantitative RT-PCR confirmed these data, showing a progressive reduction (1 or 2 logs) to a 'negligible quantity' of PML-RARalpha fusion transcript (ratio PML-RARalpha/ABL x 10(4) ABL < 10(-1)) in all but one patient treated with pulsed ATRA therapy. These data were confirmed with qualitative and quantitative RT-PCR. After a median follow-up of 17 months from the start of ATRA therapy, 4/5 patients (80%) are in continuous complete molecular remission. To our knowledge, this is the first clinical observation that intermittent ATRA therapy (without chemotherapy) is effective not only in inducing but also in maintaining long-term molecular remission in APL patients. This approach could therefore be effective, if confirmed in larger series, in relapsed/refractory patients unsuitable for high-dose therapy and SCT; it may be proposed as induction therapy for selected older APL patients if considered not to be eligible for combined ATRA/CHT due to inadequate performance status or concurrent disease.

Topics: Adult; Aged; Antineoplastic Agents; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Kinetics; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Neoplasm Proteins; Neoplasm, Residual; Oncogene Proteins, Fusion; Pilot Projects; Remission Induction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Neoplasm; Tretinoin

It has been postulated that recurrence of disease in some patients with newly-diagnosed APL induced into CR, and subsequently maintained, with single agent oral ATRA results from the decline in ATRA levels that occurs with repeated dosing. Administration of liposomal ATRA (lipoATRA) circumvents, for perhaps several months, the decrease in ATRA levels and produces CRs in patients with relapsed APL. These findings led us to administer lipoATRA "monotherapy" to patients with newly-diagnosed APL. Patients received lipoATRA (90 mg/m2) for induction and continued to receive the drug, by itself, for 9 months unless 2 PCR tests done within 2-4 weeks of each other at a sensitivity level of 10(-4) were positive at 3 or 6 months from CR date, in which case idarubicin was added to lipoATRA. If the PCR test was negative 9 months from CR date, treatment stopped. 34 patients were enrolled, of whom 79% entered CR. The PCR test at time of CR was positive in 23/24 patients, but was negative in 24/26 (92%) 3 months later. Of most interest 11 of the 26 evaluable responding patients have remained PCR negative (tested Q 3 months) with a median follow-up of 18 months (range up to 34 months). It is generally believed that this type of result would be unlikely with oral ATRA monotherapy. Recurrence of morphologic APL has occurred in 4 patients, at 5, 6, 12, and 12 months, with a median follow-up time of 18 months in the patients remaining alive in CR. Comparison of this lipoATRA +/- idarubicin trial with oral ATRA + idarubicin induction and idarubicin + POMP maintenance, our previous trial, indicates similar survival, CR, and DFS in CR rates, with a suggestion that lipoATRA may produce lower CR rates and hence shorter survival in patients with high-risk disease (wbc count > 10,000/microliter. Nonetheless, the rates and duration of PCR negativity produced by lipoATRA monotherapy suggest that lipoATRA is a superior anti-APL agent than oral ATRA.

Topics: Administration, Oral; Antineoplastic Combined Chemotherapy Protocols; Drug Carriers; Humans; Idarubicin; Infusions, Intravenous; Leukemia, Promyelocytic, Acute; Liposomes; Polymerase Chain Reaction; Remission Induction; Survival Rate; Time Factors; Treatment Outcome; Tretinoin

We examined the incidence, clinical course, and outcome of patients with newly diagnosed acute promyelocytic leukemia (APL) who developed the retinoic acid syndrome (RAS) treated on the Intergroup Protocol 0129, which prospectively evaluated the role of alltrans retinoic acid (ATRA) alone during induction and as maintenance therapy. Forty-four of 167 (26%) patients receiving ATRA for induction developed the syndrome at a median of 11 days of ATRA (range, 2-47). The median white blood cell (WBC) count was 1,450/microL at diagnosis and was 31,000/microL (range, 6,800-72,000/microL) at the time the syndrome developed. ATRA was discontinued in 36 of the 44 patients (82%) and continued in 8 patients (18%), with subsequent resolution of the syndrome in 7 of the 8. ATRA was resumed in 19 of the 36 patients (53%) in whom ATRA was stopped and not in 17 (47%). The syndrome recurred in 3 of those 19 patients, with 1 death attributable to resumption of the drug. Ten of these 36 patients received chemotherapy without further ATRA, and 8 achieved complete remission (CR). Among 7 patients in whom ATRA was not restarted and were not treated with chemotherapy, 5 achieved CR and 2 died. Two deaths were definitely attributable to the syndrome. No patient receiving ATRA as maintenance developed the syndrome. (Blood. 2000;95:90-95)

Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Cytarabine; Daunorubicin; Dexamethasone; Female; Fever; Glucocorticoids; Humans; Incidence; Infant; Leukemia, Promyelocytic, Acute; Lung; Male; Middle Aged; Pericardial Effusion; Pleural Effusion; Remission Induction; Respiratory Distress Syndrome; Syndrome; Tretinoin; Weight Gain

The type V (for variable) promyelocytic leukemia retinoic acid receptor (PML-RAR)alpha transcript, found in approximately 8% of adult patients with acute promyelocytic leukemia (APL), is defined molecularly by truncation of PML exon 6 and frequent insertion of genetic material from RARalpha intron 2. To more fully characterize the molecular features of PML-RARalpha V-type transcripts and to determine whether V-form APL patients have a distinct clinical presentation or prognosis, we analyzed 18 adult V-form APL patients enrolled on Intergroup protocol 0129 (INT-0129). Truncations in PML exon 6 ranged from 8 to 146 nucleotides, and 3 to 127 extra nucleotides (1 to 42 extra amino acids) were inserted at the PML exon 6/RARalpha exon 3 junction in 13 cases. No distinguishing morphologic, cytogenetic, or immunophenotypic features of V-form blasts were identified. A total of 5 of 7 patients induced with ATRA and 8 of 11 patients who received chemotherapy for induction achieved complete remission (CR). Six patients have relapsed, 4 after chemotherapy induction and 2 after ATRA. Nine patients (50%) are alive, 6 in continuous CR, 2 after salvage therapy for relapsed or refractory disease, and 1 after alternative treatment following early removal from protocol. Although the failure rate for V-form APL patients was high (61%), the low power of the current study to detect clinically significant differences precludes a meaningful comparison of clinical outcomes between the 18 V-form cases and non-V-form adult APL patients enrolled on INT-0129. (Blood. 2000;95:398-403)

Topics: Adult; Amino Acid Sequence; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Base Sequence; Cytarabine; Daunorubicin; Exons; Female; Humans; Karyotyping; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Neoplasm Proteins; Oncogene Proteins, Fusion; Prognosis; Protein Isoforms; Remission Induction; Sequence Deletion; Transcription, Genetic; Tretinoin

Despite achieving complete remission with retinoic acid (RA), most patients with acute promyelocytic leukemia (APL) have minimal residual disease detectable by reverse transcription-PCR (RT-PCR) amplification. HuM195, a humanized monoclonal antibody reactive with the cell surface antigen CD33, specifically targets and kills myeloid leukemia cells. We studied whether HuM195 could eliminate minimal residual disease in patients with APL by using RT-PCR. After attaining clinical complete remission with RA and/or chemotherapy, patients received HuM195 twice weekly for 3 weeks. Patients in first remission were given consolidation chemotherapy, generally with three cycles of idarubicin and cytarabine. Patients in second or greater remission did not receive chemotherapy. All patients received six monthly courses of maintenance with two doses of HuM195. Twenty-five of 27 patients treated in first remission had positive RT-PCR determinations before HuM195 treatment. Of the 22 patients evaluable for conversion of positive RT-PCR assays, 11 (50%) became RT-PCR negative after HuM195 treatment without additional therapy. Within the subset of patients who received RA alone as induction, 8 of 18 evaluable patients (44%) had negative RT-PCR determinations after HuM195 treatment but before chemotherapy. Among similar patients treated on earlier studies, 7 of 34 patients (21%) induced into remission with RA and then maintained on the drug for 1 month were RT-PCR negative before chemotherapy (P = 0.07). Twenty-five of 27 patients with newly diagnosed APL (93%) remain in clinical complete remission for 7+ to 58+ months, with median follow-up of 29 months. Seven patients in second or third remission and one patient in molecular relapse were also treated. Only one of these patients became RT-PCR negative after treatment with HuM195. These data suggest that HuM195 has activity against minimal residual disease in APL, particularly in newly diagnosed patients.

Topics: Adolescent; Adult; Aged; Alitretinoin; Antibodies, Monoclonal; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Antineoplastic Agents; Disease-Free Survival; Female; Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Remission Induction; Sialic Acid Binding Ig-like Lectin 3; Time Factors; Tretinoin

From January 1990 to August 1997, 29 consecutive patients were treated with newly diagnosed primary acute promyelocytic leukemia (APL) at the authors' Institution. Of these, 27 (16 boys and 11 girls) were evaluable. Median age at diagnosis was 6.3 (range: 1.9-15.7) years. This population was treated with two consecutive protocols: 13 patients were included in the AML-HPG-90 protocol and 14 in the AML-HPG-95. The initial treatment was the same for both protocols: an induction 8-day phase with cytarabine, idarubicin, and etoposide was followed by a consolidation with cyclophosphamide, cytarabine, 6-mercaptopurine, vincristine, doxorubicin, and prednisone. Two courses of intensification with high-dose (HD) cytarabine and etoposide were given in the first study. Only one intensification course was administered in the second study, with HD cytarabine plus idarubicin or etoposide decided by randomization. Complete remission was achieved in 67% (18/27) of cases. Mortality on induction was quite high, 30% (8/27) mainly due to hemorrhages from disseminated intravascular coagulation (DIC). The event-free survival estimate for all patients was 0.47 (SE: 0.1). From April 1994, all-trans-retinoic acid (ATRA) was administered just during the first days of the induction phase (median: 9, range: 2-27) to stop or prevent DIC. Eighteen patients received ATRA and 9 did not. Three patients developed signs of ATRA syndrome during the first days of administration but no one died due to this toxicity. The impact of a short course of ATRA on early control of DIC was studied by analyzing the number of platelet, cryoprecipitate, and fresh frozen plasma transfusions during the induction phase in both groups. No statistical differences in complete remission rate, early mortality, need of transfusion of blood components for DIC, and survival estimates could be established between patients who received ATRA and those who did not. ATRA used in a short-course schedule during induction of APL did not stop early mortality due to DIC. Moreover, survival results did not improve with this method of ATRA usage. Longer periods of ATRA administration during APL therapy are strongly recommended.

Topics: Adolescent; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Cytogenetics; Dexamethasone; Disease-Free Survival; Disseminated Intravascular Coagulation; Drug Administration Schedule; Female; Fibrin Fibrinogen Degradation Products; Fibrinogen; Hemorrhage; Hemorrhagic Disorders; Humans; Leukemia, Promyelocytic, Acute; Male; Platelet Count; Retrospective Studies; Risk Factors; Survival; Time Factors; Tretinoin

A prospective multicenter study was performed to investigate the clinical and molecular results of intensified double induction therapy including high-dose cytarabine (ara-C) in combination with ATRA in newly diagnosed acute promyelocytic leukemia (APL), followed by consolidation and 3 years maintenance therapy. Fifty-one patients, diagnosed and monitored from December 1994 to June 1999, were evaluated. The median age was 43 (16-60) years. The morphologic diagnosis was M3 in 40 (78%) and M3v in 11 (22%) patients. In 15 (30%) patients the initial white blood cell counts were > or =5 x 10(9)/l. The cytogenetic or molecular proof of the translocation t(15;17) was a mandatory prerequisite for eligibility. The diagnosis was confirmed by karyotyping in 46 and by RT-PCR of the PML/RARalpha transcript in 45 cases. The rate of complete hematological remission was 92% and the early death rate 8%. Monitoring of minimal residual disease by RT-PCR of PML/RARalpha (sensitivity 10(-4)) showed negativity in 29 of 32 (91%) evaluable cases after induction, in 23 of 25 (92%) after consolidation, and in 27 of 30 (90%) during maintenance, after a median time of 2, 4 and of 18 months after diagnosis, respectively. After a median follow-up of 27 months, the estimated actuarial 2 years overall and event-free survival were both 88% (79, 97), and the 2 years relapse-free survival 96% (90, 100). The high antileukemic efficacy of this treatment strategy is demonstrated by a rapid and extensive reduction of the malignant clone and by a low relapse rate. The results suggest that the intensity of the induction chemotherapy combined with ATRA is one of the factors which may have a critical influence on the outcome of APL. A randomized trial should assess the value of an induction therapy including ATRA and high-dose ara-C in comparison to standard-dose ara-C.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Base Sequence; Cytarabine; DNA Primers; Female; Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Tretinoin

First results of a randomized trial (APL91 trial) and other randomized or non-randomized studies have shown that ATRA followed by chemotherapy significantly increased event-free survival (EFS) and survival, and decreased the incidence of relapse by comparison to chemotherapy alone in newly diagnosed APL. We present here long-term follow-up of the APL91 trial. In this trial, 101 patients had been randomized between ATRA followed by three courses of daunorubicin-AraC chemotherapy (ATRA group) and the same chemotherapy alone (chemotherapy group). Results were reanalyzed 73 months after closing of patient entry. Updated results of APL 91 trial found a Kaplan-Meier estimate of EFS and relapse rate at 4 years of 63% and 31% in the ATRA group, as compared to 17% and 78% in the chemotherapy group (P= 10(-4) and relative risk 2.95, P= 10(-4) and relative risk 3.68, respectively). Kaplan-Meier survival at 4 years was 76% in the ATRA group and 49% in the chemotherapy group (P= 0.026, relative risk 2.7). In the chemotherapy group, seven of the 27 relapses occurred after 18 months, but no relapse was seen after 43 months. In the ATRA group, four of the 17 relapses occurred after 18 months, including two late relapses (at 58 and 74 months). In the chemotherapy group, 23 of the 25 patients who relapsed achieved a second CR with ATRA, and the Kaplan-Meier estimate of second relapse was 40% at 30 months. In the ATRA group, the 10 patients who relapsed and were retreated with ATRA achieved a second CR. In conclusion, long-term results of APL91 trial confirm the superiority of the combination of ATRA and chemotherapy over chemotherapy alone in newly diagnosed APL, and that ATRA should be incorporated in the front-line treatment of APL.

Topics: Antineoplastic Agents; Humans; Leukemia, Promyelocytic, Acute; Leukocyte Count; Prognosis; Tretinoin

Preliminary independent reports of the Italian GIMEMA and the Spanish PETHEMA trials for newly diagnosed acute promyelocytic leukemia (APL) indicated a similarly high antileukemic efficacy in terms of complete remission and disease-free survival rates. To better investigate these studies and the prognostic factors influencing relapse risk, this study analyzed the updated results of 217 patients with PML/RAR alpha-positive APL enrolled in GIMEMA (n = 108) and PETHEMA (n = 109). All patients received identical induction (AIDA schedule) and maintenance. For consolidation, GIMEMA patients received 3 courses including idarubicin/cytarabine, mitoxantrone/etoposide, and idarubicin/cytarabine/thioguanine, whereas PETHEMA patients received the same drugs and dose schedule of idarubicin and mitoxantrone with the omission of nonintercalating agents. Depending on whether molecular relapses were classified as censored or uncensored events, the 3-year Kaplan-Meier estimates of relapse-free survival (RFS) for the combined series were 90 +/- 2% and 86 +/- 2%, respectively. Minor differences observed between the 2 patient cohorts were negligible. Multivariate regression analysis of RFS showed that initial leukocyte (WBC) and platelet counts were the only variables with independent prognostic value. The resulting predictive model for RFS demonstrated its capability of segregating patients into low-risk (WBC count 40 x 10(9)/L), intermediate-risk (WBC count 10 x 10(9)/L) groups, with distinctive RFS curves (P <.0001). The conclusions are that omission of nonanthracycline drugs from the AIDA regimen is not associated with reduced antileukemic efficacy and a simple predictive model may be used for risk-adapted therapy in this disease. (Blood. 2000;96:1247-1253)

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cohort Studies; Cytarabine; Etoposide; Female; Humans; Idarubicin; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Mitoxantrone; Multivariate Analysis; Predictive Value of Tests; Recurrence; Risk; Thioguanine; Tretinoin

We report herein the clinical results of a multicenter trial of the Japan Adult Leukemia Study Group for cases of newly diagnosed acute promyelocytic leukemia (APL) treated with all-trans retinoic acid and chemotherapy (JALSG AML-92 study). Of 196 evaluable patients, 173 (88%) achieved complete remission (CR). Multivariate analysis showed that no or minor purpura at diagnosis and age less than 30 years were favorable factors for achievement of CR. There was a significant difference in the 4-year event-free survival between the AML-92 study (54%) and both the AML-87 (32%) and AML-89 (32%) studies which consisted of intensive chemotherapy. Since prognosis in patients with APL largely depends on chemotherapy, it is important to consider more effective chemotherapy during induction and consolidation therapy.

Topics: Aclarubicin; Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Disease-Free Survival; Drug Administration Schedule; Female; Humans; Leukemia, Promyelocytic, Acute; Male; Mercaptopurine; Middle Aged; Mitoxantrone; Prognosis; Receptors, Retinoic Acid; Remission Induction; Retinoic Acid Receptor alpha; Tretinoin

Early hemorrhagic death (within the first 10 d of treatment [EHD]) is reported as the main cause of death during induction therapy for acute promyelocytic leukemia (APL). In order to evaluate possible differences in the incidence of EHD during induction regimens based on all-trans retinoic acid (ATRA), we retrospectively analyzed a consecutive series of 86 APL patients, diagnosed and treated at our Institution from 1982. Forty-three patients received combination chemotherapy with anthracyclines and cytosine arabinoside (January 1982 to December 1991), while induction of the remaining 43 was based on ATRA alone or on a combination of ATRA and anthracyclines (January 1992 to October 1996). There were significantly less induction deaths in the ATRA group [9 (chemotherapy group-CT) vs. 2 (ATRA group-RA) overall and 8(CT) vs. 1(RA) of EHD; p = 0.01]. Hemostatic evaluations showed an earlier reduction of D-dimer in the ATRA group. No cases of morphological resistance were observed in the ATRA group after induction. In addition, the number of relapses occurring in the first 24 months from the achievement of complete remission (CR) was significantly lower in the ATRA group (15 vs. 7; p = 0.01), with a disease free survival at 2 yr of 67% vs. 31%. In conclusion, ATRA appears to be able to significantly reduce the incidence of EHD, increasing the number of possible long-term remissions.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Cytarabine; Daunorubicin; Hemorrhage; Humans; Leukemia, Promyelocytic, Acute; Mercaptopurine; Methotrexate; Remission Induction; Retrospective Studies; Tretinoin

In spite of the recent improvement in the outcome of acute promyelocytic leukaemia (APL) with treatment combining all trans retinoic acid (ATRA) and chemotherapy (CT), some patients with this disease still have a poor outcome. The prognostic significance of chromosomal abnormalities in addition to t(15;17) in APL is uncertain. We examined the prognostic significance of secondary chromosomal changes in 292 patients included in a European trial who were treated with ATRA and CT. The incidence of chromosomal abnormalities in addition to t(15;17) was 26% and trisomy 8 was the most frequent secondary change (46% of the cases with secondary changes). No significant differences were seen with regard to age, sex, initial white blood cell count, % of circulating blasts, platelet count, fibrinogen level and incidence of microgranular variants between patients with or without additional rearrangements. Outcome was also similar between patients with t(15;17) alone and patients with t(15;17) and other clonal abnormalities for complete remission (92% vs. 93% respectively), event-free survival at 2 years (76.1% vs. 78.1% respectively), relapse at 2 years (16.7% vs. 11.6% respectively) and overall survival at 2 years (79.9% vs. 79.5% respectively). Analysis according to the type of induction treatment (ATRA followed by CT or ATRA plus CT) or the type of maintenance treatment (with ATRA, low-dose CT or both) also failed to show any difference between the two groups. Thus, in a large cohort of APL patients treated with ATRA and CT, additional chromosomal abnormalities had no impact on prognosis.

Topics: Adult; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Chromosome Aberrations; Chromosomes, Human, Pair 12; Chromosomes, Human, Pair 15; Chromosomes, Human, Pair 16; Chromosomes, Human, Pair 17; Chromosomes, Human, Pair 21; Chromosomes, Human, Pair 6; Chromosomes, Human, Pair 7; Chromosomes, Human, Pair 8; Chromosomes, Human, Pair 9; Cohort Studies; Cytarabine; Daunorubicin; Disease-Free Survival; Female; Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Prognosis; Remission Induction; Survival Rate; Translocation, Genetic; Tretinoin; Trisomy

A new synthetic retinoid, Am80, is effective in treating acute promyelocytic leukemia relapsed from all-trans-retinoic acid-induced complete remission (CR). We report here the long-term clinical outcomes of patients who achieved second CR with Am80. Of 24 evaluable patients, 14 achieved a second CR by Am80 therapy. Of those patients, 4 relapsed within 6 months, despite subsequent consolidation chemotherapy. Six patients underwent sibling or unrelated HLA-matched allogeneic bone marrow transplantation (BMT), and 4 are alive without relase for more than 49 months after achieving second CR. Four of 8 patients who did not receive BMT are alive without relapse for more than 49 months. Promyelocytic leukemia-retinoic acid receptor alpha (PML-RAR alpha) fusion transcript was undetectable by reverse transcriptase-polymerase chain reaction in all living patients. Therefore, if patients achieve second CR with Am80 and HLA-matched donors are available, BMT is the treatment of choice. However, it is noteworthy that CR was maintained for more than 49 months in half of the patients who did not receive BMT.

Topics: Adult; Aged; Antineoplastic Agents; Benzoates; Female; Follow-Up Studies; Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Prognosis; Recurrence; Remission Induction; Retinoids; Tetrahydronaphthalenes; Tretinoin

This study was conducted to compare the results of treatment of acute promyelocytic leukemia (APL) with all-trans retinoic acid alone (ATRA) or a combination therapy of ATRA followed by chemotherapy. Forty-three patients treated between February 1992 and February 1996 were included in this study. Eighteen patients were treated with ATRA alone and 25 patients were treated with ATRA followed by chemotherapy. The cytogenetic analysis was done in 41 patients at presentation, following treatment, and at follow-up. A complete response (CR) was achieved in 13 (72%) patients on ATRA and 19 (76%) on ATRA followed by chemotherapy. Eleven of 13 patients with response to ATRA alone relapsed with median survival of eight months (range, 1 to 28). One patient died of hepatitis in CR and one patient is alive 2 years after diagnosis. In the combination therapy arm, 10 patients are in CR with a median follow-up of 22 months (range, 6 to 56 months). After achieving a CR, four patients died due to infections during chemotherapy therapy, and only 5 of 19 patients have relapsed. Major cytogenetic response was seen in 8 of the 10 patients in whom cytogenetic data was available after treatment with ATRA at the time of remission. Similarly, 13 of 15 for whom data was available showed a major cytogenetic response after treatment with ATRA plus chemotherapy. Prior to relapse, 80% of the patients had an increase in the percentage of t(15;17) cells in the marrow. Patients with a complete hematological response but no cytogenetic response relapsed within six months. Ten patients died prior to response evaluation. Two patients who received ATRA died of retinoic acid syndrome, one of pneumonia, and one of intracranial hemorrhage. Of the six patients on ATRA and chemotherapy, four died of retinoic acid syndrome (RAS), one of intracranial hemorrhage, and one of left ventricular failure. Only one patient is alive at 24 months following treatment with ATRA alone. The relapse-free survival is 42% at four years for patients treated with ATRA followed by chemotherapy. This trial is a historical comparison of ATRA alone and ATRA with subsequent combination chemotherapy. Nonetheless, the trial shows a significant improvement in the event free survival of patients receiving chemotherapy as consolidation following ATRA.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Cause of Death; Child; Cytarabine; Daunorubicin; Female; Fever; Humans; Leukemia, Promyelocytic, Acute; Lung; Male; Middle Aged; Prospective Studies; Recurrence; Remission Induction; Survival Rate; Tretinoin; Weight Gain

Topics: Aged; Cell Adhesion Molecules; Coronary Thrombosis; Humans; Leukemia, Promyelocytic, Acute; Middle Aged; Tretinoin

All-trans retinoic acid (ATRA) is an essential component of the treatment of acute promyelocytic leukemia (APL), but the optimal timing and duration remain to be determined. Molecular characterization of this disease can refine the diagnosis and could be potentially useful in monitoring response to treatment. Patients defined morphologically to have APL were randomized to receive a 5-day course of ATRA before commencing chemotherapy or to receive daily ATRA commencing with chemotherapy and continuing until complete remission (CR). The chemotherapy was that used in current MRC Leukaemia Trials. Outcome comparisons were by intention to treat with additional analysis for relevant risk factors. Patients were characterized by molecular techniques for the fusion products of the t(15;17) and monitored by reverse transcriptase-polymerase chain reaction (RT-PCR) during and after treatment. Two hundred thirty-nine patients were randomized. Treatment with extended ATRA resulted in a superior remission rate (87% v 70%, P <.001), due to fewer early and induction deaths (12% v 23%, P =.02), and less resistant disease (2% v 7%, P =.03), which was associated with a significantly more rapid recovery of neutrophils and platelets. Extended ATRA reduced relapse risk (20% v 36% at 4 years, P =.04) and resulted in superior survival (71% v 52% at 4 years, P =.005). Presenting white blood cell count (WBC) was a key determinant of outcome. The 70% of patients who presented with a WBC less than 10 x 10(9)/L had a better CR (85% v 62%, P =.0001) and reduced relapse risk (22% v 42%, P =.002) and superior survival (69% v 43%, P <. 0001). Within the low count group, extended ATRA resulted in a better CR (94% v 76%, P =.001), reduced relapse risk (13% v 35%, P =. 04), and improved survival (80% v 57%, P =.0009). There was no evidence of benefit in patients presenting with a higher WBC (>10 x 10(9)/L). Molecular monitoring after the third chemotherapy course had a correlation with risk of relapse. The relapse risk was 57% if the RT-PCR was positive versus 27% if the RT-PCR was negative (P =. 006). APL patients who present with a low WBC derive substantial benefit from combining ATRA with induction chemotherapy until remission is achieved, whereas patients with a higher WBC did not benefit. Molecular characterization of disease can improve diagnostic precision and a positive RT-PCR after consolidation identifies patients at a higher risk of relapse.

Topics: Adolescent; Adult; Aged; Child; Child, Preschool; Chromosomes, Human, Pair 15; Chromosomes, Human, Pair 17; Female; Humans; Infant; Kinetics; Leukemia, Promyelocytic, Acute; Leukocyte Count; Male; Middle Aged; Prognosis; Remission Induction; Tretinoin

Complete remission induced by all-trans retinoic acid (ATRA) in acute promyelocytic leukemia is short lived, and several consolidation chemotherapy courses usually are given to reduce the relapse rate. To assess the value of short-term intensive consolidation, 38 patients with newly diagnosed acute promyelocytic leukemia entered a prospective study in which induction therapy with ATRA immediately was followed by a single course of mitoxantrone plus high-dose cytarabine (3 g/m2 every 12 hours, days 1-4), with no further treatment. Complete remission was achieved in 31 patients (81.6%) after a median time of 49 days of ATRA (to which chemotherapy was added at entry in 10 patients with leukocytosis). Thirty patients received the planned consolidation course. After a median follow-up of 36 months, four of these patients have relapsed and 24 are still in first complete remission, for an estimated disease-free survival of 75% at 60 months. The authors conclude that this single course consolidation of ATRA-induced remission provides excellent long-term control of acute promyelocytic leukemia.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Female; Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Mitoxantrone; Prospective Studies; Remission Induction; Survival Analysis; Tretinoin

The aberrant expression of tissue factor (TF) in acute promyelocytic leukemia (APL) cells has been implicated in the pathogenesis of the APL coagulopathy. In this study, we found that in APL patients receiving ATRA or As2O3 treatment, the improvement in hypercoagulobility and hyperfibrinolysis paralleled the correction of plasma fibrinogen level and amelioration of bleeding symptoms. Notably, clinical improvement was also correlated to ATRA/As2O3-induced rapid decrease of membrane procoagulant activity (PCA) and TF contents of APL blasts. Consistent with the in vivo findings, the membrane PCA, TF antigen and its mRNA level within NB4 cells were rapidly down-regulated by 1 microM ATRA or As2O3, while 0.2 microg/ml DNR increased these TF parameters prior to its effect upon apoptosis induction. The down-regulation of TF mRNA by ATRA was partially de novo protein synthesis-dependent and at least partially attributed to a mechanism of destabilizing TF mRNA. On the other hand, in addition to its modulation on mRNA, As2O3 could also induce an accelerated TF protein turnover. These distinct effects were corroborated with the properties of these agents in causing the degradation of PML-RARalpha protein. All three therapeutic agents, however, enhanced the potential of NB4 cells to stimulate the expression of TF and PCA in endothelium. Taken together, our data suggest that the rapid and distinct regulation of TF on APL cells by these therapeutic agents might at least partially contribute to their effects on APL coagulopathy.

Topics: Adolescent; Adult; Antineoplastic Agents; Arsenic Trioxide; Arsenicals; Blood Coagulation; Daunorubicin; Drug Screening Assays, Antitumor; Endothelium, Vascular; Female; Fibrinolysis; Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Oxides; Thromboplastin; Tretinoin

All transretinoic acid (ATRA) followed by daunorubicin (DNR)-AraC chemotherapy (CT) has improved the outcome of acute promyelocytic leukemia (APL) by comparison to CT alone. In a randomized trial, (1) we compared 2 induction schedules (ATRA followed by CT [ATRA-->CT] and ATRA plus CT [ATRA+CT, with CT added on day 3 of ATRA treatment]) and (2) we assessed the role of maintenance treatment. Four hundred thirteen patients CT and ATRA+CT (initially randomized patients); patients with a WBC count greater than (high WBC count group, n = 163) and patients 66 to 75 years of age with a WBC count greater than 5,000/microL (elderly group, n = 42) were not initially randomized and received ATRA+CT from day 1 and ATRA -->CT, respectively. All patients achieving CR received 2 additional DNR-AraC courses (only 1 in patients 66 to 75 years of age) and were then randomized for maintenance between no treatment, intermittent ATRA (15 days every 3 months) for 2 years, continuous low-dose CT (6 mercaptopurine + methotrexate) for 2 years, or both, using a 2-by-2 factorial design. Overall, 381 (92%) of the patients achieved complete remission (CR), 31 (7%) suffered an early death, and only 1 patient had leukemic resistance. ATRA syndrome occurred in 64 patients (15%) and was fatal in 5 cases. The CR rate was similar in all induction treatment groups. Event-free survival (EFS) was significantly lower in the high WBC group (P =.0002) and close to significance in the elderly group (P =.086) as compared with initially randomized patients. Relapse at 2 years was estimated at 6% in the ATRA+CT group, versus 16% in the ATRA-->CT group (P =.04, relative risk [RR] =.41). EFS at 2 years was estimated at 84% in the ATRA+CT group, versus 77% in the ATRA-->CT group (P =.1, RR =.62). Two hundred eighty-nine patients were randomized for maintenance. The 2-year relapse rate was 11% in patients randomized to continuous maintenance CT and 27% in patients randomized to no CT (P =.0002) and 13% in patients randomized to intermittent ATRA and 25% in patients randomized to no ATRA (P =.02). An additive effect of continuous maintenance CT and intermittent ATRA was seen, and only 6 of the 74 patients who received both maintenance treatments had rel

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Drug Administration Schedule; Female; Humans; Infant; Leukemia, Promyelocytic, Acute; Male; Mercaptopurine; Methotrexate; Middle Aged; Remission Induction; Treatment Outcome; Tretinoin

In two patients with acute promyelocytic leukemia (APL) treated with all-trans retinoic acid (ATRA) in combination with chemotherapy, we demonstrated that cells with apoptotic morphology were recognized in a small fraction of whole blood cells (0.2-0.4%) at the regression phase of leukocytosis with mostly maturing aberrant granulocytes of APL clone origin. Moreover, in a light-density cell fraction ( < 1.077) of peripheral blood or marrow cells obtained from three patients, DNA fragmentation was detected by agarose gel electrophoresis temporarily. These findings may suggest that, during the treatment with ATRA, a small fraction of APL cells maturing toward the stage of terminal differentiation underwent apoptosis in vivo, which might be enriched by the combination of chemotherapy to ATRA administration.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Differentiation; Child; DNA Fragmentation; Female; Humans; Leukemia, Promyelocytic, Acute; Male; Tretinoin; Tumor Cells, Cultured

Evaluation of trans-retinoic acid (ATRA) in combination with cytostatic drugs in treatment of acute promyelocytic leukemia (APL).. In a multicenter study APL was treated according to protocols APL 01.97 and APL 06.87 in 28 patients (14 males and 14 females, median age 36 years).. Administration of ATRA in combination with standard program 7 + 3 (cytosine-arabinoside 100 mg/m2 twice a day v.v. day 1-7, daunorubicin 60 mg/m2 v.v. day 1-3) induced a complete remission in 25 patients (90%). Early lethality was 10% (3 patients died). Resistant APL was not registered. Retinoid syndrome was diagnosed in 15 patients, one patient died. 2-year overall and recurrence-free survival made up 72 and 82%, respectively.. ATRA combination with cytosine-arabinoside and daunorubicin is a novel treatment of acute promyelocytic leukemia providing a high rate of complete remission and long-term survival.

Topics: Adolescent; Adult; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Female; Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Remission Induction; Time Factors; Treatment Outcome; Tretinoin

All-trans retinoic acid administered orally (oral ATRA) may not regularly lead to either molecular complete remissions (CRs) or prolonged hematologic CRs (HCR) unless combined with chemotherapy. Because serum tretinoin concentrations are higher, and maintained longer, after use of liposomal-encapsulated ATRA (lipoATRA) rather than oral ATRA, we investigated lipoATRA monotherapy in newly diagnosed acute promyelocytic leukemia (APL). Patients received lipoATRA 90 mg/m(2) every other day for remission induction. The same dose was given 3 times a week until 9 months had elapsed from HCR date. Treatment then stopped. Chemotherapy (idarubicin 12 mg/m(2) daily days 1-2 for 2 courses) was to be added only if 2 polymerase chain reaction (PCR) tests, performed 2 weeks apart, were positive at 3, 6, or 9 months from HCR date. The sensitivity level of the PCR was 10(-4). We treated 18 patients (median age, 54 years; median white blood cell [WBC] count 4,500/microL). The HCR rate was 12/18 (67%, 95% confidence interval [CI], 41% to 87%). This rate was similar to that we observed in a previous study using oral ATRA + idarubicin. Nine of 10 patients studied at HCR date were PCR-positive. Subsequently, however, overall (+/- idarubicin) rates of PCR positivity were 0/12 at 3 months, 1/10 at 6 months, 1/7 at 9 and 12 months, and 0/4 at 15 to 17 months. Idarubicin has been added in 3 patients, with this addition occurring at 6 months in 2 patients and at 9 months in 1 patient. Among patients who had not received idarubicin when the PCR was evaluated, 0 of 12 were PCR-positive at 3 months, 1 of 10 was positive at 6 months, 1 of 6 was positive at 9 months, 0 of 4 were positive at 12 months, and 0 of 3 were positive at 15 to 17 months. Morphologic APL has recurred in 1 patient, with a median follow-up time of 13 months in the 11 patients remaining in first CR. The median follow-up time is 91/2 months (range, 3 to 17) in the 9 patients who have received only lipoATRA and who remain PCR-negative and in first CR. Our data suggest that lipoATRA is an effective means of producing molecular CR in newly diagnosed APL.

Topics: Administration, Oral; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Confidence Intervals; Drug Administration Schedule; Drug Carriers; Gene Rearrangement; Humans; Idarubicin; Leukemia, Promyelocytic, Acute; Liposomes; Neoplasm Proteins; Oncogene Proteins, Fusion; Polymerase Chain Reaction; Remission Induction; Tretinoin

Fourteen patients with PML/RARalpha-positive acute promyelocytic leukemia (APL) were given salvage therapy at the time of first molecular relapse. All patients had achieved first molecular remission after the AIDA protocol (all-trans retinoic acid [ATRA] + idarubicin) and were being prospectively monitored by reverse transcriptase-polymerase chain reaction (RT-PCR). Molecular relapse was defined as reappearance of RT-PCR-positivity for the PML/RARalpha fusion (sensitivity 10(-4)) in 2 successive marrow samples collected during postconsolidation monitoring. The median duration of first molecular remission was 7.5 months (range, 2 to 25). Salvage therapy consisted of oral ATRA for 30 days followed by 4 daily courses of chemotherapy (CHT) with cytarabine 1 g/m(2)/d and mitoxantrone 6 mg/m(2)/d. Second molecular remission was obtained in 12 of 14 patients (86%). Seven of these 12 attained molecular remission after ATRA alone. Of the 2 patients who persisted PCR(+) after CHT, 1 died in remission and 1 progressed to hematologic relapse. Of 12 patients PCR(-), 8 received consolidation with autologous bone marrow transplantation (ABMT), and 4 received ATRA-containing maintenance. Ten patients in this group are in sustained second molecular remission at a median time of 9.5+ months (range, 4 to 22+) and 2 underwent hematologic relapse 6 and 13 months, respectively, after transient second molecular remission. The 2-year Kaplan and Meier survival estimate from time of relapse was 92% (95% confidence interval [CI]: 61% to 98%) in this series, and 44% (95% CI: 35% to 52%) in a previous series of 37 patients who received the same treatment at the time of hematologic recurrence (P <.05, by log-rank test). This study suggests that early administration of salvage therapy is advantageous in APL and represents the first experience on therapy of molecular relapse in acute leukemia.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Follow-Up Studies; Humans; Idarubicin; Leukemia, Promyelocytic, Acute; Middle Aged; Mitoxantrone; Neoplasm Proteins; Oncogene Proteins, Fusion; Recurrence; Remission Induction; Reverse Transcriptase Polymerase Chain Reaction; Salvage Therapy; Survival Analysis; Time Factors; Tretinoin

The results of the treatment of 43 patients with acute promyelocytic leukemia (PML) are reported: 27 were treated initially with all-trans-retinoic acid (ATRA), whereas 16 were treated with conventional chemotherapy. All patients received myelosuppressive chemotherapy after the initial treatment. Respectively, the complete remission rate was 92% and 37% (P < 0.01), the 5-day mortality rate was 0% and 44% (P < 0.001), and the 28-day mortality rate was 4% and 44% (P < 0.001). The median disease-free survival was 12 and 1 months (P < 0.01), whereas the 12-month disease-free survival was 50% and 13% (P < 0.01) and the 36-month disease-free survival was 41% and 9% (P < 0.01). Thirteen of the patients treated with ATRA were given the treatment fully as outpatients. ATRA given as initial therapy decreased significantly early mortality in promyelocytic leukemia patients; because some promyelocytic leukemia patients given ATRA as initial therapy can be treated as outpatients, the costs of this treatment modality may be diminished.

Topics: Adolescent; Adult; Ambulatory Care; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Child; Disease-Free Survival; Female; Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Prospective Studies; Remission Induction; Tretinoin

The Spanish PETHEMA group designed a protocol for newly diagnosed PML/RARalpha-positive acute promyelocytic leukemia (APL) in which induction and consolidation followed the original AIDA regimen, except for the omission of cytarabine and etoposide from consolidation. Induction consisted of 45 mg/m(2) all-trans retinoic acid (ATRA) daily until complete remission (CR) and 12 mg/m(2) idarubicin on days 2, 4, 6, and 8. Patients in CR received 3 monthly chemotherapy courses: idarubicin 5 mg/m(2)/d x 4 (course no. 1), mitoxantrone 10 mg/m(2)/d x 5 (course no. 2), and idarubicin 12 mg/m(2)/d x 1 (course no. 3). Maintenance therapy consisted of 90 mg/m(2)/d mercaptopurine orally, 15 mg/m(2)/wk methotrexate intramuscularly, and, intermittently, 45 mg/m(2)/d ATRA for 15 days every 3 months. Between November 1996 and December 1998, 123 patients with newly diagnosed PML/RARalpha-positive APL from 39 centers were enrolled. A total of 109 patients achieved CR (89%; 95% confidence interval [CI], 83 to 95), 12 died of early complications, and the remaining 2 were resistant. Consolidation treatment was associated with very low toxicity and no deaths in remission were recorded. Molecular assessment of response by reverse transcriptase-polymerase chain reaction (RT-PCR) showed conversion to PCR-negative in 48 of 99 (51%) and 82 of 88 patients (93%) after induction and consolidation, respectively. The 2-year Kaplan-Meier estimates of overall survival and event-free survival were 82% +/- 4% and 79% +/- 4%, respectively. For patients who achieved CR, the 2-year disease-free survival (DFS) was 92% +/- 3%. These data indicate that a significant reduction in toxicity might be obtained in APL using a less intensive consolidation without apparently compromising the antileukemic effect. These results also suggest a minor role for cytarabine and etoposide in the treatment of newly diagnosed PML/RARalpha-positive APL patients.

Topics: Adolescent; Adult; Aged; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Idarubicin; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Neoplasm Proteins; Oncogene Proteins, Fusion; Treatment Outcome; Tretinoin

All-trans-retinoic acid (ATRA), chemotherapy, and arsenic trioxide (As2O3) have been found to be effective in the treatment of acute promyelocytic leukemia (APL). Here we present a single institutional retrospective study with long-term follow-up to better define the prognostic factors and a rationale for the use of ATRA, chemotherapy, and As2O3 in the treatment of newly diagnosed and relapsed APL patients.. Newly diagnosed patients with APL entering complete remission were followed up for 3 to 95 months (n = 120). Univariate and multivariate analyses were performed to identify potential prognostic factors, including age and sex; initial white blood cell (WBC) count and peak WBC level of hyperleukocytosis during induction therapy; dose of ATRA in induction; days from induction therapy to remission; postremission therapy; type of PML-RAR alpha isoform; and follow-up of reverse transcription-polymerase chain reaction (RT-PCR).. The median relapse-free survival (RFS) was 26 months, and median overall survival (OS) was still not reached. The estimated 5-year RFS and OS were 34.0% +/- 6.0% and 52.5% +/- 7.9%, respectively. Initial WBC count (> or = 20 x 10(9)/l), peak level of WBC during induction, and type of postremission therapy were significantly related to survival. Our multivariate study showed that only peak level of WBC count during induction therapy and type of postremission therapy were associated with RFS and that initial WBC count was associated with OS. In relapsed patients, As2O3 was very effective and remained as the most important factor for their entering remission and survival after relapse.. Through this retrospective study with long-term follow-up, some conclusions can be drawn: 1) Low-dose ATRA is as effective as the standard dose in terms of survival; 2) Initial and peak levels of WBC count during induction therapy are associated with survival; 3) A combination of chemotherapy and ATRA is better than chemotherapy or ATRA alone as postremission therapy; 4) Patients with the long form of PML-RAR alpha tend to have a more favorable OS but not RFS when compared with patients with the short form; 5) Persistent negative RT-PCR in remission is associated with favorable RFS and OS; 6) As2O3 is an effective agent for relapsed patients.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Child; Female; Follow-Up Studies; Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Neoplasm Proteins; Oncogene Proteins, Fusion; Oxides; Prognosis; Reverse Transcriptase Polymerase Chain Reaction; Survival Rate; Tretinoin

To compare the therapeutic effects and reactions of intra venous arsenic trioxide and all-trans retinoic acid in treating patients with acute promyelocytic leukemia (APL).. 75 cases of APL were randomized either to arsenic trioxide (37) or to all-trans retinoic acid (38). The rates of complete remission (CR), disease free survival (DFS) and side effects were observed.. In the two groups of patients with APL, the rate of CR was 86.4% and 84.2%. There was also no significant difference in the rate of DSF phase of CR (P > 0.05). The side effects of these two medications in therapeutic dose were mild and there was no cross resistance between them.. Arsenic trioxide can lead to apoptosis of leukemic cells and might be a new promising drug to induce differentiation.

Topics: Adolescent; Adult; Antineoplastic Agents; Apoptosis; Arsenic Trioxide; Arsenicals; Child; Disease-Free Survival; Female; Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Oxides; Tretinoin

This study evaluated whether relapse of acute promyelocytic leukemia (APL) patients from clinical remissions achieved and/or maintained with all-trans retinoic acid (RA) in combination with intensive chemotherapy is associated with leukemic cellular resistance to RA and with alterations in the PML-RARalpha fusion gene. We studied matched pretreatment and relapse specimens from 12 patients who received variable amounts of RA, primarily in nonconcurrent combination with daunorubicin and cytarabine (DA) on Eastern Cooperative Oncology Group (ECOG) protocol E2491, and from 8 patients who received DA only on protocol E2491. Of 10 RA-treated patients evaluable for a change in APL cell sensitivity to RA-induced differentiation in vitro, 8 showed diminished sensitivity at relapse, whereas, of 6 evaluable patients treated with DA alone, only 1 had marginally reduced sensitivity. From analysis of sequences encoding the principal functional domains of the PML and RARalpha portions of PML-RARalpha, we found missense mutations in relapse specimens from 3 of 12 RA-treated patients and 0 of 8 DA-treated patients. All 3 mutations were located in the ligand binding domain (LBD) of the RARalpha region of PML-RARalpha. Relative to normal RARalpha1, the mutations were Leu290Val, Arg394Trp, and Met413Thr. All pretreatment analyses were normal except for a C to T base change in the 3'-untranslated (UT) region of 1 patient that was also present after relapse from DA therapy. No mutations were detected in the corresponding sequences of the normal RARalpha or PML (partial) alleles. Minor additional PML-RARalpha isoforms encoding truncated PML proteins were detected in 2 cases. We conclude that APL cellular resistance occurs with high incidence after relapse from RA + DA therapy administered in a nonconcurrent manner and that mutations in the RARalpha region of the PML-RARalpha gene are present in and likely mechanistically involved in RA resistance in a subset of these cases.

Topics: Adolescent; Adult; Aged; Antibiotics, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cell Differentiation; Cytarabine; Daunorubicin; DNA Mutational Analysis; DNA, Neoplasm; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Female; Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Neoplasm Proteins; Neoplasm Recurrence, Local; Neoplastic Stem Cells; Oncogene Proteins, Fusion; Point Mutation; Remission Induction; Tretinoin; Tumor Cells, Cultured

All trans-retinoic acid (ATRA) syndrome is a life-threatening complication of uncertain pathogenesis that can occur during the treatment of acute promyelocytic leukemia (APL) by ATRA. Since its initial description, however, no large series of ATRA syndrome has been reported in detail. We analyzed cases of ATRA syndrome observed in an ongoing European trial of treatment of newly diagnosed APL. In this trial, patients 65 years of age or less with an initial white blood cell count (WBC) less than 5,000/microL were initially randomized between ATRA followed by chemotherapy (CT) (ATRA-->CT group) or ATRA with CT started on day 3; patients with WBC greater than 5,000/microL received ATRA and CT from day 1; patients aged 66 to 75 received ATRA-->CT. In patients with initial WBC less than 5, 000/microL and allocated to ATRA-->CT, CT was rapidly added if WBC was greater than 6,000, 10,000, 15,000/microL by days 5, 10, and 15 of ATRA treatment. A total of 64 (15%) of the 413 patients included in this trial experienced ATRA syndrome during induction treatment. Clinical signs developed after a median of 7 days (range, 0 to 35 days). In two of them, they were in fact present before the onset of ATRA. In 11 patients, they occurred upon recovery from the phase of aplasia due to the addition of CT. Respiratory distress (89% of the patients), fever (81%), pulmonary infiltrates (81%), weight gain (50%), pleural effusion (47%), renal failure (39%), pericardial effusion (19%), cardiac failure (17%), and hypotension (12%) were the main clinical signs, and 63 of the 64 patients had at least three of them. Thirteen patients required mechanical ventilation and two dialysis. A total of 60 patients received CT in addition to ATRA as per protocol or based on increasing WBC; 58 also received high dose dexamethasone (DXM); ATRA was stopped when clinical signs developed in 30 patients. A total of 55 patients (86%) who experienced ATRA syndrome achieved complete remission (CR), as compared with 94% of patients who had no ATRA syndrome (P = .07) and nine (14%) died of ATRA syndrome (5 cases), sepsis (2 cases), leukemic resistance (1 patient), and central nervous system (CNS) bleeding (1 patient). None of the patients who achieved CR and received ATRA for maintenance had ATRA syndrome recurrence. No significant predictive factors of ATRA syndrome, including pretreatment WBC, could be found. Kaplan Meier estimates of relapse, event-free survival (EFS), and survival at 2 years were 32% +/-

Topics: Acute Kidney Injury; Adult; Aged; Antibiotics, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cardiovascular Diseases; Cytarabine; Dexamethasone; Disease-Free Survival; Female; Humans; Incidence; Leukemia, Promyelocytic, Acute; Leukocyte Count; Life Tables; Male; Middle Aged; Pericardial Effusion; Pleural Effusion; Proportional Hazards Models; Remission Induction; Respiration Disorders; Survival Rate; Syndrome; Treatment Outcome; Tretinoin

The use of all-trans retinoic acid (RA) for remission induction markedly increases survival of patients with acute promyelocytic leukemia (APL) compared to patients treated solely with cytotoxic chemotherapy. However, clinical resistance to this agent develops rapidly, which has been associated with a progressive decline in plasma drug concentrations. Previous studies suggested that 9-cis RA, a retinoid receptor 'pan agonist' did not induce its own catabolism to the same extent as all-trans RA. Therefore, we conducted a dose-ranging study of this compound in patients with both relapsed and newly diagnosed APL. We treated 18 patients with morphologically diagnosed APL (13 relapsed, five newly diagnosed). The daily dose of 9-cis RA ranged from 30 to 230 mg/m2/day given as a single oral dose. Four of 12 (33%) relapsed patients (three of whom were previously treated with all-trans RA) and four of five (80%) newly diagnosed patients achieved complete remission. The sole failure in the newly diagnosed group died early from an intracranial hemorrhage. One other patient with t(9;12) translocation had substantial hematologic improvement. The drug was generally well tolerated; headache and dry skin were the most common adverse reactions. Three patients were treated with corticosteroids for signs of incipient 'RA syndrome.' These preliminary data suggest that 9-cis RA is an effective agent for remission induction and deserves further investigation in patients with retinoid-sensitive APL.

Topics: Adolescent; Adult; Aged; Alitretinoin; Antineoplastic Agents; Child; Child, Preschool; Chromosomes, Human, Pair 12; Chromosomes, Human, Pair 9; Dose-Response Relationship, Drug; Female; Humans; Infant; Leukemia, Promyelocytic, Acute; Leukocyte Count; Male; Middle Aged; Platelet Count; Recurrence; Translocation, Genetic; Tretinoin

Acute promyelocytic leukemia (APL) (M3 according to FAB classification) is a subtype of acute myelogenous leukemia characterized by a specific t(15;17) (q22;q12) chromosomal translocation. The majority of APL patients achieve morphologic remission after induction chemotherapy. They can be followed from this point by cytogenetic and molecular analysis of the persistence of the PML/RAR alpha transcript. In order to determine the influence of successive courses of consolidation chemotherapy on clinical and molecular outcome, APL patients treated with all-trans retinoic acid (ATRA) and chemotherapy (AIDA-GIMEMA-LAP0493 protocol) were investigated.. Twenty-four APL patients (pts) (15 males; 9 females) were studied by RT-PCR and cytogenetic analysis at diagnosis, after induction chemotherapy, at each point after any of three consolidation courses, and every 3 months during the first years of maintenance therapy. The median follow-up was 24 months (mths) (range 7-40 mths).. All pts achieved hematologic remission after induction chemotherapy. Our results demonstrate that the majority (87%) of APL patients were still molecularly positive for the APL associated transcript after induction chemotherapy, while the majority (80%) of APL patients became PCR-after the second consolidation chemotherapy.. The role of the third consolidation chemotherapy course in converting patients with persistent molecular evidence of disease from PCR+ to PCR- was minimal. We confirm the validity of molecular follow-up after single courses of chemotherapy in monitoring the role of molecular remission.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Bone Marrow; Combined Modality Therapy; Female; Humans; Idarubicin; Immunologic Factors; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Neoplasm, Residual; Neoplastic Stem Cells; Remission Induction; RNA, Messenger; RNA, Neoplasm; Tretinoin

All-trans retinoic acid (ATRA), a potent differentiating drug for acute promyelocytic leukemia (APL), induces a high incidence of complete remission (CR) in patients with APL and is now established as a first-line therapy. However, ATRA resistance has become a clinical problem. Patients who relapsed after ATRA-induced CR have had difficulty in obtaining a second CR with ATRA therapy. Although several mechanisms have been postulated, treatment strategies to overcome resistance have not been established. We used a new synthetic retinoid, Am-80, as reinduction therapy for APL relapse after from ATRA-induced CR. Am-80 was several times more potent than ATRA in inducing differentiation in vitro. At a 6 mg/m2 dose, there were 24 evaluable patients; 14 (58%) achieved CR between days 20 and 58 (median, 37 days). Clinical response correlated with the in vitro response to Am-80. Adverse effects included retinoic acid syndrome (n = 1), hyperleukocytosis (n = 1), xerosis (n = 9), cheilitis (n = 8), hypertriglyceridemia (n = 16), and hypercholesterolemia (n = 15). Am-80 is active in APL after relapse from ATRA-induced CR. Further clinical trials are needed to establish strategies to overcome ATRA resistance.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Arsenicals; Benzoates; Biomarkers, Tumor; Cheilitis; Cytarabine; Daunorubicin; Disease-Free Survival; Drug Resistance, Neoplasm; Female; Humans; Hypercholesterolemia; Hypertriglyceridemia; Leukemia, Promyelocytic, Acute; Leukocytosis; Male; Middle Aged; Neoplasm Proteins; Oncogene Proteins, Fusion; Pilot Projects; Recurrence; Remission Induction; Salvage Therapy; Tetrahydronaphthalenes; Treatment Outcome; Tretinoin; Tumor Cells, Cultured

Thirty-seven patients with acute promyelocytic leukemia (APL) were treated with all-trans retinoic acid (ATRA). Patients received 45 mg m-2 day-1 po of ATRA until complete remission (CR) was achieved, defined as: a) presence of less than 5% blasts in the bone marrow, with b) white blood cells > 10(3)/mm3, c) platelets > 10(5)/mm3 and d) hemoglobin concentration > 8 g/dl, with no blood or platelet transfusions. Thirty-one (83.7%) patients achieved CR by day 50, and 75% of these before day 30. Correction of the coagulopathy, achieved between days 2 and 10 (mean, 3 days), was the first evidence of response to treatment. Only one patient had been previously treated with chemotherapy and three had the microgranular variant M3 form. Dryness of skin and mucosae was the most common side effect observed in 82% of the patients. Thrombosis, hepatotoxicity and retinoid acid syndrome (RAS) were observed in 7 (19%), 6 (16%) and 4 (11%) patients, respectively. Thirteen (35%) patients had to be submitted to chemotherapy due to hyperleukocytosis (above 40 x 10(3)/mm3) and six of these presented with new signs of coagulopathy after chemotherapy. Four (11%) patients died secondarily to intracerebral hemorrhage (IH) and two (5.4%) dropped out of the protocol due to severe ATRA side effects (one RAS and one hepatotoxicity). RAS and IH were related strictly to hyperleukocytosis. The reduced use of platelets and fresh frozen plasma probably lowered the total cost of treatment. We conclude that ATRA is an effective agent for inducing complete remission in APL patients.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Child; Female; Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Remission Induction; Tretinoin

To evaluate the expression and clinical significance of interleukin 6, soluble glycoprotein 130 (sgp 130), interleukin 8 and type A interleukin 8 receptor (IL-8RA) in acute promyelocytic leukemia (APL) patients during all-trans retinoic acid (ATRA) treatment.. Serum and bone marrow mononuclear cell (MNC) culture supernatant IL-6, sgp 130, IL-8 concentrations of 18 cases APL patients were measured (ELISA). Bone marrow MNC IL-8RA was measured by flow cytometry after cultured with ATRA (10(-6) mmol/L).. Serum IL-6, sgp130, IL-8 levels were higher than normal (P < 0.05), IL-6, sgp130 levels correlated with white blood cell (WBC) counts (P < 0.05) while IL-8 level correlated with body temperature (P < 0.05) at initial diagnosis after 72-hour incubation with ATRA, concentration of IL-6 of bone marrow MNC culture supenatant did not change, that of sgp130 mildly decreased, and IL-8 significantly decreased while the positive rate of IL-8RA on bone marrow MNC increased. During ATRA treatment, serum IL-6 changes were correlated with WBC changes. Peak level of IL-6 and WBC was lower in patients received intermittent therapy than continuous therapy. Serum IL-6 and IL-8 increased when complicated with infection and increase in IL-8 seemed more sensitive.. Serum levels of IL-6, sgp130, IL-8 may reflect patient's responsiveness to ATRA treatment, predict hyperleukocytosis and intercurrent infection. ATRA induces APL cell differentiation possibly via gp130 signal transduction.

Topics: Adolescent; Adult; Antigens, CD; Female; Glycoproteins; Humans; Interleukin-6; Interleukin-8; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Receptors, Interleukin; Receptors, Interleukin-8A; Signal Transduction; Tretinoin

To determine the effect of omission of cytarabine (ara-C) from treatment of newly diagnosed acute promyelocytic leukemia (APL), which allows administration of more anthracycline.. Induction consisted of all-trans retinoic acid (ATRA) 45 mg/m2 daily until complete remission (CR) and idarubicin 12 mg/m2 daily for 4 days beginning on day 5 of ATRA. Patients in CR received two courses of idarubicin 12 mg/m2 daily for 3 days and then, until 2 years post-CR date, alternated three cycles of mercaptopurine, vincristine, methotrexate, and prednisone (POMP) with one cycle of idarubicin 12 mg/m2 daily for 2 days. Results in the 43 patients treated (41 with t(15;17) on standard or Southern analysis) were compared with those in 57 historic newly diagnosed APL patients given ara-C with either doxorubicin, amsacrine (AMSA), or daunorubicin without ATRA, using logistic and Cox regression to assess effects of non-treatment-related covariates on patient outcomes.. The CR rate in the current group was 77% (95% confidence interval [CI], 62% to 88%) and was not significantly different from the historic rate. In contrast, disease-free survival (DFS) in CR is superior in the current group (probability at 1 year 0.87; 95% CI, 0.73 to 1.0). This has translated into superior overall DFS for the current group (P = .03 adjusting for the predictive covariates initial WBC and platelet count; 1-year DFS probability 0.67; 95% CI, 0.52 to 0.82; median follow-up 102 weeks). The current treatment appears better both in patients with and without t(15; 17) on standard cytogenetic analysis.. Given the difficulties inherent in comparing sequential studies and recognizing the multiple differences in treatment between current and historic groups, our results suggest that a large randomized trial incorporating use of ATRA should assess the utility of omitting ara-C from treatment of newly diagnosed APL, thus allowing delivery of more anthracycline.

Topics: Adolescent; Adult; Aged; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Female; Humans; Idarubicin; Leukemia, Promyelocytic, Acute; Logistic Models; Male; Mercaptopurine; Methotrexate; Middle Aged; Prednisone; Proportional Hazards Models; Remission Induction; Treatment Outcome; Tretinoin; Vincristine

Hemostatic molecular markers were serially monitored in a prospective fashion during remission induction therapy with all-trans retinoic acid (ATRA) in sixteen patients with acute promyelocytic leukemia (APL). One patient with leukocytosis before treatment and three patients who later developed hyperleukocytosis also received chemotherapy with behenoyl Ara-C and daunorubicin. Plasma levels of E-fragment of fibrin and fibrinogen degradation product (FDP-E), FDP-D dimer (D-D), thrombin-antithrombin complex (TAT), and plasmin-alpha 2 plasmin inhibitor complex (PIC) were markedly elevated in all but one patient before treatment, and these parameters decreased to normal or near normal ranges in most patients within the first 7 days of treatment. Interestingly, we have found that these parameters were again elevated during the later course of ATRA therapy (after day +7) in eleven patients for various reasons including cytotoxic chemotherapy (3 cases), fever (5 cases; 2 cases with apparent infection, 3 cases without known etiology), Caesarean section (1 case), and no apparent etiology (2 cases). Three patients showed bleeding complications during re-elevation of molecular markers, but none developed thrombosis. Plasma elastase-alpha 1 proteinase inhibitor complex (E-alpha 1 PI) was markedly elevated in all patients at diagnosis and did not decrease significantly during ATRA therapy. Plasma tissue factor antigen was mildly elevated in one out of four patients studied, and thrombomodulin was elevated in two out of ten patients tested. These results confirmed the rapid normalization of coagulopathy during the early phase of remission induction therapy with ATRA but suggest that re-elevation of molecular markers occurs frequently during the later course of ATRA therapy.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Biomarkers; Blood Coagulation; Child; Female; Fibrinolysis; Follow-Up Studies; Hemostasis; Humans; Leukemia, Promyelocytic, Acute; Leukocytes; Male; Middle Aged; Pancreatic Elastase; Prospective Studies; Remission Induction; Thrombomodulin; Thromboplastin; Tretinoin

Differentiation therapy with all-trans retinoic acid (ATRA) has marked a major advance and become the first choice drug in the treatment of acute promyelocytic leukemia (APL). However, patients who relapse from ATRA-induced complete remission (CR) have difficulty in obtaining a second CR with a second course of ATRA therapy alone. We tested the efficacy of a new synthetic retinoid, Am80, in APL that had relapsed from CR induced by ATRA in a prospective multicenter study. Am80 is approximately 10 times more potent than ATRA as an in vitro differentiation inducer, is more stable to light, heat, and oxidation than ATRA, has a low affinity for cellular retinoic acid binding protein, and does not bind to retinoic acid receptor-gamma. Patients received Am80, 6 mg/m2, orally alone daily until CR. Of 24 evaluable patients, 14 (58%) achieved CR. The interval from the last ATRA therapy was not different between CR and failure cases. The clinical response was well correlated with the in vitro response to Am80 in patients examined. Adverse events included 1 retinoic acid syndrome, 1 hyperleukocytosis, 9 xerosis, 8 cheilitis, 16 hypertriglyceridemia, and 15 hypercholesterolemia, but generally milder than those of ATRA, which all patients had received previously. Am80 is effective in APL relapsed from ATRA-induced CR and deserves further trials, especially in combination with chemotherapy.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Benzoates; Cell Differentiation; Chemical and Drug Induced Liver Injury; Combined Modality Therapy; Cytarabine; Daunorubicin; Drug Resistance, Neoplasm; Female; Gastrointestinal Diseases; Humans; Leukemia, Promyelocytic, Acute; Leukocytosis; Male; Middle Aged; Pain; Prospective Studies; Receptors, Retinoic Acid; Recurrence; Remission Induction; Retinoic Acid Receptor gamma; Retinoids; Salvage Therapy; Tetrahydronaphthalenes; Treatment Outcome; Tretinoin

Two hundred fifty-three patients with newly diagnosed acute promyelocytic leukemia (APL) were eligible to enter the multicentric GIMEMA-AIEOP "AIDA" trial during the period July 1993 to February 1996. As a mandatory prerequisite for eligibility, all patients had genetic evidence of the specific t(15;17) lesion in their leukemic cells confirmed by karyotyping or by reverse transcription-polymerase chain reaction (RT-PCR) of the PML/RAR alpha fusion gene (the latter available in 247 cases). Median age was 37.8 years (range, 2.2 to 73.9). Induction treatment consisted of oral all-trans retinoic acid (ATRA), 45 mg/m2/d until complete remission (CR), given with intravenous Idarubicin, 12 mg/m2/d on days 2, 4, 6, and 8. Three polychemotherapy cycles were given as consolidation. Hematologic and molecular response by RT-PCR was assessed after induction and after consolidation. At the time of analysis, 240 of the 253 eligible patients were evaluable for induction. Of these, 11 (5%) died of early complications and 229 (95%) achieved hematologic remission. No cases of resistant leukemia were observed. Of 139 cases studied by RT-PCR after induction, 84 (60.5%) were PCR-negative and 55 (39.5%) PCR-positive. One hundred sixty-two patients were evaluable by RT-PCR at the end of consolidation. Of these, 159 (98%) tested PCR-negative and 3 (2%), PCR-positive. After a median follow up of 12 months (range, 0 to 33), the estimated actuarial event-free survival for the whole series of 253 eligible patients was 83% +/- 2.6% and 79% +/- 3.2% at 1 and 2 years, respectively. This study indicates that the AIDA protocol is a well-tolerated regimen that induces molecular remission in almost all patients with PML/RAR alpha-positive APL. Preliminary survival data suggest that a remarkable cure rate can be obtained with this treatment.

Topics: Adolescent; Adult; Aged; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Bone Marrow; Child; Child, Preschool; Chromosomes, Human, Pair 15; Chromosomes, Human, Pair 17; Disease-Free Survival; Female; Humans; Idarubicin; Leukemia, Promyelocytic, Acute; Leukocytosis; Male; Middle Aged; Neoplasm Proteins; Neoplasm, Residual; Oncogene Proteins, Fusion; Polymerase Chain Reaction; Prospective Studies; Remission Induction; Syndrome; Translocation, Genetic; Treatment Outcome; Tretinoin

In each case of acute promyelocytic leukemia (APL) one of three PML-RAR alpha mRNA types is produced, depending on the break/fusion site in the PML gene that is linked to a common RAR alpha gene segment: a short (S)-form type, PML exon 3 RAR alpha exon 3; a long (L)-form type, PML exon 6 RAR alpha exon 3; or a variable (V)-form type, variably deleted PML exon 6 RAR alpha exon 3. We evaluated whether PML-RAR alpha mRNA type is associated with distinct pretreatment clinical characteristics and therapeutic outcome in previously untreated adult APL patients registered to protocol INT 0129 by the Eastern Cooperative Oncology Group, the Southwest Oncology Group, and the Cancer and Leukemia Group B. Of 279 clinically eligible cases, 230 were molecularly evaluable, and of these, 111 were randomized to receive remission induction therapy with all-trans retinoic acid (ATRA) and 119 with conventional chemotherapy. Nine cases not excluded by central pathology review were PML-RAR alpha negative, and notably, none of five of these cases treated with ATRA achieved complete remission (CR). Among 221 PML-RAR alpha-positive cases, there were 82 S-form cases (37%), 121 L-form cases (55%), and 18 V-form cases (8%). Before any antileukemic therapy, the S-form type, compared with the L-form type, was associated with higher values for the white blood cell (WBC) count (median 2,500/microL v 1,600/microL; P = .009), the percentage of blood blasts plus promyelocytes (median 29% v 8.5%; P = .03), and the absolute blood blasts plus promyelocytes (884/microL v 126/microL; P = .019). Also, an increased percentage of S-form versus L-form cases had the M3 variant phenotype, 24% v 12% (P = .036). There were no differences between S-form and L-form cases in either CR rate (79% v 69%; P = .14) or disease free survival distribution (multivariate analysis adjusting for the association of S-form type and higher WBC count; P = .40). We conclude that the S-form type is associated with previously-identified adverse risk WBC parameters but that the identification of the S-form or L-form type of PML-RAR alpha mRNA, per se, does not predict clinical outcome or add to the value of an increased WBC count as a negative prognostic indicator in APL patients.

Topics: Adult; Antineoplastic Agents; Chromosomes, Human, Pair 15; Chromosomes, Human, Pair 17; Cloning, Molecular; Exons; Hemoglobins; Humans; Introns; Leukemia, Promyelocytic, Acute; Leukocyte Count; Neoplasm Proteins; Oncogene Proteins, Fusion; Platelet Count; Prognosis; RNA, Messenger; Treatment Outcome; Tretinoin

We analyzed the results of treating patients with newly diagnosed acute promyelocytic leukemia (APL) with all-trans retinoic acid (ATRA) in the JALSG AML-92 study and compared them with those of the AML-87 and AML-89 studies, which consisted of standard chemotherapy. In the AML-92 study, patients were scheduled to receive 45 mg/ m2 oral ATRA daily until achievement of a complete remission (CR). If patients had initial leukocyte counts of > 3.0 x 10(9)/l, they received 40 mg/m2 daunorubicin (DNR) for 3 days and 200 mg/m2 behenoyl cytarabine (BHAC) for 5 days in addition to ATRA. During remission induction therapy, if the patients showed peripheral blood myeloblast and promyelocyte counts of > 1.0 x 10(9)/l, they received additional DNR and BHAC on the same schedule. After achievement of a CR, patients received three courses of consolidation and six courses of maintenance/intensification chemotherapy. Of 196 evaluable patients, 173 (88%) achieved a CR: 59 of 62 (95%) treated with ATRA alone, 41 of 49 (84%) treated with ATRA plus later chemotherapy, 63 of 73 (86%) treated with ATRA plus initial chemotherapy, and 10 of 12 (83%) treated with ATRA plus both initial and later chemotherapy. The CR rate in AML-92 was significantly higher than that in AML-89, but not than that achieved in AML-87. In addition, the early mortality and relapse rates in AML-92 were significantly lower than those in AML-89, but were not than those in AML-87. At a median follow-up of 36 months the predicted 4-year event-free survival (EFS) rate for 196 evaluable patients and the 4-year disease-free survival (DFS) rate for the CR cases were 54% and 62%, respectively. There was a significant difference in DFS between AML-92 and AML-87 (P = 0.0418) but not between AML-92 and AML-89 (P = 0.0687). In contrast, significant differences in EFS between AML-92 and both AML-87 (P = 0.0129) and AML-89 (P = 0.005) were observed. These results suggest that non-cross-resistant therapy combined with ATRA and intensive chemotherapy for APL contributes synergistically to the significant improvement in EFS.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Japan; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Prospective Studies; Remission Induction; Treatment Outcome; Tretinoin

All-trans-retinoic acid induces complete remission in acute promyelocytic leukemia. However, it is not clear whether induction therapy with all-trans-retinoic acid is superior to chemotherapy alone or whether maintenance treatment with all-trans-retinoic acid improves outcome.. Three hundred forty-six patients with previously untreated acute promyelocytic leukemia were randomly assigned to receive all-trans-retinoic acid or daunorubicin plus cytarabine as induction treatment. Patients who had a complete remission received consolidation therapy consisting of one cycle of treatment identical to the induction chemotherapy, then high-dose cytarabine plus daunorubicin. Patients still in complete remission after two cycles of consolidation therapy were then randomly assigned to maintenance treatment with all-trans-retinoic acid or to observation.. Of the 174 patients treated with chemotherapy, 120 (69 percent) had a complete remission, as did 124 of the 172 (72 percent) given all-trans-retinoic acid (P=0.56). When both induction and maintenance treatments were taken into account, the estimated rates of disease-free survival at one, two, and three years were 77, 61, and 55 percent, respectively, for patients assigned to chemotherapy then all-trans-retinoic acid; 86, 75, and 75 percent for all-trans-retinoic acid then all-trans-retinoic acid; 75, 60, and 60 percent for all-trans-retinoic acid then observation; and 29, 18, and 18 percent for chemotherapy then observation. By intention-to-treat analysis, the rates of overall survival at one, two, and three years after entry into the study were 75, 57, and 50 percent, respectively, among patients assigned to chemotherapy, and 82, 72, and 67 percent among those assigned to all-trans-retinoic acid (P= 0.003).. All-trans-retinoic acid as induction or maintenance treatment improves disease-free and overall survival as compared with chemotherapy alone and should be included in the treatment of acute promyelocytic leukemia.

Topics: Adolescent; Adult; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Cytarabine; Daunorubicin; Disease-Free Survival; Female; Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Remission Induction; Survival Rate; Treatment Failure; Tretinoin

Between February 1992 and November 1996 we treated 30 newly diagnosed acute promyelocytic leukaemia (APL) patients either with oral all-trans-retinoic acid (ATRA) alone (45 mg m-2) or with a simultaneous combination of ATRA (45 mg m-2), daunorubicin (DNR, 50 mg/m-2 for 3 days) and cytosine arabinoside (ARA-C, 200 mg m-2 for 7 days). There were 15 patients in each group. Patients with a white blood cell count < 5 x 10(9)/l at diagnosis received only ATRA as an induction therapy. Patients with initial white blood cell count > 5 x 10(9)/l received a combination of ATRA, DNR and ARA-C as an induction therapy. Within the first 20 days of induction, there were two early deaths in the group of patients receiving only ATRA, and six early deaths in the group of patients treated with a combination of ATRA and chemotherapy. Ten out of 13 patients (76.9%) receiving ATRA only achieved complete remission (CR) whereas seven out of nine patients (77.8%) receiving ATRA with chemotherapy achieved CR. Initial median peripheral white blood cell counts were significantly lower in the group of patients treated with ATRA alone (2.3 x 10(9)/l) than in the group of patients receiving ATRA and chemotherapy (14.0 x 10(9)/l). Morphological evidence of differentiation was noted in all patients entering CR. Patients in both groups who achieved CR received one course of standard '3 + 7' chemotherapy (DNR 45 mg m-2, 1-3 days, ARA-C 200 mg m-2, 1-7 days) followed by two courses of standard '2 + 5' chemotherapy (DNR 50 mg m-2 1-2 days, ARA-C 200 mg m-2 1-5 days) as a consolidation therapy. Patients not achieving remission (three out of 13 in the ATRA group and two out of nine in ATRA+chemotherapy group) did not respond to salvage chemotherapy and all died within 3 months of diagnosis. Only one out of 10 patients (10%) in CR, treated with ATRA is in relapse after 18 months. In patients treated with ATRA alone two out of 10 (20%) survived 58 months following diagnosis whereas in the ATRA+chemotherapy group one out of seven has already survived their 58th month since diagnosis. Four out of eight patients with an early death died of retinoic acid syndrome. Other toxicities due to ATRA were minimal (cheilitis, xerosis, dermatitis, diarrhoea, liver damage or pseudotumor cerebri).

Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Female; Follow-Up Studies; Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Tretinoin

An intermittent and cyclic regimen with All-Trans Retinoic Acid (ATRA) and intensive chemotherapy was conducted due to pharmacokinetic studies on ATRA for acute promyelocytic leukemia (APL) in children. We have treated 17 children with APL using ATRA for remission induction followed by an intermittent schedule of ATRA plus intensive chemotherapy (APL-ATRA protocol). There were 10 males and 7 females. The median age was 9.0 years old. The median baseline white blood cell count was 12.1 x 10(3)/microliter, hemoglobin 7.8 g/dl, platelet 4.5 x 10(4) microliters at diagnosis. Sixteen patients showed t(15; 17) translocation. RT-PCR analysis was available in 15 patients and showed PML/RAR alpha rearrangement in all patients. Overall, 13 or 17 newly diagnosed patients (88%) achieved complete remission and EFS was 67%. Compared to the control (same chemotherapy without ATRA regimen), remission induction and EFS were significantly increased. The toxicity of ATRA consisted of retinoic acid syndrome in 1 and pseudotumor cerebli in another. Other toxicities included headache, chelitis, gastrointestinal trouble and bone pain. These results suggest that intermittent and cyclic regimen with ATRA and intensive chemotherapy (APL-ATRA protocol) is highly effective for APL patients.

Topics: Aclarubicin; Administration, Oral; Adolescent; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Child; Cyclophosphamide; Cytarabine; Daunorubicin; Doxorubicin; Drug Administration Schedule; Female; Humans; Leukemia, Promyelocytic, Acute; Male; Mercaptopurine; Prednisolone; Tretinoin; Vincristine

A clinical trial was conducted in order to evaluate the therapeutic effect and side effects of low-dose all-trans retinoic acid (ATRA) in the treatment of acute promyelocytic leukemia (APL). First of all, we compared the pharmacokinetic features in normal individuals with a single oral dose of ATRA at 15 mg/m2 and 45 mg/m2, respectively. The results showed that maximal plasma concentration with oral ATRA at 15 mg/m2 was high enough (10(-6) mol/L) to induce APL cell differentiation. Based on these results, 27 cases of de novo APL patients were treated with oral ATRA at a dose of 15-20 mg/m2/day and 24 of the 26 (92%) evaluable cases achieved clinical complete remission (CR) after 13 to 67 dyas of ATRA treatment. No patient experienced retinoic acid syndrome (RAS) and DIC. The Cmax with a single dose of ATRA on day 1 of treatment and immediately after obtaining of CR with ATRA in three cases demonstrated similar values in one patient and an about 2 fold decrease in two patients. Moreover comparison with a relatively well-matched previous group of 20 APL patients treated with high-dose ATRA showed that low-dose ATRA is as effective as high-dose in treating APL patients and may provide the advantages of decrease of the degree of hyperleukocytosis and side effects.

Topics: Adolescent; Adult; Aged; Female; Humans; Leukemia, Promyelocytic, Acute; Leukocyte Count; Male; Middle Aged; Remission Induction; Tretinoin

The response of acute promyelocytic leukemia (APL) peripheral blood and bone marrow cells to trans-retinoic acid (RA) was cytogenetically characterized during RA treatment using the techniques of premature chromosome condensation (PCC) and fluorescence in situ hybridization (FISH). Before treatment, the predominant immature bone marrow cells were found to have t(15;17), whereas the residual mature granulocytes were diploid and lacked evidence of the translocation. In response to RA treatment, an increase in the leukocyte count was noted. The majority of these cells exhibited a t(15;17). Subsequently (eg, between days 6 and 23), 32% to 91% of the maturing myeloid cells still exhibited t(15;17). The appearance of t(15;17) in gradually maturing elements suggests that RA contributed to a release of the maturation block of the leukemic elements. As responding patients obtained complete remission, diploid elements without evidence of the translocation prevailed in the blood and bone marrow. In 16 patients studied after 1 month in complete remission, all but 2 showed all diploid cells. The residual t(15;17) cells disappeared 18 days later in 1 patient, whereas the second patient exhibited clinical evidence of relapse 20 days later. These results suggest that response of patients with APL to RA is associated with maturation, subsequent loss of the mature leukemic elements, and preferential regeneration of normal diploid hematopoietic elements.

Topics: Adolescent; Adult; Aged; Animals; Blood Cells; Bone Marrow; Cell Differentiation; Child; Chromosomes, Human; Chromosomes, Human, Pair 15; Chromosomes, Human, Pair 17; Cricetinae; Cricetulus; Diploidy; Female; Humans; Hybrid Cells; Immunologic Factors; In Situ Hybridization, Fluorescence; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Neoplasm Proteins; Neoplasm, Residual; Neoplastic Stem Cells; Oncogene Proteins, Fusion; Remission Induction; Translocation, Genetic; Tretinoin

Topics: Cell Differentiation; Humans; Leukemia, Promyelocytic, Acute; Neoplasm Proteins; Nuclear Proteins; Promyelocytic Leukemia Protein; Prospective Studies; Receptors, Retinoic Acid; Retinoic Acid Receptor alpha; RNA, Neoplasm; Survival Analysis; Transcription Factors; Translocation, Genetic; Tretinoin; Tumor Suppressor Proteins

Ten patients with acute promyelocytic leukemia (APL) were treated with all-trans retinoic acid (ATRA). Eight of 10 patients achieved complete remission (CR), and among the 8 newly diagnosed cases, 7 achieved CR. Five of 8 CR cases remained in CR after 8 to 30 months. Except for hypotension and a large gastric ulcer resulting from hyperhistaminemia, the adverse effects of ATRA were generally mild. Severe thrombotic tendency occurred in a patient treated with ATRA combined with tranexamic acid. Intensive chemotherapy consisting of daunorubicin (DNR) and other agents was scheduled for the patients who achieved CR with ATRA.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Female; Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Remission Induction; Thromboembolism; Treatment Outcome; Tretinoin

A clinical trial was conducted in order to evaluate the therapeutic effect and side-effects of low-dose ATRA in the treatment of acute promyelocytic leukemia (APL). We compared the pharmacokinetic features in normal individuals with single oral ATRA at 15 mg/m2 and 45 mg/m2, respectively. The results showed that maximal plasma concentration (Cpmax) with oral 15 mg/m2 ATRA was high enough (10(-6) M) to induce APL cell differentiation. Based on these results, 27 cases of de novo APL patients were treated with continuous oral ATRA at the dose of 15-20 mg/m2/day and 24/26 evaluable cases (92%) achieved clinical CR after 13 to 67 days of ATRA treatment. No patient experienced RAS and DIC. The Cpmax with a single dose of ATRA on day 1 of treatment and immediately at CR obtained with continuous ATRA in three cases demonstrated similar values in one patient and an approximately two-fold decrease in two patients. More importantly, compared with a relatively well-matched historic group of 20 APL patients treated with high-dose ATRA, our results suggest that low-dose ATRA is as effective as high-dose in treating APL patients and may provide advantages through decreased hyperleukocytosis and other side-effects.

Topics: Administration, Oral; Adult; Female; Half-Life; Humans; Immunologic Factors; Leukemia, Promyelocytic, Acute; Leukocytosis; Male; Middle Aged; Remission Induction; Tretinoin

From March 1993 to October 1993, 20 consecutive, newly diagnosed acute promyelocytic leukemia (APL) patients from 13 Italian institutions entered in a pilot study named AIDA, combining all-trans retinoic acid (ATRA) with idarubicin (IDA). ATRA was administered orally beginning on the first day of induction at the dosage of 45 mg/m2/d until complete remission (CR), whereas IDA was administered intravenously at the dosage of 12 mg/m2/d on days 2, 4, 6, and 8 of the induction. Patients who achieved CR were consolidated with 3 courses of chemotherapy without ATRA; thereafter, they were followed up for molecular and hematologic CR. The median age was 35.3 years (range, 6.5 to 67.6 years); 8 patients were males and 12 females; 4 had the hypogranular variant of APL (M3v), and 4 (2 with M3v) presented with leukocyte counts > or = 10,000/microL. Molecular analysis for the promyelocytic leukemia-retinoic acid receptor alpha (PML-RAR alpha) hybrid gene at diagnosis was performed in 16 patients by means of reverse transcription-polymerase chain reaction (RT-PCR) analysis, and all were RT-PCR+ for the hybrid gene. In the remaining 4 patients, the cytogenetic study showed the presence of the t(15;17). After a median time of 36 days (range, 28 to 52 days) 18 (90%) patients achieved CR; the remaining 2 patients died 12 and 34 days after diagnosis from myocardial infarction caused by fungal myocarditis and from massive hemoptysis, respectively. ATRA syndrome was observed in only 2 patients, and, after the prompt discontinuation of ATRA and initiation of dexamethasone, both recovered from the syndrome. However, after recovering, 1 patient achieved CR, whereas the other died at day 34 because of massive hemoptysis; other side effects were very limited. At recovery from the third consolidation course, only 3 of 14 (21.4%) tested patients were RT-PCR+ for the PML-RAR alpha hybrid gene. Of these, 2 relapsed shortly afterwards; however, in the last patient, the PML-RAR alpha disappeared at successive testing performed 2 months later. As of September 30, 1995, after a median follow-up period from diagnosis of 27 months (range, 24 to 31 months), the overall survival and event-free survival durations are 85% and 69%, respectively; moreover, 14 of 18 (78%) patients who achieved CR are still alive and in first molecular and hematologic CR. Of the 4 relapsed patients, 3 achieved a second CR with ATRA and, after further treatment, are now in molecular and hematologic CR after 4+, 16+,

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Child; DNA, Neoplasm; Female; Humans; Idarubicin; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Neoplasm Proteins; Oncogene Proteins, Fusion; Oncogenes; Pilot Projects; RNA, Neoplasm; Survival Analysis; Translocation, Genetic; Tretinoin

All-trans retinoic acid (ATRA) is widely used as a differentiation-inducing agent for acute promyelocytic leukemia (APL). However, one of the problems with this therapy is the difficulty in evaluating the extent of differentiation of leukemic cells. To determine objective indices for differentiation which can be used for judging complete remission, we treated 18 patients with acute promyelocytic leukemia, and performed sequential analysis of bone marrow, karyotype, RAR alpha gene rearrangement and PML-RAR alpha fusion gene transcript. The karyotype, RAR alpha rearrangement and PML-RAR alpha transcript returned to a normal pattern on days 31, 2, 34.8 and 47.6, respectively. We defined and analyzed maturation index (MI) by bone marrow findings as follows; (metamylocyte + band neutrophil + segmented neutrophil) (%)/(myeloblast + promyelocyte + myelocyte) (%). MI increased along with the differentiation of leukemic cells, and the days for MI exceeding 2 well correlated with the normalization of karyotype. These results suggested that MI can be used as an index of differentiation during ATRA therapy.

Topics: Adolescent; Adult; Bone Marrow Cells; Cell Differentiation; Child; Female; Gene Rearrangement; Humans; Karyotyping; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Remission Induction; Tretinoin

We studied the quantitative changes in PML/retinoic acid receptor alpha (PML/RAR alpha) fusion mRNA using the reverse transcriptase-polymerase chain reaction (RT-PCR) and the in vitro differentiation of leukemic cells from eight acute promyelocytic leukemia (APL) patients during treatment with all-trans retinoic acid (ATRA). In three patients, the intensity of the chimeric PML/RAR alpha bands decreased rapidly after the start of ATRA therapy. However, these three patients required variable periods of time to obtain complete remission (CR) (24, 29 and 100 days). In the five other patients, the chimeric bands decreased slowly, and the time until CR also varied (22, 28, 30, 39 and 67 days). As for the in vitro assay, leukemic cells from the three patients who achieved CR in a short period of time (22, 28 and 30 days) showed marked differentiation in response to 1 mumol/L ATRA, and leukemic cells from the four patients with slow or delayed clinical responses to ATRA did not show morphological differentiation in vitro. These findings suggest that the clinical response of APL patients to ATRA is predicted from the results of the in vitro differentiation assay, but not by RT-PCR analysis of the PML/RAR alpha fusion mRNA.

Topics: Adolescent; Adult; Antineoplastic Agents; Base Sequence; Bone Marrow Cells; Cell Differentiation; Cells, Cultured; Female; Forecasting; Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Molecular Sequence Data; Polymerase Chain Reaction; Prognosis; Receptors, Retinoic Acid; RNA, Messenger; Tretinoin

Laboratory evidence of disseminated intravascular coagulation (DIC) and/or fibrinolysis is present in the majority of patients with acute promyelocytic leukemia (APL). Historically, early hemorrhagic death (EHD) occurred in 10% to 30% of patients treated with chemotherapy. All-trans retinoic acid (ATRA), a differentiating agent, has a CR rate above 80% in patients, with ATRA-associated leukocytosis. We studied thrombotic events in this population and compared it to patients treated with chemotherapy alone. The results of studies using ATRA in patients with APL were reviewed. Patients received ATRA 45-50 mg/m(2) orally in two divided doses daily until complete remission. In newly diagnosed patients, Idarubicin 12 mg/m(2)/day was given intravenously for 4 to 5 days beginning on the fifth day of ATRA therapy or when the white blood cell count (WBC) was over 10x 10(3)/mu l. Thrombotic complications were noted in 3 of 31 patients during induction. Two died from thrombotic events during therapy with multiple thromboses documented at autopsy. ATRA syndrome was suspected in 2 of the patients with thromboses and only 1 of the patients without thrombosis. In previous studies, 1 of 25 APL patients treated with chemotherapy alone had thrombotic events during therapy. In conclusion, treatment of APL with ATRA may decrease the incidence of hemorrhagic complications, but does not eliminate thrombosis. While thrombotic events were not significantly increased in patients treated with ATRA, they were more common in patients suspected of having ATRA syndrome.

Topics: Adult; Amsacrine; Antibiotics, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cerebral Hemorrhage; Cohort Studies; Cytarabine; Disseminated Intravascular Coagulation; Fatal Outcome; Female; Germinoma; Hemorrhage; Humans; Idarubicin; Incidence; Infarction; Leukemia, Promyelocytic, Acute; Leukocytosis; Male; Melanoma; Middle Aged; Myocardial Infarction; Neoplasms, Multiple Primary; Remission Induction; Retrospective Studies; Spleen; Thrombosis; Treatment Outcome; Tretinoin

Granulocyte colony-stimulating factor (G-CSF) enhances the differentiation of acute promyelocytic leukemia (APL) cells induced by all-trans retinoic acid (ATRA) in vitro. Accordingly, we initiated a pilot study on G-CSF in APL patients who developed neutropenia and severe infection during remission induction therapy with ATRA. Seven out of nine treated patients displayed a marked increase in granulocyte counts without leukemic regrowth, and two displayed a dramatic decrease in leukemic blasts. However, leukemic regrowth occurred in two patients under treatment for post-ATRA relapse. Our findings suggest that administration of G-CSF combined with ATRA can improve the hematological state in APL patients not previously receiving ATRA therapy.

Topics: Adult; Aged; Antineoplastic Agents; Drug Therapy, Combination; Female; Granulocyte Colony-Stimulating Factor; Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Remission Induction; Tretinoin

Acute promyelocytic leukemia is characterized by the reciprocal translocation of chromosomes 15 and 17. All-trans retinoic acid (ATRA) efficiently induces differentiation of the abnormal promyelocytes. In this study, we had used ATRA as the primary induction therapy for 17 newly diagnosed patients, and as the salvage therapy for 11 patients who relapsed from or were resistant to chemotherapy. All patients received subsequent consolidation chemotherapy. Complete remission (CR) rate, early death rate (within 28 days of diagnosis) were then compared to an historical control of 50 APL patients treated with combination chemotherapy; and event-free survival of the 17 newly diagnosed patients was compared to the historical control. In the ATRA group, 26 of the 28 patients (93 per cent) attained complete remission. Two of 28 (7 per cent) died within 28 days of ATRA therapy. There was no case of primary resistance to ATRA. Combination chemotherapy was added to ATRA in five patients due to rapidly increasing leucocyte count. There was one case of retinoic acid syndrome which resolved with steroid. When compared to the 50 cases of historical control, there is significant improvement in the overall CR rate (92 per cent versus 59 per cent, p = 0.001) and a significant reduction in the early mortality rate (7 per cent versus 41 per cent, p = 0.001). Moreover, when the survival result of the 17 newly diagnosed patients were compared with the control, there is a significant improvement in the projected EFS at 3 years (64 per cent versus 25 per cent, p = 0.007). In conclusion, ATRA was shown to improve the CR rate, reduce induction mortality and significantly prolong the event-free survival.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cohort Studies; Cytarabine; Daunorubicin; Disease-Free Survival; Female; Humans; Leukemia, Promyelocytic, Acute; Life Tables; Male; Middle Aged; Neoplasm Proteins; Oncogene Proteins, Fusion; Prospective Studies; Remission Induction; Salvage Therapy; Survival Analysis; Treatment Outcome; Tretinoin

From February 1992 to February 1995, 77 patients with APL were treated with ATRA in induction (59 patients de novo, 6 in first relapse, 1 with APL secondary to a mielodisplastic syndrome). The dose used was 45 mg/k/day-30 mg/k/day until complete remission (CR) was achieved; of the 66 evaluable patients, 50 achieved complete remission (78%). Among the 14 patients who did not attain CR, 13 died, 10 of bleeding episodes and 3 of retinoic syndrome; one was rescued with chemotherapy. We proposed consolidation treatment with high dose Ara-C and Idarubicin to the 49 patients in complete remission; 6 could not receive it and 5 died; the disease free survival period of the other patients was 81% (CI95 90%-66%) at one year and 74% (CI95 91%-52%) at two years. We consider that our results are similar to those of other groups and we are inclined to continue with this treatment protocol.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Argentina; Child; Female; Follow-Up Studies; Humans; Leukemia, Promyelocytic, Acute; Leukocytosis; Male; Middle Aged; Remission Induction; Tretinoin

We evaluated the effect of treatment by all-trans retinoic acid (ATRA) in 9 patients with acute promyelocytic leukemia (APL). Of 6 patients who had circulating leukemic blasts before treatment, 3 initially received ATRA alone but died of respiratory failure due to retinoic acid syndrome (RAS). High dose steroid therapy did not rescue RAS in these patients. Another 3 who were given intensive chemotherapy followed by ATRA and/or granulocyte colony-stimulating factor (G-CSF) achieved complete remission (CR). Of 3 patients without peripheral leukemic blasts before treatment, 1 received intensive chemotherapy followed by G-CSF and reached CR, 1 who had been previously given ATRA did not respond to ATRA, and 1 did not initially respond sufficiently to ATRA alone but responded dramatically to ATRA plus G-CSF. In the treatment of APL, appropriate combination of ATRA, G-CSF and chemotherapy should always be taken into consideration. In addition, RAS have to be carefully avoided when applying ATRA therapy in patients who have circulating leukemic blasts before treatment.

Topics: Adult; Aged; Drug Therapy, Combination; Female; Granulocyte Colony-Stimulating Factor; Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Recombinant Proteins; Tretinoin

Administration of all-trans-retinoic acid (ATRA) on a continuous daily schedule results in a rapid and sustained decrease in plasma drug concentrations. This pharmacokinetic study was performed to determine if administration of ATRA on an intermittent schedule could overcome the rapid decrease in plasma drug concentration and provide repetitive periods of higher plasma drug exposure.. ATRA was administered on repetitive cycles of 7 consecutive days of drug followed by 7 days without drug. On the days of pharmacokinetic monitoring, following an overnight fast, a fixed single oral dose of 40 mg/m2 was administered and frequent plasma samples were obtained over 8 hours. Patients had pharmacokinetic studies performed on the first and seventh days of the first week, and on the first day of the third and eleventh weeks. ATRA was measured in plasma with a reverse-phase high-performance liquid chromatography (HPLC) assay.. Plasma exposure to ATRA as measured by the area under the plasma concentration-time curve (AUC) decreased significantly during the first week of drug administration, from a mean of 145 +/- 26 mumol/L.min on day 1 to 18 +/- 4 mumol/L.min by day 7. Plasma ATRA concentrations at the start of weeks 3 and 11 of this every-other-week schedule were equivalent to those achieved on day 1 of treatment, with mean AUCs of 177 +/- 39 and 128 +/- 30 mumol/L.min, respectively.. An intermittent schedule of ATRA administration results in repetitive periods of exposure to concentrations of ATRA normally only observed on the first day of treatment. Phase II trials to evaluate the role of intermittent schedules of administration for ATRA are planned.

Topics: Acquired Immunodeficiency Syndrome; Adult; Chromatography, High Pressure Liquid; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Tolerance; Half-Life; Humans; Leukemia, Promyelocytic, Acute; Middle Aged; Remission Induction; Sarcoma, Kaposi; Tretinoin; Up-Regulation

Topics: Antineoplastic Combined Chemotherapy Protocols; Blood Coagulation Disorders; Bone Marrow Transplantation; Cell Differentiation; Drug Resistance; Humans; Leukemia, Promyelocytic, Acute; Neoplasm, Residual; Survival Analysis; Thrombosis; Tretinoin

9-cis retinoic acid (RA) is a high-affinity ligand for both retinoic acid receptors (RARs) and retinoid "X" receptors (RXRs). Although all-trans RA does not bind to RXRs, RAR/RXR heterodimers or RXR/RXR homodimers bind to specific DNA response elements and modulate proliferation and differentiation of normal and malignant cells. Because the development of clinical resistance to all-trans RA has been associated with a progressive decrease in plasma drug concentrations, we evaluated the ability of 9-cis RA to induce in vitro cytodifferentiation in subclones of a retinoid-sensitive and resistant APL cell line (NB4) and in short-term cultures of fresh leukemic cells aspirated from patients. We also evaluated the clinical activity and pharmacokinetics of 9-cis RA (LGD 1057) in patients with APL who were previously treated with all-trans RA. In vitro tests of both retinoid-sensitive NB4 cells, as well as samples of fresh cells from 11 patients with APL, showed relatively equivalent degrees of sensitivity to both 9-cis RA and all-trans RA at concentrations ranging from 10(-6) to 10(-8) mol/L; however, no substantial cytodifferentiation was observed using either drug alone or in combination (10(-6) mol/L of each) in retinoid-resistant NB4 cells. Seven patients with APL who had previously relapsed from a remission induced by all-trans RA were treated with 9-cis RA at daily oral doses ranging from 30 to 230 mg/m2. Pharmacokinetic studies showed that the mean terminal plasma half-life of 9-cis RA (1.3 hours) changed very little after several weeks of dosing, although the mean change per dose level in area under the plasma concentration x time curves and peak plasma concentrations showed a decrease by 49% and 45%, respectively. Peak plasma concentrations equaled or exceeded concentrations that were effective against retinoid-sensitive cells in vitro. Despite these favorable pharmacokinetic results, only one of the seven patients achieved complete remission, corroborating in vitro studies of blasts from three of the nonresponders that showed a relatively equivalent degree of resistance to both retinoids. Our results suggest that while 9-cis RA may not induce its own catabolism to the same degree as all-trans RA, this feature does not appear to overcome clinically acquired resistance to all-trans RA in APL. Nonetheless, the drug can induce complete remissions in patients with APL and may be useful for extended therapy in other diseases. Future studies should address th

Topics: Administration, Oral; Adult; Aged; Biomarkers, Tumor; Cell Differentiation; Cell Division; Drug Resistance; Drug Screening Assays, Antitumor; Female; Half-Life; Humans; Immunologic Factors; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Neoplasm Proteins; Oncogene Proteins, Fusion; Recombinant Fusion Proteins; Remission Induction; Retinoids; Salvage Therapy; Treatment Outcome; Tretinoin; Tumor Cells, Cultured

All-trans retinoic acid (ATRA) induces complete remission (CR) in most cases of acute promyelocytic leukemia (APL) but its use is associated with potentially fatal pulmonary toxicity in approximately 25% of APL patients in the setting of a rapidly rising peripheral blood white cell count (WBC). The efficacy of oral corticosteroid for prophylaxis against pulmonary toxicity has been investigated in a prospective multi-center study. ATRA was administered at 45 mg/m2/day as single agent therapy throughout induction treatment in 19 patients with an initial WBC < 10 x 10(9)/l, and prednisolone 75 mg/day was added in those 12 patients in whom the WBC rose above 10 x 10(9)/l. Combination chemotherapy plus prednisolone was added to ATRA in six other patients on the basis of criteria specified in the protocol. All 19 patients who received ATRA without chemotherapy achieved CR without signs of pulmonary toxicity despite a rise in WBC to peak values as high as 112 x 10(9)/l. Pulmonary toxicity developed in two patients commenced on ATRA in association with an unusually rapid increment in WBC of 7.5 x 10(9)/l and 32.5 x 10(9)/l in the first 2 days; both were subsequently treated with chemotherapy. The low incidence of pulmonary toxicity in this study compared with that in previous trials suggests that prednisolone prophylaxis increases safety of ATRA therapy in APL irrespective of the peak WBC.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Drug Interactions; Humans; Leukemia, Promyelocytic, Acute; Leukocyte Count; Lung Diseases; Middle Aged; Prednisolone; Prospective Studies; Remission Induction; Tretinoin

Since all-trans retinoic acid (ATRA) induces complete remission in a high proportion of patients with acute promyelocytic leukemia (APL), and its effectiveness appears to be related to the plasma or serum level, a pharmacokinetic study of ATRA was undertaken in nine patients with various leukemias. After oral administration at a dose of 30 mg/m2, the time required to reach the peak plasma level of ATRA (20-1198 ng/ml) was between 120 and 240 min and the apparent plasma elimination half life was 21-51 min. In addition, 13-cis retinoic acid was detected in the plasma of seven patients, indicating the occurrence of ATRA isomerization in vivo. ATRA therapy did not induce complete remission in all patients, even when high plasma levels were achieved. Among the six APL patients given ATRA therapy, one who failed to respond had a very low plasma ATRA level. These findings suggest that it may be useful to monitor plasma levels during oral ATRA therapy in order to achieve an appropriate treatment regimen.

Topics: Adolescent; Child; Child, Preschool; Dose-Response Relationship, Drug; Female; Humans; Leukemia, Promyelocytic, Acute; Male; Myelodysplastic Syndromes; Tretinoin

All transretinoic acid (ATRA) gives complete remission (CR) rates of 80 to 90% in newly diagnosed acute promyelocytic leukemia (APL). However, it has two major drawbacks (1) a rapid rise in WBC in some patients, with potentially fatal ATRA syndrome (2) rapid relapse with maintenance therapy using ATRA alone or low dose chemotherapy. The French APL group therefore designed a treatment approach with ATRA followed by intensive chemotherapy. The latter was administered after CR achievement with ATRA, or was rapidly added to ATRA in case of rapid rise in leukocyte counts. This combined approach, in a pilot study and in a randomized trial, proved superior to intensive chemotherapy alone, by slightly increasing the CR rate but more importantly by reducing the relapse rate. These results were confirmed by the Chinese, Japanese and New York groups. Our group (and other European groups) are now testing in a new randomized trial the better timing of ATRA and chemotherapy administration (ATRA followed by chemotherapy or ATRA plus chemotherapy) and the role (after an intensive consolidation) of maintenance treatment with intermittent ATRA, continuous low dose chemotherapy or both.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Cell Differentiation; China; Combined Modality Therapy; Cytarabine; Daunorubicin; Disease-Free Survival; Etoposide; Europe; Humans; Immunologic Factors; Leukemia, Promyelocytic, Acute; Leukocytosis; Life Tables; Middle Aged; Mitoxantrone; New York; Pilot Projects; Remission Induction; Survival Rate; Treatment Outcome; Tretinoin

Chemotherapy may decrease relapses of acute promyelocytic leukemia (APL) following induction with all-trans retinoic acid (ATRA), however the optimal timing of these two modalities remains to be determined. We treated eight patients with morphologic evidence of APL with intensive induction chemotherapy followed by ATRA (45 mg/m2/d for 10 weeks). All eight patients achieved a complete remission following chemotherapy. After a median follow-up of 29.0 months, seven patients remain in complete remission; one patient relapsed at 26.9 months. RT-PCR analysis for the PML/RAR alpha rearrangement was performed to monitor patients for evidence of minimal residual disease. Both of the patients with persistence of this rearrangement after induction chemotherapy converted to negative following ATRA. Toxicity of ATRA given in the post-remission setting was mild and consisted of headache, dry skin, and elevations of triglycerides and transaminases. No patient developed evidence of the retinoic acid syndrome. The administration of ATRA after intensive induction chemotherapy is associated with durable remissions and minimal toxicity in patients with APL. Disappearance of the PML/RAR alpha rearrangement after ATRA suggests that ATRA is effective against minimal residual disease.

Topics: Adult; Female; Humans; Leukemia, Promyelocytic, Acute; Male; Pilot Projects; Polymerase Chain Reaction; Survival Rate; Translocation, Genetic; Tretinoin

We conducted a multicenter trial of treatment with all-trans retinoic acid (ATRA) for newly diagnosed acute promyelocytic leukemia (APL) in the AML-92 study and compared it with our previous study with standard intensive chemotherapy, the AML-89 study, in the view of complete remission (CR) rate, incidence of early death, and event-free survival (EFS). Patients were scheduled to receive oral ATRA 45 mg/m2 daily until CR. If patients had leukocyte counts above 3 x 10(9)/L at the start of therapy, they received daunorubicine (DNR) 40 mg/m2 for 3 days and behenoyl cytosine arabinoside (BHAC) 200 mg/m2 for 5 days in addition to ATRA. During the ATRA therapy, if patients showed myeloblast plus promyelocyte counts higher than 1 x 10(9)/L in the peripheral blood, they received additional DNR and BHAC in the same schedule, as well. A total of 110 patients were entered into the study. Median age was 43 years (range, 16 to 74). Twenty-eight (26%) of 109 patients (one died before the start of therapy) received ATRA alone. Ninety-seven patients (89%) achieved CR; 48 of 49 (98%) aged less than 40 years, 44 of 52 (84%) aged between 40 and 69, and 5 of 8 (63%) aged above 70 achieved CR, respectively; 25 of 28 (89%) with ATRA alone, 46 of 51 (90%) with ATRA plus initial chemotherapy and 26 of 30 (87%) with ATRA plus later chemotherapy attained CR, respectively. Nine (8%) patients died within 28 days after the start of therapy. In contrast, 44 of 62 patients (71%) attained CR, and 13 (21%) died within 28 days in the AML-89 study with the combination of DNR, BHAC, 6-mercaptopurine and prednisolone. Seven developed retinoic acid syndrome and one died of it in the present study. Other toxicities associated with this drug included cheilitis, desquamation, muscle pain, and hypertriglyceridemia. Predicted 23 months EFS for all ATRA-treated patients and disease-free survival (DFS) in the CR cases were 75% and 81%, respectively, in a median follow-up period of 21 months. Compared to the AML-89 study, there was a highly significant difference in remission rate (P = .004), EFS (P = .0007), and also early mortality rate (P = .02). Present results demonstrated that ATRA with or without chemotherapy gives a statistical improvement in CR rate and early mortality rate, as well as superior survival in newly diagnosed APL.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Cytarabine; Daunorubicin; Female; Humans; Immunologic Factors; Japan; Leukemia, Promyelocytic, Acute; Leukocytosis; Life Tables; Male; Mercaptopurine; Middle Aged; Prednisolone; Prospective Studies; Remission Induction; Syndrome; Treatment Outcome; Tretinoin

Topics: Disseminated Intravascular Coagulation; Enoxaparin; Heparin, Low-Molecular-Weight; Humans; Leukemia, Promyelocytic, Acute; Tretinoin

It has been shown in vitro that retinoids and especially all-trans retinoic acid (ATRA) were able to induce maturation of malignant cells from patients with acute promyelocytic leukemia (APL). Clinical studies have confirmed in vitro observations. Oral administration of ATRA is able to induce complete remissions in the majority of APL patients, either treated de novo or after failure of conventional chemotherapy. Complete remission are observed by a differentiation process and ATRA therapy in APL represents the first model of differentiation therapy. The major adverse effect of ATRA treatment is the occurrence in some cases of a "retinoic acid syndrome" associated with rapidly, progressive rise of leukocytes. This syndrome is corrected by the addition of chemotherapy. A progressive acquired resistance appears during ATRA treatment and for this reason post remission chemotherapy is indispensable. The superiority of the combination of ATRA+chemotherapy over chemotherapy alone for the incidence of relapse and for survival duration has been established in a randomized European trail (APL 91).

Topics: Female; Humans; Keratolytic Agents; Leukemia, Promyelocytic, Acute; Male; Remission Induction; Tretinoin

Acute promyelocytic leukemia (APL) is a rare subtype of acute myelogenous leukemia that is usually associated with a fatal hemorrhagic diathesis. All trans-retinoic acid (ATRA) is an active metabolite of vitamin A that differentiates the malignant cell clone, corrects the coagulopathy, and induces complete remission in the vast majority of patients with APL. Between June 1992 and September 1993, 8 patients with APL (4 previously untreated, 3 in first relapse and 1 in second relapse) received ATRA. Complete remission was achieved in 7 patients; in 5 with ATRA alone and in 2 with ATRA followed by cytotoxic chemotherapy due to the development of asymptomatic hyperleukocytosis. The earliest signs of response were the correction of the coagulopathy and an increase in the white blood cell count. Sequential morphological and immunophenotypical analyses of the bone marrow revealed differentiation of the malignant cell clone, in the absence of bone marrow hypoplasia. 4 of 5 patients treated only with ATRA until complete remission had late leukopenia. The most frequent adverse effects were dryness of skin and mucosae, hypertrigliceridemia and hypercholesterolemia, and a moderate increase in liver transaminases. An increase in the white blood cell count was common, and in two cases exceeded 35.0 x 10(9)/l. One of these patients developed multiple thrombosis of the extremities after cytotoxic chemotherapy. We frequently observed an increase in lactic dehydrogenase levels that was concomitant with the peak in the white blood cell count. The only patient on whom complete remission was not achieved was 60 years old, had chronic obstructive pulmonary disease, and died in the third week of therapy with a pulmonary distress syndrome.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adolescent; Adult; Female; Follow-Up Studies; Humans; Immunophenotyping; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Remission Induction; Tretinoin

To assess the results attained with all-trans-retinoic acid (ATRA) in a group of Cuban patients with acute promyelocytic leukaemia (PML).. Twenty-one patients with PML were studied. Their cytogenetic study was performed with G-band techniques. ATRA was given orally as a single dosis of 50 mg/m2 a day, or divided in two doses. After attaining complete remission (CR), ATRA was maintained for 1-3 months in association with minimal doses of Ara-C or alpha-interferon. A rotation of three therapeutic regimes (TRAP, POMP and DOAP) was subsequently administered.. Twelve of the patients were women and 9 men; 15 were adults and 6 were children, the median age being 19 years (range: 6-60 years). Only two patients had leucocytosis, all others presented with leucopenia. Platelet count below 30 x 10(10)/L was found in 67% of the cases, while some sort of bleeding was present in 81% of them. Laboratory evidence of disseminated intravascular coagulation was seen in 52% of the cases, and t (15; 17) appeared in 67% of the evaluable cytogenetic studies. CR was attained in 17 patients (81%) within a mean of 40 days. Headache was the commonest untoward effect of the treatment. Eight patients developed leucocytosis during treatment, white-cell count being over 20 x 10(9)/L in six of them. Fever without infectious signs was present in 5 patients, and in 3 of them the temperature recovered with steroid therapy. Two patients had retinoic acid syndrome prior to achieving CR. Four patients relapsed and 13 (76%) have maintained CR after 1 to 24 months.. The incidence of CR in this series is within the limits reported in the literature. The secondary effects of the treatment are the same than those reported by others, and they were transient and well tolerated. The response to steroids of those patients with fever secondary to ATRA is noteworthy. The efficacy of ATRA, in general terms, in the induction of CR in PML seems confirmed by these results.

Topics: Adolescent; Adult; Child; Cuba; Female; Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Remission Induction; Tretinoin

We have conducted four prospective multicenter studies for acute promyelocytic leukemia (APL) using oral 45 mg/m2 all-trans retinoic acid (ATRA) daily. The first three studies were for relapsed/refractory APL, and the fourth study for newly diagnosed APL. In the first study with ATRA alone, 18 (82%) of 22 evaluable patients achieved complete remission (CR). Initial peripheral leukemia cell counts were significantly less in the CR cases (p < 0.01); < 100/microliters in 17 of 18 CR cases, and > or = 200/microliters in all failure cases. In the second study, if initial leukemia cell counts were more than 200/microliters, chemotherapy with daunorubicin and behenoyl cytarabine was first given, and then ATRA was started. Of 42 evaluable patients, 36 (86%) achieved CR. In the third study, if initial leukemia cell counts were more than 200/microliters, chemotherapy was concomitantly given with ATRA, and if during the ATRA therapy leukemia cell counts became more than 1000/microliters, chemotherapy was added. Of 46 evaluable patients, 36 (78%) achieved CR. Patients achieving CR received standard consolidation and maintenance chemotherapy, and the 29-month predicted disease-free survival (DFS) rate is 72% for 41 cases achieving their first CR with ATRA, and 20% for 49 cases achieving their second CR with ATRA. In the fourth study for newly diagnosed APL, if leukocyte counts were more than 3000/microliters, chemotherapy was concomitantly given with ATRA, and if during the ATRA therapy leukemia cell counts became more than 1000/microliters, chemotherapy was added. Of 109 evaluable patients, 97 (89%) achieved CR, and the 19-month predicted event-free survival rate for all patients is 78%, and the DFS rate is 88% for 97 cases achieving CR. ATRA produces a high CR rate in both relapsed/refractory and newly diagnosed APL, and should be incorporated in the first-line therapy of this disease.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Child; Disease-Free Survival; Drug Administration Schedule; Female; Humans; Japan; Leukemia, Promyelocytic, Acute; Leukocyte Count; Male; Middle Aged; Prospective Studies; Recurrence; Treatment Outcome; Tretinoin

Initial results of ATRA in newly diagnosed APL showed that this drug was associated with a high complete remission (CR) rate but also (i) to a risk of hyperleukocytosis and of ATRA syndrome, (ii) to rapid relapse unless ATRA was followed by intensive chemotherapy. These findings prompted our group to design an approach combining ATRA and intensive chemotherapy in newly diagnosed APL, where chemotherapy could prevent relapses and also, in cases with increasing leukocyte counts, could prevent the ATRA syndrome. In a pilot study, this approach gave a high CR rate (96%) and (with now prolonged follow-up) a significant reduction in the incidence of relapse, as compared to a historical control treated with chemotherapy alone. The superiority of the combination of ATRA and chemotherapy over chemotherapy alone (especially for the incidence of relapse) was subsequently confirmed in a randomized European trial (APL 91 trial). We are now testing in a new European trial (APL 93 trial) whether chemotherapy should be administered with ATRA, or should follow ATRA during induction treatment, and whether maintenance therapy with intermittent ATRA, low-dose chemotherapy, or both can further reduce the risk of relapse.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Disease-Free Survival; Drug Administration Schedule; Europe; Humans; Leukemia, Promyelocytic, Acute; Leukocyte Count; Mercaptopurine; Methotrexate; Recurrence; Remission Induction; Treatment Outcome; Tretinoin

All-trans retinoic acid (ATRA) in acute promyelocytic leukemia (APL) represents the leading example of targetted drugs for inducing an in vivo differentiation of malignancy (1,2). A fixed dose of 45 mg/m2/day was proposed for the treatment of patients (3), according to the results obtained by retinoic acid derivatives in skin diseases. We report that 25 mg (4), and even 15 mg/m2/day are still effective dosages. Absence of drug resistance, rapid correction of fibrinogenopenia and the absence of hypoplasia are the apparent major advantages and consequently high frequency of early mortality generally reported during chemotherapy is expected to be reduced. In fact the same risk of early death (10%) is recorded in all available data (5), due to coagulation disorders and to a leukocyte activation syndrome. Management of these side-effects is based on the prevention and treatment of the irreversible state as soon as first symptoms appear. Actually the major advantage of ATRA treatment in addition to chemotherapy is the decrease of relapse rate (6), the increase of event-free survival, and thus the increase of survival.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Blood Coagulation Disorders; Child; Disease-Free Survival; Female; Humans; Leukemia, Promyelocytic, Acute; Leukocyte Count; Male; Middle Aged; Recurrence; Remission Induction; Treatment Outcome; Tretinoin

In an ongoing study, we treated 79 patients with a molecular diagnosis of acute promyelocytic leukemia (APL) using all-trans retinoic acid (RA) for remission induction. Newly diagnosed patients received cytotoxic chemotherapy for consolidation, and previously treated patients received extended all-trans RA therapy, or a radionuclide-conjugated monoclonal antibody as post-remission treatment. Unlike studies in Europe, full-dose chemotherapy was not given during induction for patients who developed leukocytosis. Overall, 43 of 49 newly diagnosed patients (88%) and 25 of 30 previously treated patients (83%) achieved complete remission. We did not encounter de novo resistance to all-trans RA in any patient who was positive for PML/RAR-alpha rearrangements by reverse transcription polymerase chain reaction analysis. Ten patients died during induction from intracranial or pulmonary hemorrhage (six patients) or the 'retinoic acid syndrome' (four patients). The use of leukapheresis or low-dose chemotherapy (hydroxyurea or cytosine arabinoside) for drug-induced leukocytosis did not decrease early mortality. Compared to historical controls, early mortality was not affected by treatment with all-trans RA; however, both relapse-free and overall survival were significantly increased. Maintenance therapy with all-trans RA was associated with short remission duration, and relapses while taking the drug were universally associated with resistance to further retinoid treatment. We conclude that the use of all-trans RA for remission induction, with or without full-dose chemotherapy, has significantly increased the survival of patients with APL. While early mortality has not yet been reduced, the avoidance of full-dose chemotherapy during induction has significantly reduced early morbidity. The major outstanding clinical issue is the development of strategies that maximize safety in high-risk patients for whom intracranial hemorrhage remains the major cause of death.

Topics: Antineoplastic Combined Chemotherapy Protocols; Humans; Leukemia, Promyelocytic, Acute; Recurrence; Remission Induction; Survival Analysis; Tretinoin

All-trans retinoic acid (ATRA) is very effective in newly diagnosed acute promyelocytic leukemia (APL), yielding remission (CR) rates of 80 to 90%. However, it is associated with a rapid rise in WBC in some patients, with potentially fatal ATRA syndrome. Furthermore, most patients relapse with maintenance therapy using ATRA alone or low-dose chemotherapy. The French APL group thus designed a treatment approach with ATRA followed by intensive chemotherapy. The latter was administered after CR achievement with ATRA, or was rapidly added to ATRA in the case of rapid rise in leukocyte counts. This combined approach, in a pilot study and in a randomized trial, proved superior to intensive chemotherapy alone, by slightly increasing the CR rate but more importantly by reducing the relapse rate. The French group (and other European groups) are now testing in a new randomized trial the better timing of ATRA and chemotherapy administration (ATRA followed by chemotherapy or ATRA plus chemotherapy), and the role (after an intensive consolidation) of maintenance treatment with intermittent ATRA, continuous low-dose chemotherapy, or both.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Humans; Leukemia, Promyelocytic, Acute; Tretinoin

Thall and Simon propose a Bayesian approach to phase II clinical trials with binary outcomes and continuous monitoring. The efficacy theta E of an experimental treatment E is evaluated relative to that of a standard treatment S based on data from an uncontrolled trial of E, an informative prior for theta S, and a noninformative prior for theta E. The trial continues until E is shown with high posterior probability to be either promising or not promising, or until a predetermined maximum sample size is reached. Operating characteristics are evaluated under fixed values of the success probability of E. In this paper, we propose two extensions of this decision structure, describe sample size and monitoring criteria, and provide numerical guidelines for implementation. The first extension gives criteria from early termination of trials unlikely to yield conclusive results, based on the marginal (predictive) distribution of the observed success rate. The second extension allows early termination only if E is found to be not promising compared to S. Operating characteristics of each of these designs are evaluated numerically over a range of design parameterizations. We also examine the effects of intermittent monitoring on the design's properties. An application of this approach to a leukemia biochemotherapy trial is described.

Topics: Antineoplastic Agents; Bayes Theorem; Drug Therapy; Humans; Idarubicin; Leukemia, Promyelocytic, Acute; Research Design; Tretinoin; Vidarabine

All-trans retinoic acid (ATRA) is currently being used as remission induction treatment for acute promyelocytic leukemia (APL). Conventional chemotherapy is added both during and after ATRA treatment, in order to avoid the occurrence of hyperleukocytosis, and to improve the duration of complete remission. In this study we analysed the hematopoietic recovery of 18 consecutive APL patients after standard Idarubicin or Daunorubicin +/- Cytosine-Arabinoside regimens. 9 of the patients were at the onset of the disease, (CHT group) while 9 had been pre-treated with ATRA 45 mg/sqm/day for at least 3 months (ATRA group). 500 PMN/mmc were reached after 20.8 day from the end of treatment in CHT group and after 12.0 days in ATRA group (p = 0.007). Platelets recovery was faster, even though not significantly in ATRA group. Interestingly, PMN recovery in ATRA group was even shorter (p = 0.004) than that obtained in CHT group, after the first course of chemotherapy (treatment in CR vs treatment in CR). If these results are confirmed in a larger study, a protective effect of ATRA on normal residual hemopoiesis should be postulated.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Female; Hematopoiesis; Humans; Idarubicin; Immunologic Factors; Leukemia, Promyelocytic, Acute; Leukocyte Count; Leukocytosis; Male; Middle Aged; Neutrophils; Platelet Count; Premedication; Remission Induction; Salvage Therapy; Treatment Outcome; Tretinoin

Topics: Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Humans; Leukemia, Promyelocytic, Acute; Tretinoin

Efficacy and safety of tretinoin (all-trans retinoic acid, ATRA, Ro01-5488) for refractory and relapsed acute promyelocytic leukemia were studied by multi-institutional study in Japan. 22 out of 27 (81.5%) patients with previously untreated who were intolerable to chemotherapy, relapsed and refractory were achieved CR. And 4 out of 11 (36.4%) in relapsed patients who received ATRA remission induction therapy previously responded. Side effects, such as dryness of the lip and skin, headache, increase of triglyceride, beta-lipoprotein and lactate dehydrogenase, were observed in 36 of 41 eligible patients (87.8%) but these were well tolerated. In addition to these, hyperleukocytosis in 4 cases and retinoic acid syndrome in 3 cases were observed. However, all patients were prescribed tretinoin again by adequate management.

Topics: Administration, Oral; Adolescent; Adult; Aged; Capsules; Cell Differentiation; Female; Humans; Leukemia, Promyelocytic, Acute; Lipids; Male; Middle Aged; Remission Induction; Tretinoin

All-trans retinoic acid (ATRA) is effective in the treatment of relapsed or refractory acute promyelocytic leukemia (APL), but relapse is the rule if response is unmaintained.. Seventeen patients with APL were salvaged with ATRA at a dosage of 50 mg/m2/day for 3 months or until complete remission (CR) was achieved; idarubicin (12 mg/m2/day for 4 days) was added if blast plus promyelocyte count either was or reached > or = 10 x 10(3)/microliters. After CR was achieved, patients received three courses of idarubicin (12 mg/m2 daily for 3 days) followed by three courses of mitoxantrone (5 mg/m2 daily for 3 days) and etoposide (250 mg/m2 daily for 3 days). Maintenance was with 6-mercaptopurine and methotrexate.. A CR was achieved in 14 patients (82%), the disease was refractory in 2 patients, and one patient died during induction. Three patients underwent allogeneic bone marrow transplant during CR. After a median follow-up of 26 weeks, six patients remain in CR. Median CR duration is 40 weeks (range 8-56+). Patients treated with ATRA plus chemotherapy in first salvage, when compared to a historic control group treated with chemotherapy alone, had a significantly better CR rate (87% vs. 57%; P = 0.04) and a lower induction death rate (7% vs. 29%; P = 0.08), resulting in longer median survival (26 vs. 17 weeks; P = 0.13). Four patients developed the "retinoic acid syndrome", which was fatal in one case. Three patients developed thrombotic events.. ATRA followed by chemotherapy is effective treatment for patients with APL who relapse after conventional therapy, and it may be superior to chemotherapy alone.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Drug Administration Schedule; Etoposide; Female; Humans; Idarubicin; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Mitoxantrone; Remission Induction; Salvage Therapy; Tretinoin

In an ongoing study, we treated 79 patients with a molecular diagnosis of acute promyelocytic leukemia (APL) using all-trans retinoic acid (RA) for remission induction. Newly diagnosed patients received cytotoxic chemotherapy for consolidation, and previously treated patients received extended all-trans RA therapy, or a radionuclide-conjugated monoclonal antibody as post-remission treatment. Unlike studies in Europe, full-dose chemotherapy was not given during induction for patients who developed leukocytosis. Overall, 43 of 49 newly diagnosed patients (88%) and 25 of 30 previously treated patients (83%) achieved complete remission. We did not encounter de novo resistance to all-trans RA in any patient who was positive for PML/RAR-alpha rearrangements by reverse transcription polymerase chain reaction analysis. Ten patients died during induction from intracranial or pulmonary hemorrhage (six patients) or the 'retinoic acid syndrome' (four patients). The use of leukapheresis or low-dose chemotherapy (hydroxyurea or cytosine arabinoside) for drug-induced leukocytosis did not decrease early mortality. Compared to historical controls, early mortality was not affected by treatment with all-trans RA; however, both relapse-free and overall survival were significantly increased. Maintenance therapy with all-trans RA was associated with short remission duration, and relapses while taking the drug were universally associated with resistance to further retinoid treatment. We conclude that the use of all-trans RA for remission induction, with or without full-dose chemotherapy, has significantly increased the survival of patients with APL. While early mortality has not yet been reduced, the avoidance of full-dose chemotherapy during induction has significantly reduced early morbidity. The major outstanding clinical issue is the development of strategies that maximize safety in high-risk patients for whom intracranial hemorrhage remains the major cause of death.

Topics: Antigens, Surface; Humans; Leukemia, Promyelocytic, Acute; Receptors, Retinoic Acid; Remission Induction; Transcription Factors; Transcription, Genetic; Tretinoin

With the recent pressure to control health care expenditures, the costs of patient participation in clinical trials, especially in their earliest phases, have come under increasingly intense scrutiny. We therefore reviewed our experience in patients with acute promyelocytic leukemia (APL) who were treated during the first US trial of a new experimental drug, all-trans retinoic acid (RA). The purpose of the review was to evaluate parameters of patient morbidity and financial cost associated with the use of all-trans RA compared with standard chemotherapy for induction of complete remission in newly-diagnosed patients with APL. We retrospectively compared outcomes of consecutive patients treated during the first 2 years of our studies that used all-trans RA for remission induction (1990-1992) with an identical number of patients consecutively treated with standard chemotherapy (cytosine arabinoside plus an anthracycline) during the immediately preceding period (1985-1990). Responding patients in both groups received post-remission chemotherapy. Evaluation parameters included transfusions of packed red blood cells and platelets, use of anti-bacterial and anti-fungal drugs, duration of fever, time to remission, length of hospital stay, hospital charges, and both overall and relapse-free survival. Thirty patients were evaluated in each group. Complete remission was achieved in 26 patients (87%) treated with all-trans RA, and 24 patients (77%) treated with chemotherapy (p = 0.5). In the chemotherapy group, there were five early deaths (four from hemorrhage, one from sepsis); one other patient was resistant to treatment and died at 6 months. Four patients in the all-trans RA group died prior to response from complications of the 'retinoic acid syndrome'. The median time to complete response by all criteria was 41 days (range, 18-78) for the all-trans RA group and 50 days (range, 24-121) for patients who received conventional chemotherapy (p = 0.2). Looking only at patients who achieved remission, chemotherapy-treated patients required a significantly greater number of platelet transfusions (medians, 14 vs. 4; p < 0.001) and packed red blood cell transfusions (15 vs. 4; p < 0.001). Patients who received chemotherapy also experienced a significantly larger number of days with fever (13 vs. 6; p = 0.01) that was reflected in a greater median number of days on combination antibiotics (35 vs. 21; p = 0.001) and Amphotericin B (20 vs. 0; p < 0.001).(ABSTRACT TRUNCATED

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cohort Studies; Cytarabine; Daunorubicin; Drug Therapy; Female; Humans; Idarubicin; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Remission Induction; Time Factors; Tretinoin

The reverse transcriptase-polymerase chain reaction (RT-PCR) for the fusion transcript of PML-RAR alpha can be used to detect minimal residual disease (MRD) in acute promyelocytic leukemia (APL). We have applied a semi-quantitative two-step PCR assay (sensitivity: step 1 = 1 in 10(3) cells; step 2 = 1 in 10(6) cells) to monitor the dynamics of MRD after combined therapy with all-trans-retinoic acid (ATRA) and chemotherapy (CT) in 5 patients in whom complete clinical remission (CR) was achieved. The patients received an induction treatment with ATRA for 47, 40, 38, 14 or 10 days. In three patients ATRA was followed by CT. Two patients with hyperleukocytosis at diagnosis or after ATRA received an overlapping CT starting from day 3 or 7. Four of the five patients became two-step PCR-negative in their bone marrow within 43 to 82 days after onset of therapy. Two-step PCR-negatively was achieved with ATRA plus one course of CT in these four patients who are still in continuous complete remission after 19, 18, 7 and 5 months. One of these patients did not even receive consolidation CT because of congestive heart failure. The fifth patient remained second-step PCR-positive and relapsed after 5 months. Our results indicate that the combined regimen can rapidly reduce MRD below a detection limit of 1 in 10(6) cells within 1-3 months and that these results can even by achieved by a short course of ATRA together with only one cycle of CT.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Base Sequence; Chromosomes, Human, Pair 15; Cytarabine; Daunorubicin; Humans; Leukemia, Promyelocytic, Acute; Molecular Sequence Data; Pilot Projects; Polymerase Chain Reaction; Receptors, Retinoic Acid; Retinoic Acid Receptor alpha; Sensitivity and Specificity; Tretinoin

To evaluate the safety and efficacy of all-trans retinoic acid to induce complete remission and to examine its effects on duration of remission and survival in patients with acute promyelocytic leukemia.. Phase II evaluation and comparison with historical control patients.. Tertiary care cancer referral center.. Consecutive patients with morphologic diagnoses of acute promyelocytic leukemia were treated during a 2-year period with all-trans retinoic acid (daily oral dose, 45 mg/m2). Newly diagnosed patients discontinued the drug approximately 30 days after they achieved complete remission, at which time they received three courses of combination chemotherapy. Patients treated with previous cytotoxic chemotherapy who then relapsed were continued on all-trans retinoic acid as "maintenance" therapy until they relapsed again.. 56 patients entered the study: 34 were newly diagnosed and 22 had relapsed from previous treatment. Fifty-one patients subsequently were found to have the PML/RAR-alpha gene rearrangement indicative of acute promyelocytic leukemia, and 44 of these patients achieved complete remission (86%; 95% Cl, 76% to 96%). A distinctive respiratory distress syndrome developed in 13 patients (23%) during treatment, and 5 patients (9%; Cl, 3% to 20%) died of this complication. The 5 patients who lacked PML/RAR-alpha rearrangements were withdrawn and given chemotherapy. The 13 patients given all-trans retinoic acid alone as maintenance therapy (10 of whom had relapsed from a chemotherapy-induced remission) had a median duration of remission of only 3.5 months (range, 1 to 23 months). Only 3 of 19 patients who relapsed from a remission induced by all-trans retinoic acid could be brought into remission again using this drug. The median survival time of all newly diagnosed patients has not been reached, but it now exceeds 31 months (range, 0.4 to 36+ months). No decrease in the early mortality rate was observed compared with a historical control group composed of 80 consecutive, newly diagnosed patients treated only with chemotherapy at this center; however, overall survival was superior.. All-trans retinoic acid is an effective agent to induce remission in patients with a molecular diagnosis of acute promyelocytic leukemia, but remissions are short and resistance develops rapidly. Although the incidence of early death was not reduced, the use of all-trans retinoic acid to induce remission, followed by cytotoxic chemotherapy for "consolidation," was associated with longer survival times when compared with historical controls treated only with chemotherapy. Additional studies to prevent or mitigate consequences of the "retinoic acid syndrome" and to identify specific patients who might benefit from earlier intervention with chemotherapy are needed to maximize the advantages of this approach.

Topics: Adolescent; Adult; Aged; Blood Coagulation Disorders; Child; Female; Humans; Leukemia, Promyelocytic, Acute; Leukocytosis; Leukopenia; Male; Middle Aged; Recurrence; Remission Induction; Survival Analysis; Time Factors; Tretinoin

A large number of acute promyelocytic leukemia (APL) patients, treated with all-trans retinoic acid (ATRA) and chemotherapy, were studied. The results of the studies are as follows: (1) Among 65 patients investigated for the postremissional therapy, the 5-year survival probabilities were 0.20 +/- 0.13 (mean +/- SE) in the group treated with ATRA alone, 0.47 + 0.10 (mean +/- SE) in the group using chemotherapy alone and 0.42 +/- 0.09 (mean +/- SE) in the group treated with chemotherapy and ATRA. (2) The main severe adverse effects in the ATRA treatment include retinoic acid syndrome, renal failure, and thrombosis. These sequelae were observed more frequently in cases with persistent, marked elevation of white blood cell count without significant maturation of leukemic promyelocytes. (3) APL is not a homogeneous disease in that among 50 patients studied at the molecular level, although a PML-RARA fusion gene was detected in 45 cases, one had a variant translocation t(11;17) bearing fusion gene PLZF-RARA, one presented no obvious structural alteration of the PML gene while the RARA gene was rearranged, and three patients had no rearrangement of either PML or RARA genes. (4) Using RT/PCR to detect minimal residual disease, we found positive rates of 22%, 18.4%, and 11.5%, respectively, 12, 24, and 36 months after CR. This observation justifies the use of chemotherapy for at least 3 years after CR induced by ATRA. (5) It seems likely that the fusion gene PML-RARA plays an important role in APL leukemogenesis and in its response to the ATRA treatment.

Topics: Actuarial Analysis; Antineoplastic Combined Chemotherapy Protocols; Humans; Leukemia, Promyelocytic, Acute; Mercaptopurine; Methotrexate; Survival Analysis; Tretinoin

From January 1986 to April 1991, 107 consecutive patients with acute promyelocytic leukemia (APL) were treated with retinoic acid (RA) at an oral dose of 45-60mg/m2/d, alone or in combination with chemotherapy. In 91 cases treated with RA alone, 74 (81.3%) achieved complete remission (CR). The CR rate was 75% in 16 cases treated with combined therapy. Among 50 patients closely followed for a median of 36 months (4-60), 10 received RA as continuation therapy (Group A), 10 received chemotherapy (Group B) and 30 were treated with RA and chemotherapy alternately in regular sequence (Group C). The mean survival time was 8.4, 9.7 and 21.6 months, respectively, for the 29 cases who died. The survival probability was higher in Group C than in Group A and B (P < 0.01). RA did not provoke or aggravate DIC, it did not cause marrow hypoplasia or aplasia. The side effects were relatively mild as compared with chemotherapy. CFU-GM markedly reduced before treatment was restored to normal level after CR, while the result for L-CFU was reversed. In 40 cases examined for in vitro induction of differentiation, 39 responders were culminating in CR. Aberrant karyotype t (15; 17) was positive in all 47 cases examined prior to the treatment. It disappeared in all of the 20 cases studied after achieving CR, and reappeared in 3 cases following relapse. The best regimen to maintain a longer CR duration and survival time in this study was to use RA and chemotherapy alternately as continuation therapy.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Cytarabine; Female; Harringtonines; Humans; Infant; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Prednisone; Remission Induction; Tretinoin; Vincristine

All-trans-retinoic acid (all-trans RA) induces complete remission in most patients with acute promyelocytic leukemia (APL). However, continuous oral dosing results in progressive decline in plasma drug concentrations, which is associated with relapse and resistance to this retinoid. We speculated that the decline in drug levels, indicating acquired resistance, resulted partly from inducible cytochrome-P450 oxidative enzymes, which can catabolize all-trans RA.. We studied the clinical pharmacology of all-trans RA in cancer patients to determine possible mechanisms of acquired resistance and evaluated the potential for reversal by ketoconazole, an inhibitor of cytochrome-P450 oxidative enzymes.. Serial plasma samples were obtained from 54 patients with APL or advanced lung cancer after a single oral dose of all-trans RA (45 mg/m2). In the 34 patients with advanced lung cancer, all-trans RA (45 mg/m2) was administered twice daily for 4 weeks, and, on days 2, 28, and 29, serial plasma samples were again obtained after a single 45-mg/m2 dose. One hour prior to drug administration on days 2 and 29, a single oral dose (200-1200 mg) of ketoconazole was administered. Endogenous plasma concentrations of all-trans RA and 13-cis-retinoic acid were measured in a subset of these patients and in 11 with early-stage lung cancer.. The mean area under the curve for plasma drug concentration times time (AUC) for all-trans RA on day 1 varied substantially among patients. Compared with patients with APL, the 28 patients with advanced lung cancer who completed therapy demonstrated significantly lower AUC levels on day 1 (P = .06); a subgroup with levels less than 300 ng/mL per hour on day 1 had lower endogenous plasma all-trans RA concentrations than patients with APL or early-stage lung cancer or 14 normal subjects. Following continuous oral treatment, the mean day 28 AUC for all-trans RA was significantly lower than that on day 1 (213 ng/mL per hour versus 467 ng/mL per hour; P < .01), a decline significantly attenuated by ketoconazole, which increased the mean plasma all-trans RA AUC on day 29 to 375 ng/mL per hour (P < .01).. Reported variability for the pharmacokinetics of all-trans RA may result from disease-related or population-based differences in basal catabolic rates influenced by genetic or environmental factors. However, the pattern of inducible catabolism of all-trans RA is not disease specific. Ketoconazole attenuates this accelerated catabolism, suggesting that oxidation by cytochrome-P450 enzymes is an important pathway for both constitutive and induced pathways of all-trans RA metabolism.

Topics: Carcinoma, Non-Small-Cell Lung; Cytochrome P-450 Enzyme Inhibitors; Dose-Response Relationship, Drug; Drug Interactions; Drug Tolerance; Humans; Ketoconazole; Leukemia, Promyelocytic, Acute; Lung Neoplasms; Neoplasms; Tretinoin

We treated 70 acute promyelocytic leukemia (APL) patients with daily oral 45 mg/m2 all-trans-retinoic acid (ATRA) in two multi-institutional prospective studies. Of 64 evaluable patients, 21 were refractory to initial induction chemotherapy; 10 were refractory to salvage chemotherapy; 17, five, and four were in the first, second and, third relapse, respectively; and seven were previously untreated due to old age. In the first study with ATRA from China, 18 out of 22 (82%) evaluable patients achieved complete remission (CR). Initial peripheral leukemia cell counts were significantly less in the CR cases (p < 0.01); < 100/microliters in 17 out of 18 CR cases, and > or = 200/microliters in all failure cases. In the second study with ATRA from Hoffmann-La Roche, if initial leukemia cell counts were more than 200/microliters, chemotherapy was first given and then ATRA was started. Of 42 evaluable patients, 36 (86%) achieved CR. Morphological evidence of differentiation was noted in all CR cases. Patients achieving CR received standard consolidation and maintenance chemotherapies, and the 20-month predicted disease-free survival rate is 76% for cases achieving their first CR with ATRA. Toxicities attributable to ATRA were minimal and included cheilitis, xerosis, dermatitis, gastrointestinal disorders, bone pain, liver damage, and high serum triglyceridemia.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cell Differentiation; Child; Female; Humans; Japan; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Prospective Studies; Remission Induction; Survival Rate; Tretinoin

We designed a multicenter randomized trial comparing chemotherapy with daunorubicin-Ara C (chemotherapy group) and all transretinoic acid (ATRA) combined to the same chemotherapy (ATRA group) in newly diagnosed APL patients aged 65 years or less. The major endpoint of the study was event-free survival (EFS) ("events" being defined as failure to achieve complete remission [CR], occurrence of relapse, or death in CR). Early termination of the trial was decided after the first interim analysis, as EFS was significantly higher in the ATRA group. At the time, 101 patients had been randomized (54 in the ATRA group and 47 in the chemotherapy group). In the ATRA group, 49 (91%) patients achieved CR, 5 (9%) had early death, and 0 had resistant leukemia, compared with 38 (81%), 4 (8%), and 5 (10%) patients, respectively, in the chemotherapy group. The difference in CR rate between the two groups was not significant. The duration of coagulopathy was significantly reduced in the ATRA group, compared with the chemotherapy group. In the ATRA group, six patients relapsed after 7 to 15.5 months. In the chemotherapy group, 12 patients relapsed after 1 to 16 months, and 2 died in CR. Kaplan-Meier EFS was estimated at 79% +/- 7% and 50% +/- 9% at 12 months, respectively, in the ATRA and the chemotherapy group (P = .001). Kaplan-Meier estimate of relapse was 19% +/- 8% and 40% +/- 12% at 12 months (P = .005). In conclusion, ATRA followed by chemotherapy increases EFS in newly diagnosed APL. These results strongly suggest that ATRA should be incorporated in the front line therapy of newly diagnosed APL.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Blood Coagulation Disorders; Drug Administration Schedule; Female; Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Remission Induction; Survival Rate; Tretinoin

All-trans retinoic acid (ATRA) has been shown to be active against acute promyelocytic leukemia (APL). Six patients with APL, either in relapse or resistant to initial chemotherapy were reinduced with ATRA 100 g/m2/day for 6 weeks. Complete remission was achieved in all six of them. Side effects were seen in two of them. ATRA appears to provide a relatively safe and reliable means to induce a complete remission in patients with refractory or relapsed APL.

Topics: Adolescent; Adult; Drug Resistance; Female; Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Salvage Therapy; Tretinoin

Topics: Antineoplastic Agents; Blood Coagulation Disorders; Carrier Proteins; Gene Expression; Humans; Leukemia, Promyelocytic, Acute; Prognosis; Receptors, Retinoic Acid; Tretinoin

We treated 70 patients with acute promyelocytic leukemia (APL) with daily oral 45 mg/m2 all-trans retinoic acid (ATRA) in 2 multi-institutional prospective studies. Of 63 evaluable patients, 21 were resistant to initial induction chemotherapy, 10 were resistant to salvage chemotherapy after relapse, 17 were in the first relapse, 4 in the second relapse, 4 in the third relapse, and 7 were previously untreated. In the first study with ATRA from China, 18 (82%) of 22 evaluable patients achieved CR within 8 to 53 days with a median of 29 days. Initial peripheral leukemia cell counts were significantly less in the CR cases (p < 0.01). They were less than 100/cmm in 17 of 18 CR cases, and more than 200/cmm in all failure cases. Patients achieving CR received standard consolidation and maintenance chemotherapies, and the 16-month predicted continuing CR rate is 60%. Based on the first study, in the second study with ATRA from Hoffmann-La Roche AG, if initial peripheral leukemia cell counts were more than 200/cmm, chemotherapy was first given and then ATRA was started. Of 41 evaluable patients, 36 (88%) achieved CR within 11 to 91 days with a median of 34 days. Of 3 patients who received preceding chemotherapy due to high leukemia cell counts, 2 achieved CR. Morphological evidence of differentiation was noted in all CR cases, with Auer rods in mature segmented neutrophils in 13 cases. The clinical signs of DIC decreased rapidly within a few days and disappeared in CR cases. Toxicities attributable to ATRA were minimal and included cheilitis, xerosis, dermatitis, gastrointestinal disorders, bone pain, liver damage and high serum triglyceridemia.

Topics: Administration, Oral; Chromosome Aberrations; Daunorubicin; Disseminated Intravascular Coagulation; Humans; Leukemia, Promyelocytic, Acute; Prospective Studies; Remission Induction; Tretinoin

Seven patients with acute promyelocytic leukemia (APL) were treated with all-trans retinoic acid (ATRA). Five (71.4%) achieved complete remission (CR). Most side effects were transient and well tolerated. Hyperleukocytosis was the major adverse effect. These observations confirm the efficacy of ATRA for inducing CR in APL.

Topics: Adult; Cuba; Female; Humans; Leukemia, Promyelocytic, Acute; Male; Stereoisomerism; Tretinoin

We entered 26 patients with newly diagnosed acute promyelocytic leukemia (APL) in a pilot study of all-transretinoic acid (ATRA) followed by intensive chemotherapy. Median age was 46 (range 25 to 63). No patient presented with leukocytes > 10 x 10(9)/L or had the microgranular APL variant. Cytogenetic analysis (25 patients) found a t(15;17) in 24 cases. Patients were scheduled to receive ATRA (45 mg/m2/d) until complete remission, followed by an intensive daunorubicin (DNR) + Ara C course ("4 + 7" course), then three "2 + 5" DNR + Ara C courses and maintenance chemotheapy. However, the "4 + 7" course was administered in emergency if hyperleukocytosis rapidly developed to prevent leukostasis. Twenty-five patients (96%) achieved CR, 14 with ATRA alone and 11 after the addition of the "4 + 7" course on day 2 to 30 of treatment, because leukocytes rapidly increased (9 cases), because of resistance to ATRA (1 case), and development of organomegaly (1 case). The remaining patient died on day 6, from CNS bleeding. Apart from hyperleukocytosis, side effects were usually moderate. In the 11 patients who could be studied in vitro, a very good correlation was found between in vivo and vitro differentiation and proliferation of APL blasts with ATRA. Three patients were allografted after the "4 + 7" course. Four patients did not receive this course but received the subsequent "2 + 5" courses and maintenance. The remaining patients followed the scheduled protocol. Three patients relapsed after 8, 11, and 15 months (including one allografted patient). Two patients died in CR, after 6 and 17 months. The other 20 patients remained in CR after 18+ to 34+ months (median 21). Actuarial disease free interval (DFI) and event free survival (EFS) were 87% and 77%, respectively, after 18 months. These results were compared to those obtained in our previous APL 84 trial with chemotherapy alone in newly diagnosed APL (after excluding patients included in this trial who presented with hyperleukocytosis). In APL 84 trial, the CR rate was 76%, the actuarial DFI and EFS were 59% and 48% after 18 months, respectively. Differences with the pilot study of ATRA followed by chemotherapy were significant for DFI (P = .02), EFS (P = .006), but not for CR rate (P = .08). Although this is a historical comparison, these results suggest that ATRA followed by chemotherapy may prove superior to chemotherapy alone in newly diagnosed APL, by slightly increasing the CR rate, but perhaps more important

Topics: Actuarial Analysis; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Cytarabine; Daunorubicin; Female; Follow-Up Studies; Humans; Leukemia, Promyelocytic, Acute; Male; Mercaptopurine; Methotrexate; Middle Aged; Mitoguazone; Pilot Projects; Time Factors; Treatment Outcome; Tretinoin

Fifty patients with acute promyelocytic leukemia (APL) have been treated with all-trans retinoic acid (RA). In vitro induced differentiation of primarily cultured bone marrow cells from the patients, colony-forming unit granulocyte-macrophage (CFU-GM) and L-CFU colony-forming assays, and karyotype analysis were performed over the treatment course. The very high bone marrow complete remission (CR) rate (94%) suggested that all-trans RA was superior to conventional chemotherapeutic regimens for the treatment of APL. The leukemic clone was reduced by RA-induced terminal differentiation and loss of proliferation capacity of leukemic cells. Relapse after CR in about 40% of patients was the major reason for the failure of the RA treatment. Patients who relapsed after a chemotherapy-maintained CR could be effectively reinduced to second CR by RA. However, if relapse occurred after a CR maintained by both RA and chemotherapy, the sensitivity of newly emerged leukemic clones to RA was greatly reduced. Therefore, it is suggested that RA should be replaced by conventional chemotherapy as soon as CR is achieved. Laboratory studies proved valuable in selecting cases for RA therapy and in predicting therapeutic effects and prognosis.

Topics: Adolescent; Adult; Bone Marrow; Child; Colony-Forming Units Assay; Drug Screening Assays, Antitumor; Female; Humans; Karyotyping; Leukemia, Promyelocytic, Acute; Leukocyte Count; Male; Middle Aged; Platelet Count; Recurrence; Remission Induction; Tretinoin

Retinoic acid, the active metabolite of vitamin A has been shown to differentiate in vitro human leukaemic cells from patients with acute promyeolocytic leukaemia (APL). The results obtained in vivo with the 13-cis isomer of retinoic acid in combination with or after chemotherapy in four cases of APL are described. More recently Huang et al from the Shangai Institute of Haematology have treated 24 cases of APL with all-trans retinoic acid alone. They obtained 24 complete remissions. This success prompted us to treat patients with APL and a contra-indication to chemotherapy with all-trans retinoic acid. The results confirm the great efficacy of all-trans retinoic acid in APL.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cell Differentiation; Clinical Trials as Topic; Follow-Up Studies; Humans; Leukemia, Promyelocytic, Acute; Recurrence; Remission Induction; Tretinoin

Twenty-two patients with acute promyelocytic leukemia were treated with all-trans retinoic acid (RA, 45 mg/m2 per day) for 90 days. Of the 22, four patients were previously untreated, two were resistant after conventional chemotherapy, and 16 were in first (n = 11), second (n = 4), or third (n = 1) relapse. We observed 14 complete response, four transient responses, one failure, and three early deaths. Length of hospitalization and number of transfusions were notably reduced in complete responders. Correction of coagulation disorders and an increase of WBCs were the first signs of all-trans RA efficacy. Morphologic analysis performed at days 0, 15, 30, 45, 60, and 90 showed that complete remissions were obtained without bone marrow (BM) hypoplasia. Presence of Auer rods in the maturing cells confirmed the differentiation effect of the treatment. At remission, the t(15;17) initially present in 20 patients was not found. The in vitro studies showed a differentiation in the presence of all-trans RA in 16 of the 18 tested cases. The single nonresponder to all trans RA in vitro did not respond in vivo. Adverse effects of RA therapy--skin and mucosa dryness, hypertriglyceridemia, and increase of hepatic transaminases--were frequently noted. We also observed bone pain in 11 patients and hyperleukocytosis in four patients. Whether maintenance treatment consisted of low-dose chemotherapy or all-trans RA, early relapses were observed. Five patients are still in complete remission (CR) at 4 to 13 months. Our study confirms the major efficacy of all-trans RA in M3, even in relapsing patients. Remissions are obtained by a differentiation process.

Topics: Adult; Aged; Aged, 80 and over; Cell Transformation, Neoplastic; Female; Follow-Up Studies; Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Tretinoin

Topics: Adolescent; Adult; Aged; Bone Marrow; Bone Marrow Cells; Child; Child, Preschool; Clinical Trials as Topic; Disseminated Intravascular Coagulation; Female; Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Recurrence; Remission Induction; Stereoisomerism; Tretinoin; Tumor Stem Cell Assay

Acute promyelocytic leukemia (APL) and chronic myeloid leukemia (CML) are both hematological malignancies characterized by genetic alterations leading to the formation of oncofusion proteins. The classical chromosomal aberrations in APL and CML result in the PML-RARα and BCR-ABL1 oncofusion proteins, respectively. Interestingly, our flow cytometric analyses revealed elevated free intracellular zinc levels in various leukemia cells, which may play a role in stabilizing oncofusion proteins in leukemia and thus support cell proliferation and malignancy. Long-term zinc deficiency resulted in the degradation of PML-RARα in NB4 cells (APL cell line) and of BCR-ABL1 in K562 cells (CML cell line). This degradation may be explained by increased caspase 3 activity observed in zinc deficient cells, whereas zinc reconstitution normalized the caspase 3 activity and abolished zinc deficiency-induced oncofusion protein degradation. In NB4 cells, fluorescence microscopic images further indicated enlarged and enriched lysosomes during zinc deficiency, suggesting increased rates of autophagy. Moreover, NB4 cells exhibited increased expression of the zinc transporters ZIP2, ZIP10 and ZnT3 during zinc deficiency and revealed excessive accumulation of zinc in contrast to healthy peripheral blood mononuclear cells (PBMCs), when zinc was abundantly available extracellularly. Our results highlight the importance of altered zinc homeostasis for some characteristics in leukemia cells, uncover potential pathways underlying the effects of zinc deficiency in leukemia cells, and provide potential alternative strategies by which oncofusion proteins can be degraded.

Topics: Caspase 3; Cell Differentiation; Humans; Leukemia, Promyelocytic, Acute; Leukocytes, Mononuclear; Tretinoin; Zinc

More than 95% of patients with acute promyelocytic leukemia (APL) are characterized by the reciprocal translocation t(15;17)(q24;21), which involves the promyelocytic leukemia protein (PML) gene on chromosome 15 and the retinoic acid receptor-α (RARA) gene on chromosome 17, leading to the production of the PML::RARA chimeric gene. Additional chromosomal abnormalities are described in all acute myeloid leukemias and occur in approximately one-third of patients with newly diagnosed APL. Here, we report the case of de novo APL showing the classical t(15;17)(q24;q21), a deletion of the short arm of chromosome 6 (6p), and a noncanonical molecular variant of the PML::RARA transcript. Nevertheless, the patient achieved complete remission after treatment with conventional therapy with all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). Notwithstanding that the molecular pathogenesis of this type of atypical variant still remains unknown, we conclude that this atypical PML::RARA bcr2 fusion gene associated with del(6p) does not seem to alter the effectiveness of combined treatment with ATRA and ATO.

Topics: Humans; Leukemia, Promyelocytic, Acute; Oncogene Proteins, Fusion; Promyelocytic Leukemia Protein; Tretinoin

The acute promyelocytic leukemia (APL) driver ZBTB16/RARα is generated by the t(11;17) (q23;q21) chromosomal translocation, which is resistant to combined treatment of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) or conventional chemotherapy, resulting in extremely low survival rates. In the current study, we investigated the effects of hyperthermia on the oncogenic fusion ZBTB16/RARα protein to explore a potential therapeutic approach for this variant APL. We showed that Z/R fusion protein expressed in HeLa cells was resistant to ATO, ATRA, and conventional chemotherapeutic agents. However, mild hyperthermia (42 °C) rapidly destabilized the ZBTB16/RARα fusion protein expressed in HeLa, 293T, and OCI-AML3 cells, followed by robust ubiquitination and proteasomal degradation. In contrast, hyperthermia did not affect the normal (i.e., unfused) ZBTB16 and RARα proteins, suggesting a specific thermal sensitivity of the ZBTB16/RARα fusion protein. Importantly, we found that the destabilization of ZBTB16/RARα was the initial step for oncogenic fusion protein degradation by hyperthermia, which could be blocked by deletion of nuclear receptor corepressor (NCoR) binding sites or knockdown of NCoRs. Furthermore, SIAH2 was identified as the E3 ligase participating in hyperthermia-induced ubiquitination of ZBTB16/RARα. In short, these results demonstrate that hyperthermia could effectively destabilize and subsequently degrade the ZBTB16/RARα fusion protein in an NCoR-dependent manner, suggesting a thermal-based therapeutic strategy that may improve the outcome in refractory ZBTB16/RARα-driven APL patients in the clinic.

Topics: Antineoplastic Agents; Arsenic Trioxide; HeLa Cells; Humans; Hyperthermia, Induced; Leukemia, Promyelocytic, Acute; Oncogene Proteins, Fusion; Promyelocytic Leukemia Zinc Finger Protein; Tretinoin

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Humans; Leukemia, Myeloid, Acute; Leukemia, Promyelocytic, Acute; Retinoic Acid Receptor gamma; Tretinoin

Although a growing body of evidence demonstrates that altered mtDNA content (mtDNAc) has clinical implications in several types of solid tumours, its prognostic relevance in acute promyelocytic leukaemia (APL) patients remains largely unknown. Here, we show that patients with higher-than-normal mtDNAc had better outcomes regardless of tumour burden. These results were more evident in patients with low-risk of relapse. The multivariate Cox proportional hazard model demonstrated that high mtDNAc was independently associated with a decreased cumulative incidence of relapse. Altogether, our data highlights the possible role of mitochondrial metabolism in APL patients treated with ATRA.

Topics: Antineoplastic Combined Chemotherapy Protocols; Clinical Relevance; DNA, Mitochondrial; Humans; Leukemia, Promyelocytic, Acute; Neoplasm Recurrence, Local; Treatment Outcome; Tretinoin

Topics: Antigens, Neoplasm; Cell Differentiation; Humans; Leukemia, Myeloid, Acute; Leukemia, Promyelocytic, Acute; Oncogene Proteins, Fusion; Receptors, Retinoic Acid; RNA-Binding Proteins; Tretinoin

Mitochondrial biology may influence the outcome of therapy for acute promyelocytic leukemia if arsenic trioxide is not part of the treatment. Inclusion of arsenic trioxide in the treatment regimen may cancel the adverse impact of certain mitochondrial abnormalities frequently associated with the disease. Commentary on: Pereira-Martins et al. Clinical significance of mitochondrial DNA content in acute promyelocytic leukaemia. Br J Haematol 2023;200:170-174.

Topics: Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; DNA, Mitochondrial; Humans; Leukemia, Promyelocytic, Acute; Oxides; Tretinoin

Objective Compared to prospective trials, the early death rate of newly diagnosed acute promyelocytic leukemia (APL) in the real-world clinical setting is higher. However, the early death rate was heterogeneous according to the reported institutes. Thus, the therapeutic approach at each institute may be important for preventing early death. This study evaluated the management strategy for untreated APL in our institute to avoid early death. Methods We identified consecutive 21 patients with untreated APL who received induction therapy including all-trans retinoic acid (ATRA) between July 2007 and December 2021 at the University of Tokyo Hospital. Results As therapeutic approaches, 16 patients (76%) received ATRA administration on the day of admission, and the remaining 5 received ATRA within 4 days from admission. Notably, all patients received conventional chemotherapy added to ATRA at a median of 1 day from admission (range: 0-9 days). As clinical outcomes, no patient died during induction therapy for untreated APL, and all achieved complete molecular remission. Conclusion Compared to the previous nationwide survey, a higher proportion of patients at our institute received conventional chemotherapy in addition to ATRA, and it was initiated more promptly, which may have helped prevent early death.

Topics: Antineoplastic Combined Chemotherapy Protocols; Humans; Leukemia, Promyelocytic, Acute; Prospective Studies; Remission Induction; Treatment Outcome; Tretinoin

Intracranial hemorrhage (ICH) is a major cause of early death (ED) and leads to poor prognosis in acute promyelocytic leukemia (APL). We retrospectively described 27 unselected APL patients who experienced early ICH. The ED rate was 37%. The 3-year overall survival (OS) rate was 45.4%, while the 3-year OS rate of patients who survived through induction therapy was 87.5%. No patient experienced central nervous system leukemia (CNSL). Concurrent differentiation syndrome, white blood cell count, prothrombin time and D-dimer were related to death. Although the ED rate among APL patients with early ICH was high, patients with early ICH had a favorable outcome after surviving through induction therapy. CNSL was rare despite a history of ICH during induction therapy. Compared with APL patients without ICH, it seems unnecessary to administer additional measures to prevent CNSL for this subpopulation in the era of all-trans retinoic acid and arsenic trioxide, but this needs further validation in prospective trials.

Topics: Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Humans; Intracranial Hemorrhages; Leukemia, Promyelocytic, Acute; Prospective Studies; Retrospective Studies; Tretinoin

Arsenic trioxide (ATO) and all-trans retinoic acid (ATRA) form the backbone of the treatment of acute promyelocytic leukaemia (APL), with the addition of chemotherapy for high-risk patients. We describe our experience of treating patients with APL of all risk classes with ATO and ATRA without chemotherapeutic agents. Patients received induction with ATO and ATRA followed by three cycles of consolidation with ATO and ATRA (each 1 month apart) after achieving morphological remission. Patients with intermediate- and high-risk disease received a further 2 years of maintenance with ATRA, 6-mercaptopurine and methotrexate. A total of 206 patients were included in the study. The majority of the patients were intermediate risk (51.9%), followed by high risk (43.2%). Differentiation syndrome was seen in 41 patients (19.9%). Overall, 25 patients (12.1%) died within 7 days of initiating therapy. Seven patients relapsed during follow-up. The mean (SD) estimated 5-year event-free survival (EFS) and overall survival (OS) in the entire cohort was 79% [5.8%] and 80% [5.8%] respectively. After excluding patients who died within 7 days of therapy initiation, the mean (SD) estimated 5-year EFS and OS was 90% [5.8%] and 93% [3.9%] respectively. Our study shows that treatment of all risk classes of APL with ATO and ATRA without chemotherapy is associated with excellent long-term outcomes in the real-world setting.

Topics: Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Humans; Leukemia, Promyelocytic, Acute; Oxides; Retrospective Studies; Treatment Outcome; Tretinoin

Chemotherapy, all-trans retinoic acid (ATRA), and arsenic are effective options for acute promyelocytic leukemia (APL). We conducted a 20-year retrospective analysis of newly diagnosed (ND) APL patients treated with arsenic, ATRA and mitoxantrone. After achieving complete remission (CR), patients received 3-5 cycles of chemotherapy followed by AS4S4 maintenance for 3 years. Eighty-eight ND APL patients were treated with either oral AS4S4 (n = 42) or arsenic trioxide (ATO) (n = 46). The 8-year overall survival (OS) rate was 100% in the AS4S4 group and 90% in the ATO group. The disease-free survival (DFS) rates were 100% and 87.1% (p = 0.027), respectively. Patients in the ATO group had more side effects. A subsequent cohort of 33 ND APL patients received triple therapy with oral AS4S4, ATRA, and chemotherapy. The 13-year OS and DFS rates were 100% and 90.9%. Our long-term analyses show that APL patients with oral AS4S4 had better outcomes compared to ATO, with no need for hospitalization.

Topics: Antineoplastic Combined Chemotherapy Protocols; Arsenic; Arsenic Trioxide; Arsenicals; Humans; Leukemia, Promyelocytic, Acute; Oxides; Retrospective Studies; Treatment Outcome; Tretinoin

Early death remains a major factor in survival in APL. We aimed to analyze the risk factors for differentiation syndrome and early death in acute promyelocytic leukemia (APL).. The clinical data of APL patients who were newly diagnosed at Mianyang Central Hospital from January 2013 to January 2022 were retrospectively analyzed.. Eighty-six newly diagnosed APL patients (37 males and 49 females) were included in this study. The median age was 46 (17-75) years. Sixty-one patients (70.9%) had low/intermediate-risk APL, and 25 patients (29.1%) had high-risk APL. The incidence of differentiation syndrome (DS) was 62.4%. The multivariate analysis showed that a peak white blood cell (WBC) count ≥16 × 10^9/L was an independent risk factor (OR = 11.000, 95% CI: 2.830-42.756, P = 0.001) for DS in all APL patients, while a WBC count ≥10 × 10^9/L on Day 5 was an independent risk factor for DS in low-intermediate risk APL patients (OR = 9.114, 95% CI: 2.384-34.849, P = 0.001). There were 31 patients (36.5%) with mild DS and 22 patients (25.9%) with severe DS. The multivariate analysis showed that WBC count ≥23 × 10^9/L at chemotherapy was an independent risk factor for severe DS (OR = 10.500, 95% CI: 2.344-47.034, P = 0.002). The rate of early death (ED) was 24.4% (21/86). The multivariate analysis showed that male gender (OR = 7.578,95% CI:1.136-50.551, P = 0.036), HGB < 65 g/L (OR = 16.271,95% CI:2.012-131.594, P = 0.009) and WBC count ≥7 × 10^9/L on Day 3(OR = 23.359,95% CI:1.825-298.959, P = 0.015) were independent risk factors for ED. The WBC count at diagnosis, WBC count on Day 3 and WBC count on Day 5 had moderate positive correlations with tumor necrosis factor-α (TNF-α) at diagnosis, and the correlation coefficients were 0.648 (P = 0.012), 0.615 (P = 0.033), and 0.609 (P = 0.035), respectively. The WBC count had no correlation with IL-6.. During induction treatment, cytotoxic chemotherapy may need to be initiated to reduce the risk of DS for APL patients with a low-intermediate risk WBC count ≥10 × 10^9/L on Day 5 or for all patients with a peak WBC count ≥16 × 10^9/L. Patients with WBC > 7 × 10^9/L on Day 3 have a higher risk of ED. Leukocyte proliferation is associated with TNF-α rather than IL-6, and TNF-α may be a potential biomarker for predicting ED.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Interleukin-6; Leukemia, Myeloid, Acute; Leukemia, Promyelocytic, Acute; Leukocyte Count; Leukocytes; Leukopenia; Male; Middle Aged; Retrospective Studies; Syndrome; Thrombocytopenia; Tretinoin; Tumor Necrosis Factor-alpha; Young Adult

All-trans retinoic acid (ATRA) is only effective in acute promyelocytic leukemia (APL), but not in other subtype of acute myeloid leukemia (AML). Salinomycin targets tumor cells rather than non-tumorigenic cells, and WNT/β-catenin pathway inhibition is one of the mechanisms of its anti-tumor activity. There is a crosstalk between RA and WNT/β-catenin pathway. Here, we investigate the effect of the combination of salinomycin and ATRA (S+RA) in non-APL AML cells.. Apoptosis was evaluated by cell viability and Annexin-V assay. Cell differentiation was analyzed by CD11c expression and morphology. To explore the underlying mechanisms, Western blot analysis and mitochondrial transmembrane potentials (ΔΨm) were used.. S+RA induced differentiation and apoptosis in AML cell lines and AML primary cells. S+RA inhibited the β-catenin signal pathway as determined by the decreased protein levels of β-catenin, the low-density lipoprotein receptor-related proteins 6 (LRP6), and its downstream proteins such as survivin, c-Myc, caspase-3/7, cdc25A and cyclinD1 and reduced phosphorylation level of GSK3β S9. S+RA also increased the protein levels of CCAAT/enhancer-binding proteins (C/EBPs) and PU.1 and collapsed Δψm. The above molecular and cellular changes induced by S+RA were inhibited by β-catenin specific activator and promoted by β-catenin specific inhibitor.. S+RA induced differentiation by β-catenin-inhibition-mediated up-regulation of C/EBPs and PU.1 and suppression of c-Myc. S+RA triggered apoptosis through β-catenin-inhibition-regulated ΔΨm collapse and caspase-3/7 activation. Taken together, our findings may provide novel therapeutic strategies for AML patients by targeting the WNT/β-catenin pathway.

Topics: Apoptosis; beta Catenin; Caspase 3; Cell Differentiation; Cell Line, Tumor; Humans; Leukemia, Myeloid, Acute; Leukemia, Promyelocytic, Acute; Tretinoin; Wnt Signaling Pathway

The PML::RARA fusion protein is the hallmark driver of Acute Promyelocytic Leukemia (APL) and disrupts retinoic acid signaling, leading to wide-scale gene expression changes and uncontrolled proliferation of myeloid precursor cells. While known to be recruited to binding sites across the genome, its impact on gene regulation and expression is under-explored. Using integrated multi-omics datasets, we characterize the influence of PML::RARA binding on gene expression and regulation in an inducible PML::RARA cell line model and APL patient ex vivo samples. We find that genes whose regulatory elements recruit PML::RARA are not uniformly transcriptionally repressed, as commonly suggested, but also may be upregulated or remain unchanged. We develop a computational machine learning implementation called Regulatory Element Behavior Extraction Learning to deconvolute the complex, local transcription factor binding site environment at PML::RARA bound positions to reveal distinct signatures that modulate how PML::RARA directs the transcriptional response.

Topics: Cell Line; Gene Expression Regulation; Humans; Leukemia, Promyelocytic, Acute; Multiomics; Oncogene Proteins, Fusion; Tretinoin

BACKGROUND Acute promyelocytic leukemia (APL) is a rare subtype of acute myeloid leukemia (AML) and is characterized by a genetic translocation affecting the retinoic acid receptor-alpha gene, leading to blockage in the differentiation of granulocytic cells. The accumulation of promyelocytes in bone marrow leads to cytopenias and life-threatening coagulopathies. Definitive diagnosis is made with bone marrow biopsy. Differentiation of APL from other leukemias is important to appropriately treat with all-trans retinoic acid (ATRA) and arsenic trioxide. Patients with HIV are at a higher risk to develop AML. This article identifies how multiple comorbidities and social factors can contribute to difficulties in diagnosing AML. CASE REPORT We present a 67-year-old man with a past medical history of hypertension and substance use disorder who presented with progressive exertional dyspnea and was found to have HIV, chronic hepatitis C, and APL with pancytopenia. His bone marrow biopsy confirmed AML. This was a case of co-existing HIV and aleukemic leukemia. CONCLUSIONS APL can present with pancytopenia, weakness, failure to thrive, or bleeding complications, which can be similar to presentations of those diagnosed with HIV. Diagnosis of APL can be differentiated between hypergranular and hypogranular; our patient demonstrated APL with only 52% blasts, which can make for a challenging diagnosis. Given increased mortality of APL, immediate ATRA therapy is warranted. Aleukemic leukemia is a rare presentation typically accompanied by skin manifestations. Our case highlights the importance of having high clinical suspicion for malignancy in patients with comorbidities that can interfere with the classic presentation of leukemia.

Topics: Aged; Alcoholism; Hepatitis C; HIV Infections; Humans; Leukemia, Promyelocytic, Acute; Male; Pancytopenia; Tretinoin

In acute promyelocytic leukemia (APL), increased cell burden in the peripheral blood due to either the disease itself or early treatment with all-trans retinoic acid could cause hyperleukocytosis (HL) before induction chemotherapy. However, therapeutic leukapheresis has seldom been used because of concerns of subsequent coagulopathy after this invasive procedure. The aim of this study was to evaluate the effects of leukapheresis in APL, especially for efficacy and safety.. There was a trend toward favorable 30-day survival rate for the leukapheresis group compared with the non-leukapheresis group (76.9% and 67.4%; P = 0.24). The complications including subsequent intensive unit care (P = 0.23), severe hemorrhagic events (P = 0.13) showed no significant differences between the two groups. The patients were divided into subcohorts, and the survival rates of the leukapheresis and non-leukapheresis groups were 92.3% (95% confidence interval [CI], 77.8%-100.0%) versus 58.3% (95% CI, 38.6%-78.1%) (P = 0.03) in "sequential HL" and 76.7% (95% CI, 61.5%-91.8%) versus 54.8% (95% CI, 37.3%-72.4%) (P = 0.03) in "symptomatic HL," respectively. Moreover, in the "sequential HL" subcohort, the cumulative incidence of differentiation syndrome and following adverse events were significantly lower in the leukapheresis group.. In APL with "sequential HL" or "symptomatic HL" from either the disease itself or the effect of all-trans retinoic acid, therapeutic leukapheresis could be applied to reduce leukemic cell burden without significant risks.

Topics: Antineoplastic Combined Chemotherapy Protocols; Humans; Leukemia, Promyelocytic, Acute; Leukocytosis; Retrospective Studies; Tretinoin

Acute myeloid leukemia (AML) with retinoic acid receptor γ (RARG) rearrangement has clinical, morphologic, and immunophenotypic features similar to classic acute promyelocytic leukemia. However, AML with RARG rearrangement is insensitive to alltrans retinoic acid (ATRA) and arsenic trioxide (ATO) and carries a poor prognosis. We initiated a global cooperative study to define the clinicopathological features, genomic and transcriptomic landscape, and outcomes of AML with RARG rearrangements collected from 29 study groups/institutions worldwide. Thirty-four patients with AML with RARG rearrangements were identified. Bleeding or ecchymosis was present in 18 (54.5%) patients. Morphology diagnosed as M3 and M3v accounted for 73.5% and 26.5% of the cases, respectively. Immunophenotyping showed the following characteristics: positive for CD33, CD13, and MPO but negative for CD38, CD11b, CD34, and HLA-DR. Cytogenetics showed normal karyotype in 38% and t(11;12) in 26% of patients. The partner genes of RARG were diverse and included CPSF6, NUP98, HNRNPc, HNRNPm, PML, and NPM1. WT1- and NRAS/KRAS-mutations were common comutations. None of the 34 patients responded to ATRA and/or ATO. Death within 45 days from diagnosis occurred in 10 patients (∼29%). At the last follow-up, 23 patients had died, and the estimated 2-year cumulative incidence of relapse, event-free survival, and overall survival were 68.7%, 26.7%, and 33.5%, respectively. Unsupervised hierarchical clustering using RNA sequencing data from 201 patients with AML showed that 81.8% of the RARG fusion samples clustered together, suggesting a new molecular subtype. RARG rearrangement is a novel entity of AML that confers a poor prognosis. This study is registered with the Chinese Clinical Trial Registry (ChiCTR2200055810).

Topics: Arsenic Trioxide; HLA-DR Antigens; Humans; Leukemia, Myeloid, Acute; Leukemia, Promyelocytic, Acute; Tretinoin

Caspase-1 (CASP1)-mediated classical pyroptosis plays a key role in cancer development and management, however, the role of CASP1 and its regulation has not yet been documented for acute promyelocytic leukemia (APL). Here, we found that CASP1/GSDMD had lower expression in patients with APL and most other subtypes of primary de novo acute myeloid leukemia (AML) and was increased in all-trans-retinoic acid (ATRA)-treated APL cells. We showed that ATRA increases and activates CASP1 to trigger the pyroptosis and differentiation of APL cells. Mechanistically, ATRA could induce CASP1 expression via the IFNγ/STAT1 pathway in APL cells. In conclusion, ATRA-induced activation of CASP1 may serve as a suppressor in APL progression, as it triggers pyroptotic cell death and differentiation.

Topics: Caspase 1; Cell Differentiation; Humans; Leukemia, Promyelocytic, Acute; Pyroptosis; Tretinoin

Maintenance therapy in APL is still a standard especially in high-risk patients treated with chemotherapy+ATRA combination whereas the role of the maintenance therapy in low-risk patients is controversial. This study aims to compare the efficacy and toxicity of ATRA monotherapy and ATRA+MTX+ 6-MP combination as the maintenance treatment for 2 years in APL patients who achieved molecular complete response after induction and consolidation with ATRA+chemotherapy. A total of 71 patients from 4 different centers were included in this study. After a median follow-up of 54 months (5-180 months), the 5-year RFS was 89 % in the ATRA monotherapy arm, the 5-year RFS was 78.5 % in the combined treatment arm (p = 0.643, HR:1.3, 95 % CI: 0.35-5.3). Hematological toxicity in all grades and Grade III/IV hematological toxicity was observed significantly more in the combined treatment arm than in the ATRA monotherapy arm (All grades: 76.9 % vs 18.9 %, p < 0.001; Grade III/IV: 20.5 % vs. 3.1 %, p = 0.035). Hepatotoxicity at all levels was significantly higher in the combined treatment arm than in the ATRA monotherapy arm (61.5 % vs 25 %, p = 0.002). Our study concluded that two years of ATRA monotherapy and combined maintenance therapy, both of which were found to be similar in terms of disease control and long term survival, ATRA Monotherapy could be a safer maintenance treatment option since both hematological and non-hematological toxicities were observed less often in the ATRA monotherapy arm.

Topics: Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Humans; Leukemia, Promyelocytic, Acute; Treatment Outcome; Tretinoin

Acute promyelocytic leukemia (APL) is driven by the oncoprotein PML-RARα, which recruits corepressor complexes, including histone deacetylases (HDACs), to suppress cell differentiation and promote APL initiation. All-trans retinoic acid (ATRA) combined with arsenic trioxide (ATO) or chemotherapy highly improves the prognosis of APL patients. However, refractoriness to ATRA and ATO may occur, which leads to relapsed disease in a group of patients. Here, we report that HDAC3 was highly expressed in the APL subtype of AML, and the protein level of HDAC3 was positively associated with PML-RARα. Mechanistically, we found that HDAC3 deacetylated PML-RARα at lysine 394, which reduced PIAS1-mediated PML-RARα SUMOylation and subsequent RNF4-induced ubiquitylation. HDAC3 inhibition promoted PML-RARα ubiquitylation and degradation and reduced the expression of PML-RARα in both wild-type and ATRA- or ATO-resistant APL cells. Furthermore, genetic or pharmacological inhibition of HDAC3 induced differentiation, apoptosis, and decreased cellular self-renewal of APL cells, including primary leukemia cells from patients with resistant APL. Using both cell line- and patient-derived xenograft models, we demonstrated that treatment with an HDAC3 inhibitor or combination of ATRA/ATO reduced APL progression. In conclusion, our study identifies the role of HDAC3 as a positive regulator of the PML-RARα oncoprotein by deacetylating PML-RARα and suggests that targeting HDAC3 could be a promising strategy to treat relapsed/refractory APL.

Topics: Antineoplastic Agents; Arsenic; Arsenic Trioxide; Arsenicals; Cell Differentiation; Humans; Leukemia, Promyelocytic, Acute; Nuclear Proteins; Oxides; Transcription Factors; Tretinoin; Ubiquitination

All-trans retinoic acid and arsenic trioxide are the leading choices for the treatment of acute promyelocytic leukemia. Notwithstanding the impressive differentiative properties of all-trans retinoic acid and the apoptotic properties of arsenic trioxide, some problems still occur in acute promyelocytic leukemia treatment. These problems are due to patients' relapses, mainly related to changes in the ligand-binding domain of RARα (retinoic acid receptor α) and the cardiotoxic effects caused by arsenic trioxide. We previously developed a self-nanoemulsifying drug delivery system enriched with tocotrienols to deliver all-trans retinoic acid (SNEDDS-TRF-ATRA). Herein, we have evaluated if tocotrienols can help revert ATRA resistance in an APL cell line (NB4-R2 compared to sensitive NB4 cells) and mitigate the cardiotoxic effects of arsenic trioxide in a murine model. SNEDDS-TRF-ATRA enhanced all-trans retinoic acid cytotoxicity in NB4-R2 (resistant) cells but not in NB4 (sensitive) cells. Moreover, SNEDDS-TRF-ATRA did not significantly change the differentiative properties of all-trans retinoic acid in both NB4 and NB4-R2 cells. Combined administration of SNEDDS-TRF-ATRA and arsenic trioxide could revert QTc interval prolongation caused by ATO but evoked other electrocardiogram alterations in mice, such as T wave flattening. Therefore, SNEDDS-TRF-ATRA may enhance the antileukemic properties of all-trans retinoic acid but may influence ECG changes caused by arsenic trioxide administration. SNEDDS-TRF-ATRA presents cytotoxicity in resistant APL cells (NB4-R2). Combined administration of ATO and SNEDDS-TRF-ATRA in mice prevented the prolongation of the QTc interval caused by ATO but evoked ECG abnormalities such as T wave flattening.

Topics: Animals; Arsenic Trioxide; Electrocardiography; Leukemia, Promyelocytic, Acute; Mice; Oxides; Tocotrienols; Tretinoin

Topics: Child; Humans; Leukemia, Promyelocytic, Acute; Treatment Outcome; Tretinoin

A 40-year-old male patient presented to our emergency department with a new onset of hemorrhagic diathesis. Clinically, there were marked bleeding stigmata with extensive ecchymosis in the thigh area and oral mucosal hemorrhage with otherwise general well-being.. The coagulation diagnostics performed were consistent with the picture of disseminated intravascular consumption coagulopathy. Microscopic blood count also revealed 74% morphologically atypical promyelocytes.. Bone marrow investigation confirmed the diagnosis of a microgranular variant of acute promyelocytic leukemia. In addition to coagulation optimization, therapy with all-trans retinoic acid (ATRA) was initiated immediately. Subsequently, arsenic trioxide (ATO) and the anthracycline idarubicin were added. No severe complications occurred in the following course of treatment. Moreover, the patient is currently in complete remission regarding acute promyelocytes leukemia.. Acute promyelocytic leukemia accounts for approximately 10-15% of all acute myeloid leukemias. Often, association with marked coagulation abnormalities due to disseminated intravascular consumption coagulopathy, which is present at diagnosis, APL becomes fatal if untreated. Rapid therapy initiation with ATRA and coagulation optimization, initiated as soon as the diagnosis is suspected, are crucial for prognosis.. Ein 40-jähriger, bislang gesunder Patient stellte sich mit neu aufgetretener, hämorrhagischer Diathese auf unserer Notfallstation vor. Klinisch fanden sich ausgeprägte Blutungsstigmata mit großflächigen Ekchymosen im Bereich der Oberschenkel sowie enorale Schleimhauteinblutungen, bei sonst allgemeinem Wohlbefinden.. Die durchgeführte Gerinnungsdiagnostik war mit dem Bild einer disseminierten intravasalen Verbrauchskoagulopathie vereinbar. Im mikroskopischen Blutbild fand sich zudem eine leukämische Ausschwemmung von 74% morphologisch atypischen Promyelozyten.. Die in der Folge durchgeführte Knochenmarkdiagnostik stellte die Diagnose einer akuten Promyelozytenleukämie (mikrogranulärer Variante). Neben der Gerinnungsoptimierung wurde noch vor Diagnosebestätigung auf der Notfallstation eine Therapie mit der Vitamin-A-Säure Tretinoin (. Die akute Promyelozytenleukämie macht etwa 10–15% aller akuten myeloischen Leukämien aus, geht initial häufig mit einer ausgeprägten Gerinnungsaktivierung im Sinne einer disseminierten intravasalen Verbrauchskoagulopathie einher und verläuft unbehandelt rasch tödlich. Eine rasche und bereits bei Diagnoseverdacht eingeleitete Therapie mit ATRA, wie auch eine Gerinnungsoptimierung, sind prognostisch entscheidend.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Disseminated Intravascular Coagulation; Humans; Leukemia, Promyelocytic, Acute; Male; Tretinoin; Vitamin A

Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia (AML) with a unique clinical presentation and prognosis. This study aimed to investigate the epidemiology, clinical characteristics, treatments, and clinical outcomes of Thai APL patients dominantly treated with all-trans-retinoic acid (ATRA) combined with a chemotherapy-based therapy.. This was an eight-year prospective, observational study from nine academic hospitals in the Thai Acute Leukemia Working Group (TALWG) of the Thai Society of Hematology, which included newly diagnosed Thai APL patients, aged 18 years or older. The web-based registration collected baseline charateristic, and clinical outcomes.. APL; acute promyelocytic leukemia; ATRA; all-transretinoic acid; CR; complete remission; DS; differentiation syndrome; ECOG; Eastern Cooperative Oncology Group; ED; early death; HR; hazard ratio; IQR; interquartile range; LFS; leukemia-free survival; OS; overall survival; WBC; white blood cell.

Topics: Antineoplastic Combined Chemotherapy Protocols; Humans; Leukemia, Promyelocytic, Acute; Leukocytosis; Prospective Studies; Treatment Outcome; Tretinoin

Topics: Anthracyclines; Antibiotics, Antineoplastic; Female; Humans; Leukemia, Promyelocytic, Acute; Long QT Syndrome; Tretinoin

Atypically expressed transglutaminase 2 (TG2) has been identified as a poor prognostic factor in a variety of cancers. In this study, we evaluated the contribution of TG2 to the prolonged cell survival of differentiated acute promyelocytic leukaemia (APL) cells in response to the standard treatment with combined retinoic acid (ATRA) and arsenic trioxide (ATO). We report that one advantage of ATRA + ATO treatment compared to ATRA alone diminishes the amount of activated and non-activated CD11b/CD18 and CD11c/CD18 cell surface integrin receptors. These changes suppress ATRA-induced TG2 docking on the cytosolic part of CD18 β2-integrin subunits and reduce cell survival. In addition, TG2 overexpresses and hyperactivates the phosphatidylinositol-3-kinase (PI3K), phospho-AKT S473, and phospho-mTOR S2481 signalling axis. mTORC2 acts as a functional switch between cell survival and death by promoting the full activation of AKT. We show that TG2 presumably triggers the formation of a signalosome platform, hyperactivates downstream mTORC2-AKT signalling, which in turn phosphorylates and inhibits the activity of FOXO3, a key pro-apoptotic transcription factor. In contrast, the absence of TG2 restores basic phospho-mTOR S2481, phospho-AKT S473, PI3K, and PTEN expression and activity, thereby sensitising APL cells to ATO-induced cell death. We conclude, that atypically expressed TG2 may serve as a hub, facilitating signal transduction via signalosome formation by the CD18 subunit with both PI3K hyperactivation and PTEN inactivation through the PI3K-PTEN cycle in ATRA-treated APL cells.

Topics: Arsenic Trioxide; Arsenicals; Cell Death; Humans; Integrins; Leukemia, Promyelocytic, Acute; Mechanistic Target of Rapamycin Complex 2; Phosphatidylinositol 3-Kinase; Phosphatidylinositol 3-Kinases; Protein Glutamine gamma Glutamyltransferase 2; Proto-Oncogene Proteins c-akt; PTEN Phosphohydrolase; TOR Serine-Threonine Kinases; Tretinoin

All-trans retinoic acid (ATRA) is used as standard induction therapy for acute promyelocytic leukemia (APL), but it is contraindicated for patients on hemodialysis. We present a case of a patient with APL on hemodialysis, intubated, and with marked disseminated intravascular coagulation (DIC) who was successfully treated with ATRA. A 49-year-old man was transferred to our hospital and admitted into the intensive care unit due to renal dysfunction, DIC, and pneumonia. Promyelocytes were noted in the peripheral blood, and he was diagnosed with APL after bone-marrow examination. Because of renal dysfunction, only Ara-C was used but with a reduced dose. The patient's condition improved, and he was extubated and withdrawn from dialysis on the 5

Topics: Acute Kidney Injury; Antineoplastic Combined Chemotherapy Protocols; Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Remission Induction; Renal Dialysis; Tretinoin

Although all-trans retinoic acid (ATRA) is an efficient pattern in acute promyelocytic leukemia (APL) therapy, further studies are required due to the extant clinical limitations of ATRA. It has been reported that Silymarin, an anti-cancer herbal substance extracted from milk thistle (Silybum marianum), is able to regulate apoptosis in various types of cancer cells through different mechanisms of action. This study investigated the apoptosis-inducing effect of Silymarin (SM) alone and in combination with ATRA on human acute promyelocytic NB4 cells. Examination using MTT assay indicated that SM treatment leads to growth inhibition in NB4 cells in a dose-dependent manner. The IC50 values of SM and ATRA were calculated 90 μM and 2 μM, respectively. Cell cycle analysis by flow cytometry revealed that a more increase in the sub-G1 phase (a sign of apoptosis) when cells were exposed to SM in combination with ATRA. The incidence of apoptosis was confirmed through Hoechst 33258 staining and Annexin V-FITC analysis. The results showed that Silymarin enhances ATRA-induced apoptosis. The flow cytometric analysis also indicated an enhancement in levels of ROS in the treated cells with both compounds. The real-time PCR illustrated that SM targets apoptosis by down-regulation in Survivin and Bcl-2 while up-regulation in Bax. The findings showed that the combination of the two compounds is more effective in the induction of apoptosis in NB4 cells. Molecular docking studies indicated that Sylibin, as a primary compound of the SM, binds to the BH3 domain of Bcl-2 and the BIR domain of Survivin with various affinities. Based on the findings, it seems that SM used alone and in combination with ATRA may be beneficial for inducing apoptosis in APL cells.

Topics: Apoptosis; Cell Differentiation; Cell Line, Tumor; Humans; Leukemia, Promyelocytic, Acute; Molecular Docking Simulation; Proto-Oncogene Proteins c-bcl-2; Silymarin; Survivin; Tretinoin

Topics: Humans; Leukemia, Promyelocytic, Acute; Tretinoin

Acute promyelocytic leukemia (APL) is a unique subtype of acute myeloid leukemia (AML) which is characterized by specific clinical and biological features. Typical APL cases are caused by PML::RARA fusion gene and are exquisitely sensitive to all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). Rarely, APLs are caused by atypical fusions involving RARA or, in fewer cases still, fusions involving other members of the retinoic acid receptors (RARB or RARG). To date, seven partner genes of RARG have been reported in a total of 18 cases of variant APL. Patients with RARG fusions showed distinct clinical resistance to ATRA and had poor outcomes. Here, we report PRPF19 gene as a novel partner of RARG and identify a rare interposition-type gene fusion in a variant APL patient with a rapidly fatal clinical course. The incomplete ligand-binding domain of RARG in the fusion protein may account for the clinical ATRA resistance in this patient. These results broaden the spectrum of variant APL associated molecular aberrations. Accurately and timely identification of these rare gene fusions in variant APL is essential to guide therapeutic decisions.

Topics: Arsenic Trioxide; DNA Repair Enzymes; Humans; Leukemia, Myeloid, Acute; Leukemia, Promyelocytic, Acute; Nuclear Proteins; Receptors, Retinoic Acid; RNA Splicing Factors; Tretinoin

Topics: Cell Differentiation; Humans; Leukemia, Myeloid, Acute; Leukemia, Promyelocytic, Acute; Receptors, Retinoic Acid; Tretinoin

Topics: Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Humans; Leukemia, Promyelocytic, Acute; Oncogene Proteins, Fusion; Oxides; Repressor Proteins; Retinoic Acid Receptor alpha; Tretinoin

The promyelocytic leukemia-retinoic acid receptor-α (PML::RARA) fusion is the hallmark of acute promyelocytic leukemia (APL) and is observed in over 95% of APL cases. RARA and homologous receptors RARB and RARG are occasionally fused to other gene partners, which differentially affect sensitivity to targeted therapies. Most APLs without RARA fusions have rearrangements involving RARG or RARB, both of which frequently show resistance to all-trans-retinoic acid (ATRA) and/or multiagent chemotherapy for acute myeloid leukemia (AML). We present a 13-year-old male diagnosed with variant APL with a novel FNDC3B::RARB in-frame fusion that showed no response to ATRA but responded well to conventional AML therapy. While FNDC3B has been identified as a rare RARA translocation partner in ATRA-sensitive variant APL, it has never been reported as a fusion partner with RARB and it is only the second known fusion partner with RARB in variant APL. We also show that this novel fusion confers an RNA expression signature that is similar to APL, despite clinical resistance to ATRA monotherapy.

Topics: Adolescent; Fibronectins; Genomics; Humans; Leukemia, Myeloid, Acute; Leukemia, Promyelocytic, Acute; Male; Oncogene Proteins, Fusion; Retinoic Acid Receptor alpha; Translocation, Genetic; Tretinoin

Topics: Humans; Leukemia, Promyelocytic, Acute; Tretinoin

Topics: Antineoplastic Agents; Arsenic Trioxide; Arsenicals; Humans; Leukemia, Promyelocytic, Acute; Oxides; Recurrence; Tretinoin

To investigate the effect of a water-soluble novel dihydroartemisinin dimer containing nitrogen atoms SM 1044 on the apoptosis of all-trans retinoic acid (ATRA) resistant acute promyelocytic leukemia (APL) NB4-R1 cells and its potential mechanism.. The effects of SM 1044 on cell apoptosis, mitochondrial transmembrane potential, and the level of reactive oxygen species (ROS) were assessed by flow cytometry. Expressions of apoptosis-related proteins were determined by Western blot. The effects of SM 1044 on MAPK (ERK, JNK) signaling pathway, PML/RARα fusion protein, and expressions of apoptosis-related proteins were detected by Western blot.. SM 1044 could significantly induce apoptosis and the loss of mitochondrial transmembrane potential in NB4-R1 cells, and activate apoptosis-related proteins caspase-3, caspase-8, caspase-9 and poly (ADP-ribose) polymerase (PARP). SM 1044 could also induce NB4-R1 cells to produce ROS. Western blot showed that SM 1044 activated the phosphorylation of MAPK (ERK, JNK) signaling pathway and down-regulated the expression of PML/RARα fusion protein.. SM 1044 can induce apoptosis of ATRA resistant APL NB4-R1 cells, which may be related to ROS/ERK and ROS/JNK signaling pathway, and can also induce by down-regulating PML/RARα fusion protein.. 新型含氮双氢青蒿素二聚体对人白血病细胞株NB4-R1细胞凋亡的影响.. 探讨新型水溶性含氮双氢青蒿素二聚体SM 1044对全反式维甲酸耐药急性早幼粒细胞白血病细胞株NB4-R1细胞凋亡的影响及其可能的机制。.. 流式细胞术检测SM 1044对细胞凋亡、线粒体跨膜电位以及细胞活性氧（ROS）水平的影响，Western blot检测SM 1044对MAPK（ERK、JNK）信号通路以及PML/RARα融合蛋白的影响和凋亡相关蛋白表达的变化。.. SM 1044能够显著诱导NB4-R1细胞发生细胞凋亡以及线粒体跨膜电位丢失，同时能活化凋亡相关蛋白caspase-3、caspase-8、caspase-9以及抗多腺苷二磷酸核糖聚合酶；SM 1044可诱导NB4-R1细胞产生ROS；Western blot检测结果显示，SM 1044能够激活MAPK（ERK、JNK）信号通路的磷酸化，同时下调PML/RARα融合蛋白的表达。.. SM 1044能够诱导全反式维甲酸耐药急性早幼粒细胞白血病细胞株NB4-R1细胞凋亡，其诱导凋亡可能与ROS/ERK以及ROS/JNK信号通路有关，此外，SM 1044也可通过下调PML/RARα融合蛋白诱导细胞凋亡。.

Topics: Apoptosis; Cell Differentiation; Cell Line; Humans; Leukemia, Promyelocytic, Acute; Oncogene Proteins, Fusion; Reactive Oxygen Species; Tretinoin

In this study, we present a case of acute myeloid leukemia characterized by the t(11;12)(p15;q13) translocation, exhibiting clinical, immunophenotypical, and morphological features consistent with acute promyelocytic leukemia (APL). The RNA sequencing analysis of the patient's bone marrow samples revealed the presence of the NUP98-retinoic acid receptor gamma (RARG) (NUP98::RARG) gene resulting from the translocation. Furthermore, the presence of a mutation in the ARID1B gene in the patient under study indicates a potential association with resistance to all-trans retinoic acid (ATRA).

Topics: DNA-Binding Proteins; Humans; Leukemia, Myeloid, Acute; Leukemia, Promyelocytic, Acute; Mutation; Transcription Factors; Translocation, Genetic; Tretinoin

Acute promyelocytic leukemia (APL) is a hematological disease characterized by the expression of the oncogenic fusion protein PML-RARα. The current treatment approach for APL involves differentiation therapy using all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). However, the development of resistance to therapy, occurrence of differentiation syndrome, and relapses necessitate the exploration of new treatment options that induce differentiation of leukemic blasts with low toxicity. In this study, we investigated the cellular and molecular effects of MK-8776, a specific inhibitor of CHK1, in ATRA-resistant APL cells. Treatment of APL cells with MK-8776 resulted in a decrease in PML-RARα levels, increased expression of CD11b, and increased granulocytic activity consistent with differentiation. Interestingly, we showed that the MK-8776-induced differentiating effect resulted synergic with ATO. We found that the reduction of PML-RARα by MK-8776 was dependent on both proteasome and caspases. Specifically, both caspase-1 and caspase-3 were activated by CHK1 inhibition, with caspase-3 acting upstream of caspase-1. Activation of caspase-3 was necessary to activate caspase-1 and promote PML-RARα degradation. Transcriptomic analysis revealed significant modulation of pathways and upstream regulators involved in the inflammatory response and cell cycle control upon MK-8776 treatment. Overall, the ability of MK-8776 to induce PML-RARα degradation and stimulate differentiation of immature APL cancer cells into more mature forms recapitulates the concept of differentiation therapy. Considering the in vivo tolerability of MK-8776, it will be relevant to evaluate its potential clinical benefit in APL patients resistant to standard ATRA/ATO therapy, as well as in patients with other forms of acute leukemias.

Topics: Arsenic Trioxide; Caspase 3; Caspases; Cell Differentiation; Humans; Leukemia, Promyelocytic, Acute; Oncogene Proteins, Fusion; Tretinoin

Transglutaminase 2 (TG2) is a critical cancer cell survival factor that activates several signalling pathways to foster drug resistance, cancer stem cell survival, metastasis, inflammation, epithelial-mesenchymal transition, and angiogenesis. All-trans retinoic acid (ATRA) and chemotherapy have been the standard treatments for acute promyelocytic leukaemia (APL), but clinical studies have shown that arsenic trioxide (ATO), alone or in combination with ATRA, can improve outcomes. ATO exerts cytotoxic effects in a variety of ways by inducing oxidative stress, genotoxicity, altered signal transduction, and/or epigenetic modification. In the present study, we showed that ATO increased ROS production and apoptosis ratios in ATRA-differentiated NB4 leukaemia cells, and that these responses were enhanced when TG2 was deleted. The combined ATRA + ATO treatment also increased the amount of nuclear factor erythroid 2-related factor 2 (NRF2) transcription factor, an adaptive regulator of the cellular oxidative stress response, and calpain proteolytic activity, resulting in TG2 degradation and the reduced survival of WT leukaemia cells. We further showed that the induced TG2 protein expression was degraded in the MCF-7 epithelial cell line and primary peripheral blood mononuclear cells upon ATO treatment, thereby sensitising these cell types to apoptotic signals.

Topics: Apoptosis; Arsenic Trioxide; Arsenicals; Calpain; Humans; Leukemia, Promyelocytic, Acute; Leukocytes, Mononuclear; Oxides; Protein Glutamine gamma Glutamyltransferase 2; Reactive Oxygen Species; Tretinoin

Melatonin is a powerful biological agent that has been shown to inhibit angiogenesis and also exerts anti-inflammatory effects. It is well known that new blood vessel formation (angiogenesis) has become an urgent issue in leukemia as well as solid tumors. Acute promyelocytic leukemia (APL) is a form of liquid cancer that manifests increased angiogenesis in the bone marrow of patients. Despite high-rate curable treatment with all-trans-retinoic acid (ATRA) and recently arsenic-trioxide (ATO), early death because of hemorrhage, coagulopathy, and Disseminated intravascular coagulation (DIC) remains still a concerning issue in these patients. It is, therefore, urgent to seek treatment strategies with antiangiogenic capabilities that also diminish coagulopathy and hyperfibrinolysis in APL patients. In this study, a coculture system with human umbilical vein endothelial cells (HUVECs) and NB4 APL cells was used to investigate the direct effect of melatonin on angiogenesis and its possible action on tissue factor (TF) and tissue-type plasminogen activator-1 (TPA-1) expression. Our experiments revealed that HUVEC-induced angiogenesis by cocultured NB4 cells was suppressed when melatonin alone or in combination with ATRA was added to the incubation medium. Melatonin at concentrations of 1 mM inhibited tube formation of HUVECs and also decreased interleukin-6 secretion and VEGF mRNA expression in HUVEC and NB4 cells. Taken together, the results of this study demonstrate that melatonin inhibits accelerated angiogenesis of HUVECs and ameliorates the coagulation and fibrinolysis indices stimulated by coculturing with NB4 cells.

Topics: Arsenic Trioxide; Endothelial Cells; Humans; Leukemia, Promyelocytic, Acute; Melatonin; Tretinoin

Significant variations exist related to the end of induction practices in the management of Acute Promyelocytic Leukemia (APL). These variations include all-trans retinoic acid (ATRA)-arsenic trioxide (ATO) in fixed doses versus continuation until hematologic complete remission (CR) and performance versus omission of post-induction bone marrow biopsy to confirm morphological CR. A retrospective chart review was conducted of 61 patients (42 low/intermediate-risk and 19 high-risk) aged ≥ 18 years with newly diagnosed APL treated with fixed duration ATRA-ATO +/- cytoreduction at a tertiary medical center from December 2012 through March 2020. Of the 54 patients with post-induction bone marrow biopsy results, 52 (96%) demonstrated no morphologic evidence of APL while the remaining were equivocal. After 2.6 years median follow-up, no relapses occurred. The estimated 2-year overall survival rate of 95% suggests excellent outcomes with a fixed ATO induction regimen and safe omission of post-induction bone marrow biopsy irrespective of hematologic parameters.

Topics: Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Bone Marrow; Humans; Leukemia, Promyelocytic, Acute; Oxides; Remission Induction; Retrospective Studies; Treatment Outcome; Tretinoin

Membranous CD14 is crucial in the phagocytic activity of neutrophils. However, the role of CD14(+) microparticles (MPs) derived from apoptotic neutrophils (apo-MP) during the phagocytic process is not clear. All trans-retinoic acid (ATRA) induces acute promyelocytic leukemic NB4 cells along granulocytic differentiation. In this study, we investigated the role of CD14(+)apo-MP in the cell-cell interaction during the phagocytic process of apoptotic cells by viable ATRA-NB4 cells. We firstly demonstrate that CD14 expression and phagocytic activity of NB4 cells were upregulated simultaneously after ATRA treatment in a time-dependent manner, and both were significantly enhanced via concurrent lipopolysaccharide treatment. The phagocytic activity of ATRA-NB4 cells and lipopolysaccharide-treated ATRA-NB4 cells were both significantly attenuated by pre-treating cells with an antibody specific to either CD14 or TLR4. Further flow cytometric analysis demonstrates that apoptotic ATRA-NB4 cells release CD14(+)apo-MP in an idarubicin dosage-dependent manner. Both CD14 expression and the phagocytic activity of viable ATRA-NB4 cells were significantly enhanced after incubation with apo-MP harvested from apoptotic ATRA-NB4 cells, and the apo-MP-enhanced phagocytic activity was significantly attenuated by pre-treating apo-MP with an anti-CD14 antibody before incubation with viable cells. We conclude that CD14(+)apo-MP derived from apoptotic ATRA-NB4 cells promotes the phagocytic activity of viable ATRA-NB4 cells in engulfing apoptotic cells.

Topics: Apoptosis; Humans; Leukemia, Promyelocytic, Acute; Lipopolysaccharides; Phagocytosis; Tretinoin

Although all-trans retinoic acid (ATRA)-induced differentiation has transformed acute promyelocytic leukemia (APL) from the most fatal to the most curable hematological disease, resistance to ATRA in high-risk APL patients remains a clinical challenge. In this paper, we discovered that dihydroorotate dehydrogenase (DHODH) inhibition overcame ATRA resistance. 416, a potent DHODH inhibitor previously obtained in our group, inhibited the occurrence of APL in cells and model mice. Excitingly, 416 effectively overcame ATRA resistance in vitro and in vivo by inducing apoptosis and differentiation. Further mechanistic studies showed that PML/RARα lost the regulation of Bcl-2 and c-Myc in NB4-R1 cells, which probably contributed to ATRA resistance. Notably, 416 maintained its Bcl-2 and c-Myc down-regulation effect in NB4-R1 cells and overcome ATRA resistance by inhibiting DHODH. In conclusion, our study highlights the potential of 416 for APL therapy and overcoming ATRA resistance, supporting the further development of DHODH inhibitors for clinical use in refractory and relapsed APL.

Topics: Animals; Antineoplastic Agents; Cell Differentiation; Dihydroorotate Dehydrogenase; Drug Resistance, Neoplasm; Leukemia, Promyelocytic, Acute; Mice; Tretinoin

Therapeutic advances in acute promyelocytic leukemia (APL) have transformed it into today's most curable form of leukemia. However, recommended agents, including arsenic trioxide, idarubicin, or daunorubicin, are not easily available in low-middle-income countries, where outcomes remain suboptimal. We aimed to assess the efficacy and safety of more accessible anthracyclines.. We conducted a retrospective cohort study including sixty-one patients diagnosed with APL over a 15-year period. Patients received low-dose all-trans retinoic acid (ATRA, 25 mg/m. Thirty (49.18%) patients received mitoxantrone, and 31 (50.82%) received doxorubicin. The median follow-up was 24.6 months (1-146). Twenty-eight (93.3%) patients achieved complete remission (CR) in the mitoxantrone group and 28 (87.1%) in the doxorubicin group (p=0.103), and the median time to CR was 40 and 31 days, respectively. Mitoxantrone had a 6.7% early mortality rate and a 16.7% relapse rate compared with doxorubicin (3.2% and 32.3%, respectively). No differences were found in survival (p = 0.795), hospitalization days (p = 0.261), or adverse events (p = 0.554).. Using mitoxantrone or doxorubicin as induction therapy in newly diagnosed APL is a safe and adequate alternative with comparable outcomes to first-line agents in scenarios where the latter might not be readily available, such as in low-middle-income countries.

Topics: Anthracyclines; Doxorubicin; Humans; Induction Chemotherapy; Leukemia, Promyelocytic, Acute; Mitoxantrone; Remission Induction; Retrospective Studies; Treatment Outcome; Tretinoin

The innovative combination of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) has established a new chapter of curative approach in acute promyelocytic leukemia (APL). The disease characteristics and prognostic influence of additional cytogenetic abnormalities (ACA) in APL with modern therapeutic strategy need to be elucidated.. In the present study, we retrospectively investigated disease features and prognostic power of ACA in 171 APL patients treated with ATRA-ATO-containing regimens.. Patients with ACA had markedly decreased hemoglobin levels than that without ACA (p = 0.021). Risk stratification in the ACA group was significantly worse than that in the non-ACA group (p = 0.032). With a median follow-up period of 62.0 months, worse event-free survival (EFS) was demonstrated in patients harboring ACA. Multivariate analysis showed that ACA was an independent adverse factor for EFS (p = 0.033). By further subgroup analysis, in CD34 and CD56 negative APL, patients harboring ACA had inferior EFS (p = 0.017; p = 0.037).. To sum up, ACA remains the independent prognostic value for EFS, we should build risk-adapted therapeutic strategies in the long-term management of APL when such abnormalities are detected.

Topics: Antineoplastic Combined Chemotherapy Protocols; Arsenicals; Chromosome Aberrations; Humans; Leukemia, Promyelocytic, Acute; Oxides; Progression-Free Survival; Retrospective Studies; Treatment Outcome; Tretinoin

Topics: Homoharringtonine; Humans; Leukemia, Promyelocytic, Acute; Ligands; Oncogene Proteins, Fusion; Protein Domains; Retinoic Acid Receptor alpha; Tretinoin

Here we report a new fusion gene, STRN3-RARA, in acute promyelocytic leukemia (APL). It cooperates with UTX deficiency to drive full-blown APL in mice. Although STRN3-RARA leukemia quickly relapses after all-trans retinoic acid treatment, it can be restrained by cepharanthine.

Topics: Animals; Leukemia, Promyelocytic, Acute; Mice; Oncogene Proteins, Fusion; Tretinoin

Acute Promyelocytic Leukemia (APL) is associated with excellent long-term outcomes. However, early mortality due to coagulopathy remains a challenge. In this study we examined the bleeding and thrombotic manifestations, as well as incidence of Early Death secondary to thrombosis/hemorrhage (ED-TH) in patients with APL. Early death (ED) was defined as death occurring within 30 days of induction therapy. Two-hundred forty-eight patients were included in the study. Overall, 57 patients had evidence of a major bleed/thrombosis at presentation or during induction therapy, including 44 patients with a major bleed, 8 patients with thrombosis and 5 patients with both evidence of thrombosis and a major bleed. Forty patients (16.1%) had ED, of which 21 had ED-TH. The cumulative incidence of death due to thrombo-hemorrhagic complications at 30 days was 8.4%. On univariate analysis, increasing Prothrombin time (PT)(p-<0.001), white blood cell count (p < 0.001) and activated Partial thromboplastin time (aPTT) (p < 0.001) were statistically significantly associated with increased risk of ED-TH. However, on multivariate analysis, only increasing PT (p-0.025) and aPTT (p-0.041) were significantly associated with increased risk of ED-TH.

Topics: Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Hemorrhage; Humans; Leukemia, Promyelocytic, Acute; Thrombosis; Tretinoin

Topics: Humans; Inclusion Bodies; Induction Chemotherapy; Leukemia, Promyelocytic, Acute; Peroxidase; Tretinoin

One of the defining features of acute myeloid leukemia (AML) is an arrest of myeloid differentiation whose molecular determinants are still poorly defined. Pharmacological removal of the differentiation block contributes to the cure of acute promyelocytic leukemia (APL) in the absence of cytotoxic chemotherapy, but this approach has not yet been translated to non-APL AMLs. Here, by investigating the function of hypoxia-inducible transcription factors HIF1α and HIF2α, we found that both genes exert oncogenic functions in AML and that HIF2α is a novel regulator of the AML differentiation block. Mechanistically, we found that HIF2α promotes the expression of transcriptional repressors that have been implicated in suppressing AML myeloid differentiation programs. Importantly, we positioned HIF2α under direct transcriptional control by the prodifferentiation agent all-trans retinoic acid (ATRA) and demonstrated that HIF2α blockade cooperates with ATRA to trigger AML cell differentiation. In conclusion, we propose that HIF2α inhibition may open new therapeutic avenues for AML treatment by licensing blasts maturation and leukemia debulking.

Topics: Cell Differentiation; Gene Expression Regulation; Humans; Leukemia, Myeloid, Acute; Leukemia, Promyelocytic, Acute; Transcription Factors; Tretinoin

To explore the effect of cytokine levels on early death and coagulation function of patients with newly diagnosed acute promyelocytic leukemia (APL).. Routine examination was performed on 69 newly diagnosed APL patients at admission. Meanwhile, 4 ml fasting venous blood was extracted from the patients. And then the supernatant was taken after centrifugation. The concentrations of cytokines, lactate dehydrogenase (LDH) and ferritin were detected by using the corresponding kits.. It was confirmed that cerebral hemorrhage was a major cause of early death in APL patients. Elevated LDH, decreased platelets (PLT) count and prolonged prothrombin time (PT) were high risk factors for early death (. Elevated cytokine levels in newly diagnosed APL patients increase the risk of early bleeding and death. In addition to the interaction between cytokines themselves, ferritin and LDH positively affect the expression of cytokines, thus affecting the prognosis of APL patients.. 细胞因子对初诊急性早幼粒细胞白血病患者早期死亡的影响.. 探索细胞因子对初诊急性早幼粒细胞白血病（APL）患者早期死亡及凝血功能障碍的影响。.. 69例初诊APL患者入院时完善常规检查，采集空腹静脉血4 ml，离心后取上清液，通过相应试剂盒检测细胞因子浓度及铁蛋白、乳酸脱氢酶（LDH）的浓度。.. 初诊APL患者细胞因子水平升高导致早期出血及死亡风险增加。铁蛋白及LDH正向影响细胞因子表达，从而影响APL患者预后，细胞因子之间也相互影响。.

Topics: Blood Coagulation Disorders; Cytokines; Ferritins; Humans; Interleukin-10; Interleukin-17; Interleukin-5; Interleukin-6; Leukemia, Promyelocytic, Acute; Tretinoin

Acute promyelocytic leukemia (APML) is a medical emergency that can initially present with neuro-ophthalmologic signs. Early recognition is crucial, and immediate treatment with all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) can be life-saving. The goal of this study was to describe patients who first presented to neuro-ophthalmology and were subsequently diagnosed with APML.. We retrospectively reviewed consecutive patients seen at a tertiary neuro-ophthalmology centre. Patients with an unknown diagnosis of APML at presentation who subsequently went on to receive this diagnosis were included. Clinical characteristics, neuro-ophthalmologic findings, and outcome were retrieved.. A total of 3 patients (2 women and 1 men) with a mean age of 30.7 (range 24-33) years were included in the study. Neuro-ophthalmologic diagnoses at presentation were severe hemorrhagic papilledema related to dural venous sinus thrombosis, hemorrhagic bilateral optic disc edema, and left homonymous hemianopia related to an occipital lobe hemorrhage. At diagnosis, the average hemoglobin was 83.7g/L (range 78-104), and the platelet count was 39.3 × 109/L (range 15-77). All patients were treated with ATRA and ATO. One patient developed papilledema and sixth nerve palsies related to this treatment, which resolved with acetazolamide. Clinical follow-up ranged from 6 to 12 months, and all patients were in clinical remission about systemic APML.. Neuro-ophthalmologic symptoms may be the first manifestations of APML, and a complete blood count is an essential test in patients presenting with optic disc edema, especially if hemorrhagic.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Female; Humans; Leukemia, Promyelocytic, Acute; Male; Ophthalmology; Papilledema; Retrospective Studies; Treatment Outcome; Tretinoin; Young Adult

The survival of patients with acute promyelocytic leukemia (APL) has dramatically improved with the use of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). However, because of the complexity of the initial management, early mortality (EM) remains a major contributor to treatment failure. It is less known whether advances in treatment, urgent access to specialized care, and broad availability of ATRA/ATO have reduced EM in the last 2 decades. Furthermore, the influence of sociodemographic factors on the risk of EM also remains unclear.. This study used the Surveillance, Epidemiology, and End Results program to characterize the impact of sociodemographic factors on the rates of EM and overall survival (OS) in patients with APL diagnosed between 1992 and 2015.. In all, 2224 cases were identified (895 who were younger than 40 years and 1329 who were 40 years old or older); 47.9% had a county-level median household income of $59,630 or higher, 49.0% belonged to counties where more than 31% of adults held at least a bachelor's degree, and 86.0% resided in urban areas. The rate of EM declined from 31.5% in 1992-1995 to 15.9% in 2012-2015 for all patients. It improved for patients younger than 40 years (27.4% in 1992-1995 vs 5.4% in 2012-2015; P < .001) and for patients 40 years old or older but not to the same extent (35.2% in 1992-1995 vs 22.2% in 2012-2015; P = .02). Importantly, improvements in EM were not seen among patients residing in rural areas, with the rate remaining higher than 20% in 2012-2015. The 3-year OS rate was 49.2% for patients with APL diagnosed in 1992-1995 and 76.4% for patients diagnosed in 2012-2015.. These findings confirm consistent improvements in EM and OS for patients with APL and point to the challenge of further extending these improvements in EM rates to older patients and to those living in rural areas.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Humans; Leukemia, Promyelocytic, Acute; Oxides; Sociodemographic Factors; Treatment Outcome; Tretinoin; United States

Acquired genetic mutations can confer resistance to arsenic trioxide (ATO) in the treatment of acute promyelocytic leukemia (APL). However, such resistance-conferring mutations are rare and do not explain most disease recurrence seen in the clinic. We have generated stable ATO-resistant promyelocytic cell lines that are less sensitive to all-trans retinoic acid (ATRA) and the combination of ATO and ATRA compared with the sensitive cell line. Characterization of these resistant cell lines that were generated in-house showed significant differences in immunophenotype, drug transporter expression, anti-apoptotic protein dependence, and promyelocytic leukemia-retinoic acid receptor alpha (PML-RARA) mutation. Gene expression profiling revealed prominent dysregulation of the cellular metabolic pathways in these ATO-resistant APL cell lines. Glycolytic inhibition by 2-deoxyglucose (2-DG) was sufficient and comparable to the standard of care (ATO) in targeting the sensitive APL cell line. 2-DG was also effective in the in vivo transplantable APL mouse model; however, it did not affect the ATO-resistant cell lines. In contrast, the resistant cell lines were significantly affected by compounds targeting mitochondrial respiration when combined with ATO, irrespective of the ATO resistance-conferring genetic mutations or the pattern of their anti-apoptotic protein dependency. Our data demonstrate that combining mitocans with ATO can overcome ATO resistance. We also show that this combination has potential for treating non-M3 acute myeloid leukemia (AML) and relapsed APL. The translation of this approach in the clinic needs to be explored further.

Topics: Animals; Apoptosis Regulatory Proteins; Arsenic Trioxide; Arsenicals; Leukemia, Promyelocytic, Acute; Mice; Oxides; Tretinoin

Topics: Humans; Leukemia, Plasma Cell; Leukemia, Promyelocytic, Acute; Tretinoin

Acute promyelocytic leukemia (APL) is a specific subtype of acute myeloid leukemia (AML) characterized by block of differentiation at the promyelocytic stage and the presence of PML-RARA fusion. In rare instances, RARA is fused with other partners in variant APL. More infrequently, non-RARA genes are rearranged in AML patients resembling APL. However, the underlying disease pathogenesis in these atypical cases is largely unknown. Here, we report the identification and characterization of a NUP98- JADE2 fusion in a pediatric AML patient showing APL-like morphology and immunophenotype. Mechanistically, we showed that NUP98-JADE2 could impair all-trans retinoic acid (ATRA)-mediated transcriptional control and myeloid differentiation. Intriguingly, NUP98-JADE2 was found to alter the subcellular distribution of wild-type JADE2, whose down-regulation similarly led to attenuated ATRA-induced responses and myeloid activation, suggesting that NUP98-JADE2 may mediate JADE2 inhibition. To our knowledge, this is the first report of a NUP98-non-RAR rearrangement identified in an AML patient mimicking APL. Our findings suggest JADE2 as a novel myeloid player involved in retinoic acid-induced differentiation. Despite lacking a rearranged RARA, our findings implicate that altered retinoic acid signaling by JADE2 disruption may underlie the APL-like features in our case, corroborating the importance of this signaling in APL pathogenesis.

Topics: Child; Humans; Leukemia, Myeloid, Acute; Leukemia, Promyelocytic, Acute; Nuclear Pore Complex Proteins; Receptors, Retinoic Acid; Tretinoin

Arsenic trioxide (ATO) treats Acute Promyelocytic Leukemia (APL). ATO is converted from inorganic arsenic (iAs) to methylated (MAs) and dimethylated (DMAs) metabolites, which are excreted in the urine. Methylation of iAs is important in detoxification, as iAs exposure is deleterious to health. We examined ATO metabolism in 25 APL patients, measuring iAs, MAs, and DMAs. Plasma total iAs increased after ATO administration, followed by a rapid decline, reaching trough levels by 4-6 h. We identified two patterns of iAs metabolism between 6 and 24 h after infusion: in Group 1, iAs increased and were slowly converted to MAs and DMAs, whereas in Group 2, iAs was rapidly metabolized. These patterns were associated with smoking and different treatments: ATO with all-trans retinoic acid (ATRA) alone vs. ATO preceded by ATRA and chemotherapy. Our data suggest that smoking and prior chemotherapy exposure may be associated with ATO metabolism stimulation, thus lowering the effective blood ATO dose.

Topics: Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Humans; Leukemia, Promyelocytic, Acute; Oxides; Tretinoin

Topics: Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Bone Marrow; Humans; Leukemia, Promyelocytic, Acute; Necrosis; Tretinoin

Pediatric acute promyelocytic leukemia (APL) is one of the most curable subtypes of acute myeloid leukemia of childhood. But it may have many early complications, especially in developing countries. This study aims to describe the outcome and complications of pediatric APL patients in Bangladesh. This prospective observational study was conducted in the pediatric hematology and oncology department of Bangabandhu Sheikh Mujib Medical University, Dhaka from September 2017 to March 2019. In this study, PML:RAR-α (Promyelocytic leukemia-retinoic acid receptor-α) positive APL cases were included and observed while being treated with risk-directed ATRA (All-trans-retinoic acid) based chemotherapy. Among twenty PML:RAR-α positive APL cases, 13 children were in the high risk group and hemorrhagic manifestations were present in 95% of patients. Post-induction remission was achieved in 85% of the patients. 3-year overall survival was 70% (45-85% with 95% confidence interval). There was no refractory disease or relapses. Neutropenic sepsis was the most common complication and also the most common cause of mortality. In Bangladesh, the 3-year overall survival of pediatric APL is 70% (45-85% with 95% CI). Post-chemotherapy neutropenic sepsis is the most common complication and also the most common cause of mortality in this potentially curable malignancy in Bangladesh.

Topics: Bangladesh; Child; Humans; Leukemia, Promyelocytic, Acute; Neoplasms; Sepsis; Tretinoin

A 57-year-old man with acute promyelocytic leukaemia (APML) received induction therapy including all-trans-retinoic acid (ATRA). At day 15, he developed dyspnoea, haemoptysis and hypoxia. Thorax CT demonstrated diffuse ground-glass opacity and consolidation predominantly in dorsal regions, which may reflect increased vascular permeability. He was diagnosed with differentiation syndrome. After dexamethasone was administered and chemotherapy suspended, his symptoms improved and abnormal lesions mostly disappeared on follow-up CT examinations. We report a short-term high-resolution CT series of differentiation syndrome.

Topics: Antineoplastic Combined Chemotherapy Protocols; Follow-Up Studies; Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Syndrome; Tomography, X-Ray Computed; Tretinoin

The role played by lipids in the process of granulocytic differentiation activated by all-trans retinoic acid (ATRA) in Acute-Promyelocytic-Leukemia (APL) blasts is unknown. The process of granulocytic differentiation activated by ATRA in APL blasts is recapitulated in the NB4 cell-line, which is characterized by expression of the pathogenic PML-RARα fusion protein. In the present study, we used the NB4 model to define the effects exerted by ATRA on lipid homeostasis. Using a high-throughput lipidomic approach, we demonstrate that exposure of the APL-derived NB4 cell-line to ATRA causes an early reduction in the amounts of cardiolipins, a major lipid component of the mitochondrial membranes. The decrease in the levels of cardiolipins results in a concomitant inhibition of mitochondrial activity. These ATRA-dependent effects are causally involved in the granulocytic maturation process. In fact, the ATRA-induced decrease of cardiolipins and the concomitant dysfunction of mitochondria precede the differentiation of retinoid-sensitive NB4 cells and the two phenomena are not observed in the retinoid-resistant NB4.306 counterparts. In addition, ethanolamine induced rescue of the mitochondrial dysfunction activated by cardiolipin deficiency inhibits ATRA-dependent granulocytic differentiation and induction of the associated autophagic process. The RNA-seq studies performed in parental NB4 cells and a NB4-derived cell population, characterized by silencing of the autophagy mediator, ATG5, provide insights into the mechanisms underlying the differentiating action of ATRA. The results indicate that ATRA causes a significant down-regulation of CRLS1 (Cardiolipin-synthase-1) and LPCAT1 (Lysophosphatidylcholine-Acyltransferase-1) mRNAs which code for two enzymes catalyzing the last steps of cardiolipin synthesis. ATRA-dependent down-regulation of CRLS1 and LPCAT1 mRNAs is functionally relevant, as it is accompanied by a significant decrease in the amounts of the corresponding proteins. Furthermore, the decrease in CRLS1 and LPCAT1 levels requires activation of the autophagic process, as down-regulation of the two proteins is blocked in ATG5-silenced NB4-shATG5 cells.

Topics: 1-Acylglycerophosphocholine O-Acyltransferase; Autophagy; Autophagy-Related Protein 5; Cardiolipins; Cell Differentiation; Cell Line, Tumor; Drug Resistance, Neoplasm; Ethanolamine; Humans; Leukemia, Promyelocytic, Acute; Lipidomics; Membrane Proteins; Mitochondria; Oncogene Proteins, Fusion; Tretinoin

Topics: Humans; Leukemia, Promyelocytic, Acute; Tretinoin

Topics: Humans; Leukemia, Promyelocytic, Acute; Risk Factors; Tretinoin

Idiopathic intracranial hypertension (IIH) (pseudotumor cerebri) is a rare side effect of all-trans retinoic acid (ATRA). IIH cases have been observed after the concomitant use of ATRA with azole group antimicrobials such as fluconazole and voriconazole. Here, we discuss about the diagnosis and treatment process of the IIH emerging in a young acute promyelocytic leukemia (APL) case with the ATRA impact, which can be increased by posaconazole.. ATRA treatment and posaconazole were interrupted. Systemic acetazolamide and dexamethasone treatment were initiated. After significant clinical response was observed, ATRA treatment was resumed without posaconazole and a similar clinical condition did not recur.. The combined use of ATRA and azole group drugs increases the risk of developing IIH. Patients with APL who developed IIH during the concomitant use of ATRA and fluconazole or voriconazole have been reported. To the best of our knowledge, our case is the first APL case with a IIH who treated with ATRA-based therapy and used posaconazole. In case of development of side effects, drugs should be interrupted and this combination should be avoided if possible after appropriate approach and clinical improvement.

Topics: Adult; Fluconazole; Humans; Leukemia, Promyelocytic, Acute; Male; Papilledema; Pseudotumor Cerebri; Tretinoin; Triazoles; Voriconazole; Young Adult

There is no established treatment for patients with acute promyelocytic leukemia (APL) refractory to targeted therapies with all-trans retinoic acid (ATRA) and/or arsenic trioxide (ATO). We report here a case of an 8-month-old girl with APL who failed standard ATRA-combined chemotherapy. Although molecular remission was achieved after introducing ATRA/ATO combination therapy, molecular relapse occurred during the ATO consolidation courses. Subsequent molecular remission was rapidly achieved after administering 2 doses of gemtuzumab ozogamicin. She was successfully treated with unrelated cord blood transplantation using reduced-intensity conditioning. Gemtuzumab ozogamicin might be a preferable choice for patients with APL refractory to standard therapy.

Topics: Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Cord Blood Stem Cell Transplantation; Female; Gemtuzumab; Humans; Infant; Leukemia, Promyelocytic, Acute; Oxides; Treatment Outcome; Tretinoin

Topics: Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Humans; Kaplan-Meier Estimate; Leukemia, Promyelocytic, Acute; Treatment Outcome; Tretinoin

At initial diagnosis, central nervous system (CNS) involvement in acute promyelocytic leukemia (APL) is rare. Here, we report a case of newly diagnosed APL with CNS involvement that was successfully treated with all-trans retinoic acid (ATRA)-combined chemotherapy. A 64-year-old woman was referred to our hospital to evaluate a bleeding tendency, and she was diagnosed with APL. Induction chemotherapy with ATRA via a nasogastric tube was initiated under mechanical ventilation because of respiratory failure and disturbance of consciousness. Although her respiratory condition improved a few days after initiating treatment, the disturbance of consciousness remained. Brain magnetic resonance imaging showed mixed signals of tumor infiltration and acute cerebral infarction with a focus on the right cerebellum. The patient was diagnosed with CNS involvement of APL and acute cerebral infarction. Three months after the initiation of induction therapy, her consciousness improved along with the reduction in CNS involvement, and complete molecular remission was achieved. Thus, patients with APL can have CNS involvement at initial diagnosis. Administering ATRA via nasogastric tube can be a good therapeutic option in patients with difficulty swallowing due to disturbance of consciousness.

Topics: Antineoplastic Combined Chemotherapy Protocols; Central Nervous System; Female; Humans; Induction Chemotherapy; Leukemia, Promyelocytic, Acute; Middle Aged; Remission Induction; Tretinoin

Topics: Arsenic; Arsenic Trioxide; Arsenicals; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Promyelocytic, Acute; Oxides; Sulfonamides; Tretinoin

Topics: Arsenic Trioxide; Cell Nucleus; Humans; Leukemia, Promyelocytic, Acute; Tretinoin

Acute promyelocytic leukemia (APL) differs from other forms of acute myeloid leukemia (AML), including coagulopathy, hemorrhage, disseminated intravascular coagulation (DIC), and treatment success with all-trans retinoic acid (ATRA). Despite ATRA, early deaths (ED) are still common in APL. Here, we evaluated factors associated with ED and applicability of scoring systems used to diagnose DIC. Ninety-one APL patients (55 females, 36 males, and median age 40 years) were included. ED was defined as deaths attributable to any cause between day of diagnosis and following 30th day. DIC was assessed based on DIC scoring system released by the International Society of Thrombosis and Hemostasis (ISTH) and Chinese Diagnostic Scoring System (CDSS). Patients' median follow-up time was 49.2 months, and ED developed in 14 (15.4% of) cases. Patients succumbing to ED had higher levels of the Eastern Cooperative Oncology Group Performance Status (ECOG PS), lactate dehydrogenase (LDH), and ISTH DIC, and lower fibrinogen levels (p <0.05). In multivariate Cox regression analysis, age >55 and ECOG PS ≥2 rates were revealed to be associated with ED. Based on ISTH and CDSS scores, DIC was reported in 47.3 and 58.2% of the patients, respectively. Despite advances in APL, ED is still a major obstacle. Besides the prompt recognition and correction of coagulopathy, those at high ED risk are recommended to be detected rapidly. Implementation of local treatment plans and creating awareness should be achieved in hematological centers. Common utilization of ATRA and arsenic trioxide (ATO) may be beneficial to overcome ED and coagulopathy in APL patients.

Topics: Adult; Disseminated Intravascular Coagulation; Female; Humans; Leukemia, Promyelocytic, Acute; Male; Retrospective Studies; Risk Factors; Thrombosis; Tretinoin

Acute promyelocytic leukemia (APL) is driven by the oncoprotein PML/RARα, which destroys the architecture of PML nuclear bodies (NBs). PML NBs are critical to tumor suppression, and their disruption mediated by PML/RARα accelerates APL pathogenesis. However, the mechanisms of PML NB disruption remain elusive. Here, we reveal that the failure of NB assembly in APL results from neddylation-induced aberrant phase separation of PML/RARα. Mechanistically, PML/RARα is neddylated in the RARα moiety, and this neddylation enhances its DNA-binding ability and further impedes the phase separation of the PML moiety, consequently disrupting PML NB construction. Accordingly, deneddylation of PML/RARα restores its phase separation process to reconstruct functional NBs and activates RARα signaling, thereby suppressing PML/RARα-driven leukemogenesis. Pharmacological inhibition of neddylation by MLN4924 eradicates APL cells both in vitro and in vivo. Our work elucidates the neddylation-destroyed phase separation mechanism for PML/RARα-driven NB disruption and highlights targeting neddylation for APL eradication.

Topics: Humans; Leukemia, Promyelocytic, Acute; Nuclear Bodies; Promyelocytic Leukemia Nuclear Bodies; Promyelocytic Leukemia Protein; Signal Transduction; Tretinoin

Topics: Humans; Leukemia, Promyelocytic, Acute; Machine Learning; Tretinoin

The present study aimed to investigate the efficacy and safety for alternate application of all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) combined with idarubicin (IDA)/daunorubicin (DNR) in treatment of acute promyelocytic leukemia (APL). A total of 72 ALP patients were divided into the low/medium risk and high risk groups according to the WBC and PLT levels. All APL patients received induction therapy, consolidation therapy and maintenance therapy in treatment under careful nursing monitoring. The complete response (CR) rate was 87.5% (63/72), with 95.12% (39/41) in the low/medium risk group, which was markedly higher than the 77.42% (24/31) high risk group. The PML/RAR α fusion negative rate was also markedly higher in the low/medium risk group (95.12%, 39/41) than the high risk group (77.42%, 24/31). The duration for PML/RAR α fusion negative was also significantly shorter in the low/medium risk group. Recurrence was found in cases in the low/medium risk group, markedly lower than cases in the high risk group. The overall survival (OS) time was markedly longer in low/medium risk patients high. Alternate application of the combination strategy could achieve well CR rate with less complications. And patients with low/medium risk had better clinical outcomes and prognosis than high risk patients.

Topics: Antineoplastic Agents; Arsenic Trioxide; Cohort Studies; Daunorubicin; Humans; Idarubicin; Leukemia, Promyelocytic, Acute; Prospective Studies; Tretinoin

According to a hierarchical model, targeting leukemia-initiating cells (LICs) was speculated to achieve complete remission (CR) or cure. Nonetheless, increasing evidence emphasized the plasticity of differentiated blasts undergoing interconversion into LICs. We exploited murine models of acute promyelocytic leukemia (APL), a subtype of acute myeloid leukemia driven by the promyelocytic leukemia/retinoic acid receptor (PML-RARα) oncofusion protein, which recruits histone deacetylase (HDAC)-containing complexes. We studied APLs with different LIC frequencies and investigated the effect of two HDAC inhibitors: valproic acid (VPA), with relative selectivity towards class I HDAC enzymes and vorinostat/suberoylanilide hydroxamic acid (SAHA) (pan-HDAC inhibitor) in combination with all-trans retinoic acid (ATRA), on the bulk APL cells and APL LICs. Indeed, we found that while VPA differentiates the bulk APL cells, SAHA selectively targets LICs. ATRA + VPA + SAHA combination efficiently induced CR in an APL model with lower LIC frequency. Substituting ATRA with synthetic retinoids as etretinate which promotes APL differentiation without downregulating PML/RARα compromised the therapeutic benefit of ATRA + VPA + SAHA regimen. Altogether, our study emphasizes the therapeutic power of co-targeting the plasticity and heterogeneity of cancer -herein demonstrated by tackling LICs and bulk leukemic blasts - to achieve and maintain CR.

Topics: Animals; Antineoplastic Agents; Cell Differentiation; Disease Eradication; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Leukemia, Promyelocytic, Acute; Mice; Oncogene Proteins, Fusion; Tretinoin; Valproic Acid

Genome organization plays a pivotal role in transcription, but how transcription factors (TFs) rewire the structure of the genome to initiate and maintain the programs that lead to oncogenic transformation remains poorly understood. Acute promyelocytic leukemia (APL) is a fatal subtype of leukemia driven by a chromosomal translocation between the promyelocytic leukemia (PML) and retinoic acid receptor α (RARα) genes. We used primary hematopoietic stem and progenitor cells (HSPCs) and leukemic blasts that express the fusion protein PML-RARα as a paradigm to temporally dissect the dynamic changes in the epigenome, transcriptome, and genome architecture induced during oncogenic transformation. We found that PML-RARα initiates a continuum of topologic alterations, including switches from A to B compartments, transcriptional repression, loss of active histone marks, and gain of repressive histone marks. Our multiomics-integrated analysis identifies

Topics: Cell Differentiation; Cell Transformation, Neoplastic; Humans; Kruppel-Like Factor 4; Leukemia, Promyelocytic, Acute; Oncogene Proteins, Fusion; Transcription Factors; Tretinoin

Topics: Acute Disease; Appendicitis; Blood Coagulation Disorders; Child; Humans; Leukemia, Promyelocytic, Acute; Leukemic Infiltration; Tretinoin

The rate of complete remission of acute promyelocytic leukemia (APL) is currently over 90% because of the use of all-trans retinoic acid (ATRA) with arsenic trioxide (ATO). However, hemorrhagic mortality has emerged as the most significant barrier to APL-induced remission. Neutrophils extracellular traps (NETs/ETs) cause vascular leakage by damaging the integrity of endothelial cells. We have previously demonstrated that APL cells treated with ATRA/ATO undergo a cell death process, releasing extracellular chromatin, termed ETosis/NETosis. However, the mechanism underlying the involvement of ETs in endothelial injury in APL remain largely unknown. Here, we analysed the ability of mature and immature neutrophils to release ETs, and their interaction with platelets (PLTs) in APL. Importantly, the effect of ETs on vascular endothelium in APL was discussed. Our results showed that the ability of immature neutrophils to release ETs was impaired in APL, whereas mature neutrophils produced ETs, which were associated with activated PLTs. Moreover, ATRA+ATO induced immature neutrophil differentiation, as well as increased the release of ETs from mature neutrophils. The excessive ETs damaged endothelial cells, causing blood cell leakage. Removing ETs using DNase 1 alleviated endothelial damage and improved blood cells leakage. Our results indicate that vascular endothelial injury is at least partially associated with ETs in APL, and that targeting ETs production may be an effective approach for relieving vascular leakage and reducing the burden of bleeding in APL.

Topics: Arsenic Trioxide; Endothelial Cells; Extracellular Traps; Hemorrhage; Humans; Leukemia, Promyelocytic, Acute; Tretinoin

Acute promyelocytic leukaemia (APL) is a unique subtype of acute myeloid leukaemia (AML) characterized by haematopoietic failure caused by the accumulation of abnormal promyelocytic cells in bone marrow (BM). However, indispensable BM biopsy frequently afflicts patients in leukaemia surveillance, which increases the burden on patients and reduces compliance. This study aimed to explore whether the novel circulating long noncoding RNA LOC100506453 (lnc-LOC) could be a target in diagnosis, assess the treatment response and supervise the minimal residual disease (MRD) of APL, thereby blazing a trail in noninvasive lncRNA biomarkers of APL.. Our study comprised 100 patients (40 with APL and 60 with non-APL AML) and 60 healthy donors. BM and peripheral blood (PB) sample collection was accomplished from APL patients at diagnosis and postinduction. Quantitative real-time PCR (qRT-PCR) was conducted to evaluate lnc-LOC expression. A receiver operating characteristic (ROC) analysis was implemented to analyse the value of lnc-LOC in the diagnosis of APL and treatment monitoring. For statistical analysis, the Mann-Whitney U test, a t test, and Spearman's rank correlation test were utilized.. Our results showed that BM lnc-LOC expression was significantly different between APL and healthy donors and non-APL AML. lnc-LOC was drastically downregulated in APL patients' BM after undergoing induction therapy. Lnc-LOC was upregulated in APL cell lines and downregulated after all-trans retinoic acid (ATRA)-induced myeloid differentiation, preliminarily verifying that lnc-LOC has the potential to be considered a treatment monitoring biomarker. PB lnc-LOC was positively correlated with BM lnc-LOC in APL patients, non-APL AML patients and healthy donors and decreased sharply after complete remission (CR). However, upregulated lnc-LOC was manifested in relapsed-refractory patients. A positive correlation was revealed between PB lnc-LOC and PML-RARα transcript levels in BM samples. Furthermore, we observed a positive correlation between PB lnc-LOC and BM lnc-LOC expression in APL patients, suggesting that lnc-LOC can be utilized as a noninvasive biomarker for MRD surveillance.. Our study demonstrated that PB lnc-LOC might serve as a novel noninvasive biomarker in the treatment surveillance of APL, and it innovated the investigation and application of newly found lncRNAs in APL noninvasive biomarkers used in diagnosis and detection.

Topics: Biomarkers; Bone Marrow; Case-Control Studies; Humans; Leukemia, Myeloid, Acute; Leukemia, Promyelocytic, Acute; Neoplasm, Residual; RNA, Long Noncoding; Tretinoin

Differentiation syndrome (DS) is an inflammatory complication seen in some patients with acute promyelocytic leukemia (APL) undergoing differentiation therapy with all-trans retinoic acid (ATRA) and/or arsenic trioxide (ATO). It is unknown how DS occurs, but it is believed that it is caused by inflammatory cytokines release from differentiating leukemic cells. High mobility group box-1 (HMGB1) is a DNA-binding protein that acts as a cytokine outside of cells and may play a role in inflammation. This study was conducted to determine whether HMGB1 polymorphisms (rs1360485, rs2249825 and rs1060348) are associated with the incidence of differentiation syndrome in acute promyelocytic leukemia patients treated with all-trans retinoic acid and arsenic trioxide.. One hundred and thirty APL patients and 100 healthy controls were included. Seventeen patients with differentiation syndrome were selected according to the PETHEMA criteria. Tetra-primer ARMS polymerase chain reaction (tetra-ARMS PCR) was used to determine the genotype distribution of polymorphisms. DNA sequencing was done to validate the results.. In both healthy and APL patients, AA was the most frequent genotype in rs1360485 followed by AG and GG. CC, CG, and GG were the most frequent genotypes in rs2249825 polymorphism in the order mentioned. CC was more frequent than CT, and CT was more frequent than TT in rs1060348. There was no correlation between HMGB1 polymorphisms and the incidence of differentiation syndrome based on genetic models (p-value > 0.05).. HMGB1 polymorphisms are not probably associated with DS development in APL patients treated with ATRA and ATO.

Topics: Arsenic Trioxide; Cytokines; HMGB1 Protein; Humans; Incidence; Leukemia, Promyelocytic, Acute; Polymorphism, Genetic; Syndrome; Tretinoin

Patients with newly diagnosed acute promyelocytic leukemia (APL) are often obese or overweight, accompanied by metabolic disorders, such as dyslipidemia. However, the link between dyslipidemia and leukemia is obscure. Here, we conducted a retrospective study containing 1,412 cases (319 newly diagnosed APL patients, 393 newly diagnosed non-APL acute myeloid leukemia patients, and 700 non-tumor controls) and found that APL patients had higher triglyceride levels than non- APL and control groups. Using clinical data, we revealed that hypertriglyceridemia served as a risk factor for early death in APL patients, and there was a positive correlation between triglyceride levels and leukocyte counts. RNA sequencing analysis of APL patients having high or normal triglyceride levels highlighted the contribution of peroxisome proliferatoractivated receptor-α (PPARα), a crucial regulator of cell metabolism and a transcription factor involved in cancer development. The genome-wide chromatin occupancy of PPARα revealed that PPARα co-existed with PML/RARα within the super-enhancer regions to promote cell proliferation. PPARα knockdown affected the expression of target genes responsible for APL proliferation, including FLT3, and functionally inhibited the proliferation of APL cells. Moreover, in vivo results in mice having high fat diet-induced high triglyceride levels supported the connection between high triglyceride levels and the leukemic burden, as well as the involvement of PPARα-mediated-FLT3 activation in the proliferation of APL cells. Our findings shed light on the association between APL proliferation and high triglyceride levels and provide a genetic link to PPARα-mediated hyperlipidemia in APL.

Topics: Animals; Hyperlipidemias; Hypertriglyceridemia; Leukemia, Promyelocytic, Acute; Mice; Oncogene Proteins, Fusion; PPAR alpha; Retrospective Studies; Tretinoin; Triglycerides

Topics: Cell Differentiation; Humans; Interferon-Stimulated Gene Factor 3, gamma Subunit; Leukemia, Myeloid, Acute; Leukemia, Promyelocytic, Acute; Oncogene Proteins, Fusion; Phenotype; Tretinoin; U937 Cells

Topics: Biochemical Phenomena; Humans; Leukemia, Promyelocytic, Acute; Tretinoin

We evaluated the feasibility and long-term efficacy of the combination of cytarabine, idarubicin, and all-trans retinoic acid (ATRA) for treating patients with newly diagnosed acute promyelocytic leukemia (APL).. We included 87 patients with newly diagnosed acute myeloid leukemia and a t(15;17) or promyelocytic leukemia/retinoic acid receptor alpha (PML-RARα) mutation. Patients received 12 mg/m2/day idarubicin intravenously for 3 days and 100 mg/m2/day cytarabine for 7 days, plus 45 mg/m2/day ATRA. Clinical outcomes included complete remission (CR), relapse-free survival (RFS), overall survival (OS), and the secondary malignancy incidence during a 20-year follow-up.. The CR, 10-year RFS, and 10-year OS rates were 89.7%, 94.1%, and 73.8%, respectively, for all patients. The 10-year OS rate was 100% for patients that achieved CR. Subjects were classified according to the white blood cell (WBC) count in peripheral blood at diagnosis (low-risk, WBC < 10,000/mm3; high-risk, WBC ≥ 10,000/mm3). The low-risk group had significantly higher RFS and OS rates than the high-risk group, but the outcomes were not superior to the current standard treatment (arsenic trioxide plus ATRA). Toxicities were similar to those observed with anthracycline plus ATRA, and higher than those observed with arsenic trioxide plus ATRA. The secondary malignancy incidence after APL treatment was 2.7%, among the 75 patients that achieved CR, and 5.0% among the 40 patients that survived more than 5 years after the APL diagnosis.. Adding cytarabine to anthracycline plus ATRA was not inferior to anthracycline plus ATRA alone, but it was not comparable to arsenic trioxide plus ATRA. The probability of secondary malignancy was low.

Topics: Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Cytarabine; Follow-Up Studies; Humans; Idarubicin; Leukemia, Promyelocytic, Acute; Recurrence; Remission Induction; Treatment Outcome; Tretinoin

Treatment of acute promyelocytic leukaemia has emerged as a major success in hemato-oncology. While literature from the developed world boasts of outstanding outcomes, there is a paucity of data from the developing world. This study aimed to assess complications and outcomes of acute promyelocytic leukaemia in a resource-constrained setting.. We retrospectively collected data from patients diagnosed with APL from January 2016 to December 2020.. Sixty-four patients were treated-32 in both the Sanz high and low-risk groups. In the Sanz low-risk group, 12.5% of patients received ATRA with daunorubicin and 81.25% received ATRA with ATO. In the Sanz high-risk group, 18.8% of patients received ATRA with daunorubicin, 34.3% received ATRA with daunorubicin and ATO while 40.6% received ATRA with ATO. 56.25% of patients developed differentiation syndrome. The incidence was higher in Sanz high-risk group as compared to Sanz low-risk group. 57.4% of patients had an infection at the time of presentation. 62.5% of patients developed neutropenic fever during treatment. 17.2% of patients developed pseudotumor cerebri. The 4-year EFS and OS were 71.25 and 73.13%, respectively. Sanz low-risk group had a better 4-year EFS and OS as compared to the Sanz high-risk group. Haemoglobin at presentation and Sanz high-risk group were associated with poorer outcomes with a hazard ratio of 0.8 and 3.1, respectively. Outcomes in high-risk patients were better with the use of ATRA + ATO + daunorubicin.. In the Indian population, APL patients have a high incidence of differentiation syndrome, pseudotumor cerebri, and infections during induction. CR, EFS, and OS compared to the developed world can be achieved with optimal therapy. Low haemoglobin at presentation and Sanz high-risk group were associated with poorer outcomes. ATRA, ATO, and daunorubicin combination is the preferred protocol for treating high-risk patients.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cohort Studies; Daunorubicin; Humans; Leukemia, Promyelocytic, Acute; Pseudotumor Cerebri; Retrospective Studies; Syndrome; Treatment Outcome; Tretinoin

Cancer cell heterogeneity is a major driver of therapy resistance. To characterize resistant cells and their vulnerabilities, we studied the PLZF-RARA variant of acute promyelocytic leukemia, resistant to retinoic acid (RA), using single-cell multiomics. We uncovered transcriptional and chromatin heterogeneity in leukemia cells. We identified a subset of cells resistant to RA with proliferation, DNA replication, and repair signatures that depend on a fine-tuned E2F transcriptional network targeting the epigenetic regulator enhancer of zeste homolog 2 (EZH2). Epigenomic and functional analyses validated the driver role of EZH2 in RA resistance. Targeting pan-EZH2 activities (canonical/noncanonical) was necessary to eliminate leukemia relapse-initiating cells, which underlies a dependency of resistant cells on an EZH2 noncanonical activity and the necessity to degrade EZH2 to overcome resistance. Our study provides critical insights into the mechanisms of RA resistance that allow us to eliminate treatment-resistant leukemia cells by targeting EZH2, thus highlighting a potential targeted therapy approach. Beyond RA resistance and acute promyelocytic leukemia context, our study also demonstrates the power of single-cell multiomics to identify, characterize, and clear therapy-resistant cells.

Topics: Enhancer of Zeste Homolog 2 Protein; Humans; Leukemia, Promyelocytic, Acute; Nuclear Proteins; Receptors, Retinoic Acid; Retinoic Acid Receptor alpha; Transcription Factors; Tretinoin

The suspicion of acute myeloid leukemia (AML) is a haematological emergency that requires a rapid diagnostic workup. Symptoms are usually caused by cytopenias of all blood cell lines. The differentiation of acute promyelocytic leukemia (APL) is important because of the early death rate caused by thrombembolic and bleeding events. Rapid immunophenotypic and genetic characterization is necessary for risk stratification and therapy selection. For this purpose, a center with appropriate expertise should be contacted. Therapy has become more complex due to numerous new approvals. For certain patients, the established intensive induction therapy with cytarabine and anthracycline is now combined with targeted agents, like the antibody conjugate Gemtuzumab-Ozogamicin or the FLT3 inhibitor Midostaurin. Patients with secondary AML benefit from the liposomal chemotherapy combination CPX-351. Therapy with the hypomethylating agent Azacitidine and the BCL2-inhibitor Venetoclax (Aza/Ven) represents the standard for patients who are not fit for intensive therapy. Here, it is important to consider interactions with CYP3A4-effective drugs.In most cases, APL is treated "chemotherapy-free" with all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). In high-risk patients, the combination of chemotherapy and ATRA is still standard.Moreover, maintenance therapies were (re)established as an important therapeutic element of post-remission therapy. For example, Midostaurin is used in patients with FLT3 mutations, as is the multikinase inhibitor sorafenib after allogeneic stem cell transplantation. In addition, oral azacitidine is available for non-allogeneic transplant eligible patients in first complete remission. These new drugs have improved prognosis and resulted in a more individualized therapy mostly driven by genetic aberrations. This development will continue in the next years and will significantly improve treatment options, especially for older patients.. Für die Risikostratifizierung und Therapie der akuten myeloischen Leukämie (AML) ist eine Klassifikation nach zytogenetischen und molekulargenetischen Merkmalen erforderlich. Die Panel-Sequenzierung mittels Next-Generation-Sequencing ist inzwischen in der initialen Diagnostik der AML Routine. Durch die Bestimmung der sogenannten messbaren Resterkrankung steht ein Werkzeug zur Verfügung, das auch innerhalb der kompletten Remission noch Abstufungen hinsichtlich der Tiefe des Ansprechens zulässt.. Die Therapie der AML ist in den letzten Jahren durch zahlreiche Neuzulassungen deutlich komplexer geworden. Die etablierte intensive Induktionstherapie mit Cytarabin und Anthracyclin wird inzwischen für bestimmte Patient*innen um zielgerichtete Substanzen wie das Antikörperkonjugat Gemtuzumab-Ozogamicin (GO) oder den FLT3-Inhibitor Midostaurin ergänzt. Insbesondere Patient*innen mit einer sekundären AML profitieren von der liposomalen Chemotherapie-Fixkombination CPX-351. Die Therapie mit der hypomethylierenden Substanz Azacitidin und dem BCL2-Inhibitor Venetoclax (Aza/Ven) hat sich als Standard für Patient*innen etabliert, die nicht fit genug für eine intensive Induktionstherapie sind. Bei dieser Therapie ist die Beachtung von Interaktionen mit CYP3A4-wirksamen Medikamenten besonders wichtig. Ob ältere Patienten*innen eher von einer intensiven Chemotherapie oder Aza/Ven profitieren, ist derzeit unklar.. Auch in der Postremissionstherapie hat sich mit der (erneuten) Etablierung von Erhaltungstherapien viel verändert. So wird Midostaurin bei Patient*innen mit FLT3-Mutation eingesetzt oder der Multikinase-Inhibitor Sorafenib nach allogener Stammzell-Transplantation. Zudem steht für nicht allogen transplantierbare Patient*innen orales Azacitidin zur Verfügung. AKUTE PROMYELOZYTEN-LEUKäMIE:  Für die Therapie der APL erfolgt in den meisten Fällen eine „Chemotherapie-freie“ Behandlung mit All-trans-Retinsäure (ATRA) und Arsentrioxid (ATO). Bei hohem Risiko ist weiterhin die Kombination aus Chemotherapie und ATRA Standard.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Azacitidine; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Leukemia, Promyelocytic, Acute; Tretinoin

The coincident downregulation of NR4A1 and NR4A3 has been implicated in myeloid leukemogenesis, but it remains unknown how these two genes function in myeloid cells and how their combined downregulation promotes myeloid leukemogenesis. Since NR4A1 abrogation is thought to confer a survival and proliferation advantage to myeloid cells, we hypothesized that downregulation of NR4A3 may have a complementary effect on myeloid cell differentiation. First, we tested the association between differentiation status of leukemic cells and NR4A3 expression using two large clinical datasets from patients with different acute myeloid leukemia (AML) subtypes. The analysis revealed a close association between differentiation status and different subtypes of AML Then, we probed the effects of differentiation-inducing treatments on NR4A3 expression and NR4A3 knockdown on cell differentiation using two myeloid leukemia cell lines. Differentiation-inducing treatments caused upregulation of NR4A3, while NR4A3 knockdown prevented differentiation in both cell lines. The cell culture findings were validated using samples from chronic myeloid leukemia (CML) patients at chronic, accelerated and blastic phases, and in acute promyelocytic leukemia (APL) patients before and after all trans-retinoic acid (ATRA)-based differentiation therapy. Progressive NR4A3 downregulation was coincident with impairments in differentiation in patients during progression to blastic phase of CML, and NR4A3 expression was increased in APL patients treated with ATRA-based differentiating therapy. Together, our findings demonstrate a tight association between impaired differentiation status and NR4A3 downregulation in myeloid leukemias, providing a plausible mechanistic explanation of how myeloid leukemogenesis might occur upon concurrent downregulation of NR4A1 and NR4A3.

Topics: Cell Differentiation; DNA-Binding Proteins; Down-Regulation; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Acute; Leukemia, Promyelocytic, Acute; Receptors, Steroid; Receptors, Thyroid Hormone; Tretinoin

In patients with acute promyelocytic leukemia (APL), intracranial hemorrhage (ICH), if not identified promptly, could be fatal. It is the leading cause of failure of induction and early death. Thus, biomarkers that could promptly predict severe complications are critical. Here, cytokine differences between patients with APL with and without ICH were investigated to develop predictive models for this complication. The initial cytokine profiling using plasma samples from 39 patients and 18 healthy donors found a series of cytokines that were remarkedly different between patients with APL and healthy controls. The APL patients were subsequently divided into high and low white blood cell count groups. Results showed that tumor necrosis factor a and interleukin 8 (IL-8) were vital in distinguishing patients with APL who did or did not develop ICH. In addition, verification in 81 patients with APL demonstrated that the two cytokines were positively correlated with the cumulative incidence of ICH. Finally, in-vitro and in-vivo experimental evidence were provided to show that IL-8 influenced the migration of APL-derived NB4 cells and impaired the blood-brain barrier in PML/RARα positive blast-transplanted FVB/NJ mice. These assessments may facilitate the early warning of ICH and reduce future mortality levels in APL.

Topics: Animals; Cytokines; Interleukin-8; Intracranial Hemorrhages; Leukemia, Promyelocytic, Acute; Mice; Oncogene Proteins, Fusion; Tretinoin; Tumor Necrosis Factor-alpha

Topics: Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Promyelocytic, Acute; Oncogene Proteins, Fusion; Promyelocytic Leukemia Zinc Finger Protein; Retinoic Acid Receptor alpha; Sulfonamides; Translocation, Genetic; Tretinoin

Subcellular partitioning of therapeutic agents is highly relevant to their interactions with target molecules and drug efficacy, but studying subcellular partitioning is an enormous challenge. Here, we describe the application of nanoscale secondary ion mass spectrometry (NanoSIMS) analysis to define the subcellular pharmacokinetics of a cytotoxic chemotherapy drug, arsenic trioxide (ATO). We reasoned that defining the partitioning of ATO would yield valuable insights into the mechanisms underlying ATO efficacy. NanoSIMS imaging made it possible to define the intracellular fate of ATO in a label-free manner─and with high resolution and high sensitivity. Our studies of ATO-treated cells revealed that arsenic accumulates in the nucleolus. After prolonged ATO exposure, ∼40 nm arsenic- and sulfur-rich protein aggregates appeared in the cell nucleolus, nucleus, and membrane-free compartments in the cytoplasm, and our studies suggested that the partitioning of nanoscale aggregates could be relevant to cell survival. All-trans retinoic acid increased intracellular ATO levels and accelerated the nanoscale aggregate formation in the nucleolus. This study yielded fresh insights into the subcellular pharmacokinetics of an important cancer therapeutic agent and the potential impact of drug partitioning and pharmacokinetics on drug activity.

Topics: Antineoplastic Agents; Apoptosis; Arsenic; Arsenic Trioxide; Arsenicals; Humans; Leukemia, Promyelocytic, Acute; Oxides; Protein Aggregates; Sulfur; Tretinoin

Topics: fms-Like Tyrosine Kinase 3; Humans; Leukemia, Promyelocytic, Acute; Male; Mutation; Prognosis; Testis; Tretinoin

Topics: Antineoplastic Combined Chemotherapy Protocols; Central Nervous System; Follow-Up Studies; Humans; Leukemia, Promyelocytic, Acute; Recurrence; Remission Induction; Tretinoin

Acute promyelocytic leukemia (APL) has become curable over 95% patients under a complete chemo-free treatment with all-trans retinoic acid (ATRA) and arsenic trioxide in low-risk patients. Minimizing chemotherapy has proven feasible in high-risk patients. We evaluated oral arsenic and ATRA without chemotherapy as an outpatient consolidation therapy and no maintenance for high-risk APL. We conducted a multicenter, single-arm, phase 2 study with consolidation phases. The consolidation therapy included Realgar-Indigo naturalis formula (60 mg/kg daily in an oral divided dose) in a 4-week-on and 4-week-off regimen for 4 cycles and ATRA (25 mg/m

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Arsenic; Arsenic Trioxide; Arsenicals; Humans; Leukemia, Promyelocytic, Acute; Oxides; Treatment Outcome; Tretinoin

Acute myeloid leukaemia (AML) is a rapidly fatal blood cancer that is characterised by the accumulation of immature myeloid cells in the blood and bone marrow as a result of blocked differentiation. Methods which identify master transcriptional regulators of AML subtype-specific leukaemia cell states and their combinations could be critical for discovering novel differentiation-inducing therapies. In this proof-of-concept study, we demonstrate a novel utility of the Mogrify

Topics: Cell Differentiation; Humans; Leukemia, Myeloid, Acute; Leukemia, Promyelocytic, Acute; Network Pharmacology; Oncogene Proteins, Fusion; Transcription Factors; Tretinoin

Acute promyelocytic leukemia (APL) is liable to induce disseminated intravascular coagulation and has a high early mortality. Although the combination of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) has significantly improved the complete remission rate, there are still some patients developed drug resistance. Growing evidence suggests that natural killer (NK) cell-mediated immunotherapy as a new treatment can help slow the progression of hematological malignancies. Previous studies also indicated that some tumors exhibited excellent responsiveness to NK cells in vitro. However, many clinical trial results showed that the anti-tumor effect of NK cells infusion alone was not ideal, which may be related to the inactivation of infiltrating NK cells caused by strong immunosuppression in tumor microenvironment, but the specific mechanism remains to be further explored. In the present study, we demonstrated that low doses of tetra-arsenic tetra-sulfide (As

Topics: Animals; Arsenic; Arsenicals; Immunotherapy; Leukemia, Promyelocytic, Acute; Mice; Oxides; Sulfides; Tretinoin; Tumor Microenvironment

Topics: Animals; Leukemia, Promyelocytic, Acute; Sea Anemones; Tretinoin

Topics: Antineoplastic Combined Chemotherapy Protocols; Humans; Leukemia, Promyelocytic, Acute; Tretinoin

Internal tandem duplications of the Fms-like tyrosine kinase 3 gene (. This was a retrospective cohort study including 60 patients with APL treated with all-trans retinoic acid (ATRA) and chemotherapy. Five-year overall survival (OS) and progression-free survival (PFS) were analyzed in patient groups according to the presence of

Topics: Chromosome Aberrations; fms-Like Tyrosine Kinase 3; Humans; Leukemia, Myeloid, Acute; Leukemia, Promyelocytic, Acute; Mutation; Prognosis; Retrospective Studies; Tretinoin

Acute promyelocytic leukemia (APL) is a rare disease in children and there are some different characteristics between children and adult. We aimed to evaluate incidence, clinical characteristics and treatment outcomes of pediatric APL in Korea.. Seventy-nine pediatric APL patients diagnosed from January 2009 to December 2016 in 16 tertiary medical centers in Korea were reviewed retrospectively.. Of 801 acute myeloid leukemia children, 79 (9.9%) were diagnosed with APL. The median age at diagnosis was 10.6 years (range, 1.3 to 18.0). Male and female ratio was 1:0.93. Thirty patients (38.0%) had white blood cell (WBC) count greater than 10×109/L at diagnosis. All patients received induction therapy consisting of all-trans retinoic acid and chemotherapy. Five patients (6.6%) died during induction chemotherapy and 66 patients (86.8%) achieved complete remission (CR) after induction chemotherapy. The causes of death were three intracranial hemorrhage, one cerebral infarction, and one sepsis. Five patients (7.1%) suffered a relapse during or after maintenance chemotherapy. The estimated 4-year event-free survival and overall survival (OS) rates were 82.1%±4.4%, 89.7%±5.1%, respectively. The 4-year OS was significantly higher in patients with initial WBC < 10×109/L than in those with initial WBC ≥ 10×109/L (p=0.020).. This study showed that the CR rates and survival outcomes in Korean pediatric APL patients were relatively good. The initial WBC count was the most important prognostic factor and most causes of death were related to serious bleeding in the early stage of treatment.

Topics: Adolescent; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Disease-Free Survival; Female; Humans; Induction Chemotherapy; Infant; Leukemia, Promyelocytic, Acute; Leukocyte Count; Male; Progression-Free Survival; Remission Induction; Republic of Korea; Retrospective Studies; Treatment Outcome; Tretinoin

Topics: Cell Differentiation; Humans; Leukemia, Promyelocytic, Acute; Oncogene Proteins, Fusion; Tretinoin

Arsenic trioxide (ATO) and all-trans retinoic acid (ATRA) combination therapy yields high complete remission and disease-free survival rates in acute promyelocytic leukemia (APL). ATO is dosed on actual body weight and high ATO doses in overweight patients may contribute to increased toxicity. We performed a retrospective, two-center study comparing toxicities in patients who received the Lo-Coco et al ATRA/ATO regimen with capped ATO, ≤10 mg/dose, and non-capped ATO, >10 mg/dose. A total of 44 patients were included; 15 received doses ≤10 mg and 29 received >10 mg. During induction, there was no difference in the incidence of grade ≥3 hepatotoxicity, grade ≥3 QTc prolongation, neurotoxicity, and cardiac toxicity between groups. In consolidation, patients receiving >10 mg/dose experienced a greater incidence of neurotoxicity (66.7% vs 22.2%; p = 0.046). Capping doses saved $24634.37/patient and reduced waste of partially-used vials. At a median follow-up of 27 months, no disease relapses occurred in either group. This represents an opportunity to improve the safety profile of this highly effective regimen.

Topics: Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Humans; Leukemia, Promyelocytic, Acute; Oxides; Retrospective Studies; Treatment Outcome; Tretinoin

To analyse the influence of chromosomal aberrations in addition to t(15;17)(q22;q21) in acute promyelocytic leukaemia (APL) on clinical characteristics and treatment outcomes.. Fifty-seven patients with new APL diagnoses underwent conventional cytogenetic analysis; fluorescence in situ hybridization for t(15;17)(q22;q21) and reverse transcriptase-polymerase chain reaction detected PML/RARα in two forms: L (length) and S (short) and accepted treatment with all-trans retinoic acid and chemotherapy. Patients with additional chromosome aberrations were designated as the complex karyotype group and were compared with patients with only t(15;17), who were designated as the simple karyotype group.. Additional chromosome aberrations was observed in 18/57 patients (31.6%) at initial diagnosis. Outcome was significantly different between the simple karyotype group and the complex karyotype group for complete remission (92.3% vs. 66.7% respectively, p = .025), overall survival at 3 years (92.3% vs. 65.0%, respectively, p = .017), and progression-free survival at 3 years (81.4% vs. 44.4%, respectively, p = .024).. Additional chromosome aberrations had adverse effects on the prognosis in APL.

Topics: Chromosome Aberrations; Chromosomes, Human, Pair 17; Cohort Studies; Humans; In Situ Hybridization, Fluorescence; Leukemia, Promyelocytic, Acute; Oncogene Proteins, Fusion; Prognosis; Translocation, Genetic; Tretinoin; Vietnam

Topics: Antineoplastic Agents; Humans; Leukemia, Promyelocytic, Acute; Tretinoin

Topics: Adult; Antineoplastic Agents; Central Nervous System; Central Nervous System Neoplasms; Humans; Leukemia, Promyelocytic, Acute; Male; Neoplasm Recurrence, Local; Tretinoin

Hyperthermia destabilizes oncofusion proteins including PML/RARα and acts synergistically with standard arsenic therapy in relapsed and refractory APL. The results open up the possibility that heat shock sensitivity may be an easily targetable vulnerability of oncofusion-driven cancers.

Topics: Humans; Hyperthermia, Induced; Leukemia, Promyelocytic, Acute; Oncogene Proteins, Fusion; Tretinoin

A 46-year-old woman was diagnosed with acute promyelocytic leukemia (APL). The patient was given remission induction therapy with all-trans retinoic acid, and complete remission was achieved. Despite consolidation therapies with arsenic trioxide, daunorubicin and cytosine arabinoside (AraC), and gemtuzumab ozogamicin as well as maintenance therapy with tamibarotene, the patient experienced a relapse 6 months after the start of maintenance therapy. She was then given re-induction therapy with idarubicin+AraC and high-dose AraC, but remission was not achieved. Since the coordination of the unrelated donor had been completed at this time, she then underwent bone marrow transplantation with pre-conditioning of 4 Gy total body irradiation, fludarabine, and busulfan. However, on the 12th day after the transplantation, APL cells appeared in the peripheral blood and the disease progressed rapidly leading to the patient's death on the 15th day after the transplantation. APL usually has a good prognosis, and relapsed cases are often cured by autologous stem cell transplantation. However, this case was highly refractory to treatment and the patient deteriorated rapidly after the transplantation, suggesting a different pathogenesis from the usual from of APL.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Arsenicals; Female; Hematopoietic Stem Cell Transplantation; Humans; Karyotype; Leukemia, Promyelocytic, Acute; Middle Aged; Oxides; Transplantation, Autologous; Treatment Outcome; Tretinoin

Acute promyelocytic leukemia (APL) is one of the most curable cancers. However, relapse of the disease is a difficult issue in clinical practice and it remains a great challenge that patients have a poor effect of conventional treatment in the clinic. Therefore, new and more effective therapeutic measures are urgently needed. Herein, we report a case of relapsed and refractory APL harboring a RARA-LBD region mutation successfully treated with venetoclax (VEN).. A 37-years-old woman was admitted to our hospital with worsening spontaneous gingival bleeding and skin ecchymosis. Physical examination revealed multiple petechiae and ecchymosis in the extremities.. The patient was diagnosed with L-type PML-RARα-positive APL, harboring a RARA-LBD region mutation, low-risk, based on bone marrow cytology, immunophenotypic analysis by flow cytometry, karyotype analysis, and molecular analysis.. Complete remission was achieved after the first induction therapy of all-trans retinoic acid (ATRA) combined with arsenic trioxide, but relapse was observed only after 11 months. Reinduction with ATRA and arsenic trioxide combined with anthracycline failed. Therefore, we tried to provide a new treatment with the Bcl-2 inhibitor VEN orally (100 mg d1, 200 mg d2 to d18, followed by 300 mg daily continuously).. Clinical symptoms and laboratory indicators improved rapidly with VEN treatment. A complete hematologic response was achieved with VEN-based therapy.. Related drug resistance gene monitoring should be performed canonically in relapsed and refractory APL. Some relapsed and refractory APL that failed to respond to conventional treatment were at risk of death. Bcl-2 inhibitors are expected to be an effective salvage therapy for patients with resistance to ATRA, which is worthy of further discussion.

Topics: Adult; Antineoplastic Agents; Arsenic Trioxide; Bridged Bicyclo Compounds, Heterocyclic; Ecchymosis; Female; Humans; Leukemia, Promyelocytic, Acute; Mutation; Proto-Oncogene Proteins c-bcl-2; Recurrence; Salvage Therapy; Sulfonamides; Treatment Outcome; Tretinoin

Acute promyelocytic leukemia (APL) with variant RARA translocation, eg, t(11;17), is not sensitive to all-trans retinoic acid and requires distinct chemotherapy. However, there are some leukemic entities that may mimic aspects of the clinical and/or laboratory picture of APL and cause confusion because of karyotype nomenclature. Therefore, recognition of such entities may be of therapeutic and prognostic significance.. We present 2 cases of acute myeloid leukemia (AML) with t(11;17) that were clinically concerning for APL based primarily on clinical presentation but were ultimately diagnosed as AML with monocytic differentiation.. Both leukemias harbored KMT2A translocations, one located near but not involving RARA and the other with SEPT9.. In leukemias that clinically and/or immunophenotypically mimic APL, identification of specific gene translocations can lead to the correct diagnosis and may carry therapeutic/prognostic implications.

Topics: Gene Rearrangement; Humans; Karyotype; Leukemia, Promyelocytic, Acute; Translocation, Genetic; Tretinoin

Topics: Cell Differentiation; Cell Line; Dexrazoxane; Humans; Leukemia, Myeloid, Acute; Leukemia, Promyelocytic, Acute; Tretinoin

Historically, arsenic exposure has been associated with herpes zoster (HZ) infection, however the risk is not well characterized in arsenic trioxide (ATO) treated patients with acute promyelocytic leukemia (APL). We aimed to characterize the risk of HZ in 112 ATO treated patients with APL with and without antiviral prophylaxis (AVP). HZ occurred in 13/112 (11.6%) within 6 months of completing ATO, including one case of HZ encephalitis. AVP reduced the incidence of HZ (17.5% vs. 4.1%, RR 0.24 [95% CI 0.05-1.0,

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Herpes Zoster; Humans; Leukemia, Promyelocytic, Acute; Oxides; Tretinoin

A little number of current autophagy inhibitors may have beneficial effects on the acute myeloid leukemia (AML) patients. However, there is a strong need to figure out which settings should be activated or inhibited in autophagy pathway to prevail drug resistance and also to improve current treatment options in leukemia. Therefore, this study aimed to compare the effects of well-known inhibitors of autophagy (as 3-MA, BafA1, and HCQ) in leukemia KG-1 and HL-60 cells exposed to arsenic trioxide (ATO) and/or all-trans retinoic acid (ATRA). Cell proliferation and cytotoxicity of cells were examined by MTT assay. Autophagy was studied by evaluating the development of acidic vesicular organelles, and the autophagosomes formation was investigated by acridine orange staining and transmission electron microscopy. Moreover, the gene and protein expressions levels of autophagy markers (ATGs, p62/SQSTM1, and LC-3B) were also performed by qPCR and western blotting, respectively. The rate of apoptosis and cell cycle were evaluated using flow cytometry. We compared the cytotoxic and apoptotic effects of ATO and/or ATRA in both cell lines and demonstrated that some autophagy markers upregulated in this context. Also, it was shown that autophagy blockers HCQ and/or BafA1 could potentiate the cytotoxic effects of ATO/ATRA, which were more pronounced in KG-1 cells compared to HL-60 cell line. This study showed the involvement of autophagy during the treatment of KG-1 and HL-60 cells by ATO/ATRA. This study proposed that therapy of ATO/ATRA in combination with HCQ can be considered as a more effective strategy for targeting leukemic KG-1 cells.

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Arsenic Trioxide; Autophagy; Cell Proliferation; HL-60 Cells; Humans; Leukemia, Myeloid, Acute; Leukemia, Promyelocytic, Acute; Tretinoin; Tumor Cells, Cultured

Topics: Arsenic Trioxide; Arsenicals; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Promyelocytic, Acute; Neoplasm Recurrence, Local; Transplantation, Autologous; Tretinoin

Retinoid therapy transformed response and survival outcomes in acute promyelocytic leukemia (APL), but has demonstrated only modest activity in non-APL forms of acute myeloid leukemia (AML). The presence of natural retinoids in vivo could influence the efficacy of pharmacologic agonists and antagonists. We found that natural RXRA ligands, but not RARA ligands, were present in murine MLL-AF9-derived myelomonocytic leukemias in vivo and that the concurrent presence of receptors and ligands acted as tumor suppressors. Pharmacologic retinoid responses could be optimized by concurrent targeting RXR ligands (e.g. bexarotene) and RARA ligands (e.g. all-trans retinoic acid, ATRA), which induced either leukemic maturation or apoptosis depending on cell culture conditions. Co-repressor release from the RARA:RXRA heterodimer occurred with RARA activation, but not RXRA activation, providing an explanation for the combination synergy. Combination synergy could be replicated in additional, but not all, AML cell lines and primary samples, and was associated with improved survival in vivo, although tolerability of bexarotene administration in mice remained an issue. These data provide insight into the basal presence of natural retinoids in leukemias in vivo and a potential strategy for clinical retinoid combination regimens in leukemias beyond acute promyelocytic leukemia.

Topics: Animals; Cell Differentiation; Leukemia, Promyelocytic, Acute; Mice; Receptors, Retinoic Acid; Retinoids; Tretinoin

Although arsenic trioxide (ATO) and all-trans retinoic acid (ATRA) are well-tolerated and effective treatments for Acute Promyelocytic Leukemia (APL), Differentiation Syndrome (DS) is a lethal side effect in some patients. The pathogenesis of DS is complex and not well understood; however, it is considered as an inflammatory response due to cytokines release of differentiated cells. Moreover, adhesion molecules that are widely expressed on the surface of differentiated cells and gene expression changes of transglutaminase2 (TGM2) are mechanisms involved in the development of DS. The purpose of this study was to assess the association of single nucleotide polymorphisms (SNP) of Intercellular Adhesion Molecule-1 (ICAM-1), chemokine (C-C motif) ligand 2 (CCL2) and TGM2 as inflammatory factors with differentiation syndrome susceptibility.. DNA was extracted from 133 APL patients and 100 normal controls. Assessment according to the PETHEMA criteria revealed that 13.5% of these patients experienced differentiation syndrome. Tetra-ARMS PCR and PCR-RFLP were done to amplify DNA fragments in APL patients with and without DS. Then DNA sequencing was done to validate the results. SNPStats, SPSS and Finch TV were used to analyze the results.. A significant correlation was found between rs4811528 in the TGM2 gene and differentiation syndrome susceptibility (P = 0.002, 95% CI = 1.74-18.81, OR = 5.72) while rs5498 in ICAM-1, rs1024611 in CCL2, and rs7270785 in TGM2 genes showed no correlation with differentiation syndrome. The G allele of rs7270785 and rs4811528 showed a haplotypic association with differentiation syndrome (P = 0.03, 95% CI = 1.13-13.86, OR = 3.96).. AA genotype of the TGM2 SNP (rs4811528) may be a risk factor for development of DS in patients with APL following the use of ATRA/ATO.

Topics: Acute Kidney Injury; Adult; Antineoplastic Agents; Biomarkers, Tumor; Case-Control Studies; Cell Differentiation; Chemokine CCL2; Female; Follow-Up Studies; GTP-Binding Proteins; Humans; Intercellular Adhesion Molecule-1; Leukemia, Promyelocytic, Acute; Lung Diseases; Male; Polymorphism, Genetic; Prognosis; Protein Glutamine gamma Glutamyltransferase 2; Survival Rate; Syndrome; Systemic Inflammatory Response Syndrome; Transglutaminases; Tretinoin

Topics: Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Child; Humans; Leukemia, Promyelocytic, Acute; Oxides; Tretinoin

Retinoic acid (RA) induces granulocytic differentiation and inhibits the growth of human promyelocytic leukemia HL60 cells. α-Actinin-4 is a member of the α-actinin family, which exhibits unique mechanosensory regulation. Herein, we elucidated the effects of RA on α-actinin-4 expression during cell differentiation. RA increased the levels of α-actinin-4 protein significantly, while mRNA expression remained unchanged. In addition, RA treatment altered the intracellular localization of α-actinin-4 from the nucleus to the cytoplasm. Cells pretreated with RA, maintained α-actinin-4 protein levels after cycloheximide treatment as compared with control cells. The amount of ubiquitylated α-actinin-4 protein in RA-treated cells was less than in control cells. These results indicate that RA may inhibit nuclei transport and proteasomal degradation of α-actinin-4 protein. α-Actinin-4 may play a significant role in RA-induced differentiation, including the promotion of cytomorphology changes.

Topics: Actinin; Cell Differentiation; Cell Line, Tumor; Cell Nucleus; Cell Proliferation; Cell Survival; Cycloheximide; Cytoplasm; Gene Expression Regulation, Neoplastic; HL-60 Cells; Humans; Leukemia, Promyelocytic, Acute; Proteolysis; Tretinoin; Ubiquitination; Up-Regulation

Acute promyelocytic leukemia (APL) is a potentially curable malignancy with 4-year overall survival rates >90%. Early complications from the disease or its treatment may result in a loss of oral access and require alternative administration of medications. Tretinoin has been the backbone of APL therapy since the late 1990s and is only available as a liquid filled capsule.. Two patients with high-risk APL were unable to safely swallow tretinoin capsules due to complications of their disease.. We prepared a tretinoin slurry using tretinoin 10 mg capsules, sterile water, and mineral oil at a ratio of 1 capsule to 2.75 mL sterile water to 1.25 mL mineral oil. This was successfully administered to both patients and no doses of tretinoin slurry were missed by either patient. In the patient who has long-term follow up available, a complete remission was achieved.. Due to tretinoin's known teratogenicity, this capsule should not be crushed, cut, or open, which limits its use in patients without oral access. Alternative routes of administration, such as via a nasogastric tube or sublingually, have not been safe and effective. By preparing a tretinoin slurry in our hazardous extemporaneous compounding area, we were able to safely and effectively prepare a tretinoin slurry that was successfully administered to two patients. This alternative preparation did not alter long-term outcomes and represents a viable option for patients who do not have oral access.

Topics: Antineoplastic Combined Chemotherapy Protocols; Humans; Leukemia, Promyelocytic, Acute; Remission Induction; Survival Rate; Tretinoin

The characteristics and outcomes of patients with acute promyelocytic leukemia (APL) from sub-Saharan Africa have not been published.. We report retrospectively on consecutively diagnosed APL patients treated in Cape Town, South Africa, during 1998-2019. A total of 69 patients were treated, of whom 27 (39%) were classified as having high risk APL.. Early death rates at 7 and 30 days were 7% and 13%, respectively, including 4 patients who died before any treatment could be administered. Overall survival at 3 years was 76.5% (95% confidence interval, 63.9-85.2) for the entire cohort, and 82.5% (95% confidence interval, 69.7-90.2) if patients who died within 7 days of diagnosis were excluded. For 13 patients (18.8%), there was a delay of 5 or more days from time of initial presentation at a peripheral hospital until arrival at the leukemia center and administration of all-trans retinoic acid; only 1 of these patients died within 30 days.. Despite the challenges faced in the public healthcare system of a developing country, outcomes of APL patients treated at our center are similar to outcomes from developed countries.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Consolidation Chemotherapy; Follow-Up Studies; Humans; Induction Chemotherapy; Kaplan-Meier Estimate; Leukemia, Promyelocytic, Acute; Maintenance Chemotherapy; Male; Middle Aged; Retrospective Studies; South Africa; Time-to-Treatment; Tretinoin; Young Adult

Topics: Cell Differentiation; Humans; Leukemia, Myelomonocytic, Chronic; Leukemia, Promyelocytic, Acute; Retinoids; Tretinoin

Topics: Antineoplastic Agents; Arsenic Trioxide; Humans; Leukemia, Promyelocytic, Acute; Prognosis; Risk Assessment; Risk Factors; Tretinoin

The purpose of this study was to evaluate the efficacy and safety of different doses of anthracyclines combined with arsenic trioxide (ATO) and all-trans retinoic acid (ATRA) for induction in newly diagnosed acute promyelocytic leukemia (APL).. One hundred and forty patients were included between January 2011 and December 2017. Seventy patients received low dose anthracycline, ATO and ATRA for induction chemotherapy; and other seventy patients received standard dose anthracycline, ATO and ATRA for induction chemotherapy.. The outcomes of both groups were similar: low dose group versus standard dose group: early mortality 5.7% vs. 10.0% (. Low-dose group achieves outcomes similar to those of standard dose group for APL patients, but the low-dose group may be even safer than standard-dose group. So the low-dose anthracycline may be a better choice for newly diagnosed APL patients.

Topics: Adolescent; Adult; Aged; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Biomarkers, Tumor; Bone Marrow; Disease Management; Female; Follow-Up Studies; Humans; Kaplan-Meier Estimate; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Prognosis; Treatment Outcome; Tretinoin; Young Adult

Granulocytic sarcoma (GS) is an extramedullary myeloid tumor composed of immature cells of the granulocytic series. It rarely occurs in acute promyelocytic leukemia (APL). No case of long-term survival in an APL patient with recurrent GS has been reported.. A 54-year-old female patient was diagnosed with APL in 1995 and has been in complete remission (CR) of bone marrow morphology for 24 years; however, recurrent GS occurred successively in ovary, breast, spine, body of sternum, lymph nodes, soft tissues from 2004 to 2019.. The immunohistochemistry confirmed the diagnosis of GS, and fluorescence in situ hybridization (FISH) revealed its origin from APL.. She received surgery, and had an excellent response to all-trans retinoic acid (ATRA), DA (daunorubicin combined with cytarabine) regimens, and arsenic trioxide (ATO).. The patient achieved CR in March 2020 after radiotherapy followed by ATO and ATRA. So far, she is still in follow-up.. It is rare that recurrent GS at multiple sites is involved in APL patient with bone marrow morphology in CR. It is interesting to observe a long-term excellent response to ATRA, chemotherapy and ATO. Although multiple recurrence of GS in patients with APL is rare, the data in this case highlight the need for individualized treatment when such conditions occur.

Topics: Female; Humans; Leukemia, Promyelocytic, Acute; Middle Aged; Remission Induction; Sarcoma, Myeloid; Tretinoin

All-trans retinoic acid (ATRA) is a physiological metabolite of vitamin A and it is used for the treatment of acute promyelocytic leukemia (APL). Hypercalcemia is a rare side effect of ATRA and it may be potentiated after interaction of ATRA with azole group antifungals. Herein, we have reported an APL case with hypercalcemia that is caused by the interaction of ATRA and posaconazole.. A 49-year-old female patient was diagnosed as APL after the examinations performed upon the detection of pancytopenia when she had presented with the complaints of widespread bruising and fever. After the initiation of posaconazole and ATRA, her serum calcium levels begin to increase (10.3 to 11.1mg/dl). Her vitamin D level was 21.9 ng/ml and PTH 17.8 pg/ml, both were in the normal ranges. The Drug Interaction Probability Scale score of our case was calculated as 6, indicating that the probable adverse drug reaction. Therefore, the high level of serum calcium was attributed to the interaction between ATRA and posaconazole.. Although hypercalcemia with ATRA and other antifungal agents have been previously reported in the literature, this is the first report of hypercalcemia with the concomitant use of ATRA and posaconazole.. This case highlights the importance of monitoring ATRA's side effects when it is used in combination with drugs inhibiting the cytochrome P450 enzymes. In conclusion, the concomitant use of posaconazole and ATRA may lead to hypercalcemia and serum calcium levels return to normal ranges with the discontinuation of these drugs.

Topics: Female; Humans; Hypercalcemia; Leukemia, Promyelocytic, Acute; Middle Aged; Tretinoin; Triazoles

Topics: Disseminated Intravascular Coagulation; Humans; Induction Chemotherapy; Leukemia, Promyelocytic, Acute; Thrombomodulin; Tretinoin

Topics: Arsenic; Arsenic Trioxide; Humans; Leukemia, Promyelocytic, Acute; Tretinoin

Better understanding of the transcriptional regulatory network in acute promyelocytic leukemia (APL) cells is critical to illustrate the pathogenesis of other types of acute myeloid leukemia. Previous studies have primarily focused on the retinoic acid signaling pathway and how it is interfered with by promyelocytic leukemia/retinoic acid receptor-α (PML/RARα) fusion protein. However, this hardly explains how APL cells are blocked at the promyelocytic stage. Here, we demonstrated that C/EBPα bound and transactivated the promoter of long non-coding RNA NEAT1, an essential element for terminal differentiation of APL cells, through C/EBP binding sites. More importantly, PML/RARα repressed C/EBPα-mediated transactivation of NEAT1 through binding to NEAT1 promoter. Consistently, mutation of the C/EBP sites or deletion of retinoic acid responsive elements (RAREs) and RARE half motifs abrogated the PML/RARα-mediated repression. Moreover, silencing of C/EBPα attenuated ATRA-induced NEAT1 upregulation and APL cell differentiation. Finally, simultaneous knockdown of C/EBPα and C/EBPβ reduces ATRA-induced upregulation of C/EBPε and dramatically impaired NEAT1 activation and APL cell differentiation. In sum, C/EBPα binds and transactivates NEAT1 whereas PML/RARα represses this process. This study describes an essential role for C/EBPα in PML/RARα-mediated repression of NEAT1 and suggests that PML/RARα could contribute to the pathogenesis of APL through suppressing C/EBPα targets.

Topics: CCAAT-Enhancer-Binding Protein-alpha; Cell Differentiation; Humans; Leukemia, Promyelocytic, Acute; Retinoic Acid Receptor alpha; RNA, Long Noncoding; Transcriptional Activation; Tretinoin; Up-Regulation

Topics: Adolescent; Child; Child, Preschool; China; Female; Humans; Leukemia, Promyelocytic, Acute; Male; Thrombosis; Tretinoin; Venous Thrombosis

Differentiation syndrome (DS) is a life-threatening complication that may be seen in patients with acute promyelocytic leukaemia undergoing induction therapy with all-trans retinoic acid or arsenic trioxide. It can lead to severe inflammatory response syndrome and shock if adequate measures are not taken immediately. The radiological features of lung nodules with changes in ground-glass opacity can represent DS. The principal unique feature of the case reported here is that the diagnosis of DS was based on imaging results in the absence of a low total leukocyte count.. A 14-year-old Indian girl diagnosed with acute promyelocytic leukaemia currently undergoing a chemotherapy regimen that included all-trans retinoic acid/arsenic trioxide was sent to the radiology department for investigation of respiratory distress which she had developed soon after the initiation of chemotherapy. Her chest radiograph showed bilateral lower zone lung infiltrates. Computed tomography (CT) revealed changes in ground-glass opacity in the lower lobes with multiple lung nodules. Differential diagnosis included bacterial, viral or fungal infections, leukemic infiltrates, drug toxicity, pulmonary haemorrhage or leukostasis. She was started on dexamethasone immediately after stopping the chemotherapy with all-trans retinoic acid/arsenic trioxide and given ventilatory support. Her condition subsequently improved and her follow-up chest radiograph and CT scan showed a significant reduction of abnormal lung findings. Based on the clinical improvement and the resolution of findings on imaging following the withdrawal of all-trans retinoic acid/arsenic trioxide, we made the diagnosis of DS.. Though a rather unusual possibility, the treatment history of the patient enabled a rather crucial diagnosis in the nick of time and imaging played a pivotal role. This case further iterates the importance of keeping DS in mind when dealing with similar patients in the future.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Leukemia, Promyelocytic, Acute; Syndrome; Tretinoin

The ZBTB16-RARA fusion gene, resulting from the reciprocal translocation between ZBTB16 on chromosome 11 and RARA genes on chromosome 17 [t(11;17)(q23;q21)], is rarely observed in acute myeloid leukemia (AML), and accounts for about 1% of retinoic acid receptor-α (RARA) rearrangements. AML with this rare translocation shows unusual bone marrow (BM) morphology, with intermediate aspects between acute promyelocytic leukemia (APL) and AML with maturation. Patients may have a high incidence of disseminated intravascular coagulation at diagnosis, are poorly responsive to all-trans retinoic acid (ATRA) and arsenic tryoxyde, and are reported to have an overall poor prognosis.. The mutational profile of ZBTB16-RARA rearranged AML has not been described so far.. We performed targeted next-generation sequencing of 24 myeloid genes in BM diagnostic samples from seven ZBTB16-RARA+AML, 103 non-RARA rearranged AML, and 46 APL. The seven ZBTB16-RARA-positive patients were then screened for additional mutations using whole exome sequencing (n = 3) or an extended cancer panel including 409 genes (n = 4).. ZBTB16-RARA+AML showed an intermediate number of mutations per patient and involvement of different genes, as compared to APL and other AMLs. In particular, we found a high incidence of ARID1A mutations in ZBTB16-RARA+AML (five of seven cases, 71%). Mutations in ARID2 and SMARCA4, other tumor suppressor genes also belonging to SWI/SNF chromatin remodeling complexes, were also identified in one case (14%).. Our data suggest the association of mutations of the ARID1A gene and of the other members of the SWI/SNF chromatin remodeling complexes with ZBTB16-RARA+AMLs, where they may support the peculiar disease phenotype.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Arsenic Trioxide; Bone Marrow; Child; Chromosomes, Human, Pair 11; Chromosomes, Human, Pair 17; Disseminated Intravascular Coagulation; DNA Helicases; DNA-Binding Proteins; Female; High-Throughput Nucleotide Sequencing; Humans; Leukemia, Myeloid, Acute; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Nuclear Proteins; Oncogene Proteins, Fusion; Prognosis; Promyelocytic Leukemia Zinc Finger Protein; Retinoic Acid Receptor alpha; Transcription Factors; Translocation, Genetic; Tretinoin

Retinoic acid (RA) was proposed to increase survival of chemotherapy- treated patients with nucleophosmin-1 (NPM-1c)-mutated acute myeloid leukemia. We reported that, ex vivo, RA triggers NPM-1c degradation, P53 activation and growth arrest. PML organizes domains that control senescence or proteolysis. Here, we demonstrate that PML is required to initiate RA-driven NPM-1c degradation, P53 activation and cell death. Mechanistically, RA enhances PML basal expression through inhibition of activated Pin1, prior to NPM-1c degradation. Such PML induction drives P53 activation, favoring blast response to chemotherapy or arsenic in vivo. This RA/PML/P53 cascade could mechanistically explain RA-facilitated chemotherapy response in patients with NPM-1c mutated acute myeloid leukemia.

Topics: Humans; Leukemia, Myeloid, Acute; Leukemia, Promyelocytic, Acute; NIMA-Interacting Peptidylprolyl Isomerase; Nuclear Proteins; Oncogene Proteins, Fusion; Tretinoin; Tumor Suppressor Protein p53

The aim of this study was to characterize a large series of 154 patients with acute promyelocytic leukemia (median age, 53 years; range, 18-90 years) and evaluate real-life outcome after up-front treatment with arsenic trioxide and all-trans retinoic acid. All patients were included in the prospective NAPOLEON registry (NCT02192619) between 2013 and 2019. The acute promyelocytic leukemia was de novo in 91% (n=140) and therapy-related in 9% (n=14); 13% (n=20) of the patients were older than 70 years. At diagnosis bleeding/hemorrhage was present in 38% and thrombosis in 3%. Complete remission was achieved in 152 patients (99%), whereas two patients (1%) experienced induction death within 18 days after starting therapy. With a median follow-up of 1.99 years (95% confidence interval: 1.61-2.30 years) 1-year and 2-year overall survival rates were 97% (95% confidence interval: 94-100%) and 95% (95% confidence interval: 91-99%), respectively. Age above 70 years was associated with a significantly shorter overall survival (P<0.001) compared to that of younger patients. So far no relapses have been observed. Six patients (4%) died in complete remission at a median of 0.95 years after diagnosis (range, 0.18-2.38 years). Our data confirm the efficiency and durability of arsenic trioxide and all-trans retinoic acid therapy in the primary management of adults with low-/intermediate-risk acute promyelocytic leukemia in the real-life setting, irrespective of age.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Arsenic Trioxide; Humans; Leukemia, Promyelocytic, Acute; Middle Aged; Prospective Studies; Remission Induction; Risk Assessment; Treatment Outcome; Tretinoin; Young Adult

Topics: Arsenic; Arsenic Trioxide; Humans; Leukemia, Promyelocytic, Acute; Tretinoin

HnRNP K protein is a heterogeneous nuclear ribonucleoprotein which has been proposed to be involved in the leukemogenesis of acute promyelocytic leukemia (APL), as well as in differentiation induced by all-trans retinoic acid (ATRA). We previously demonstrated a connection between SET and hnRNP K function in head and neck squamous cell carcinoma (HNSCC) cells related to splicing processing. The objective of this study was to characterize the participation of hnRNP K and SET proteins in ATRA-induced differentiation in APL. We observed higher (5- to 40-fold) levels of hnRNP K and SET mRNA in APL patients at the diagnosis phase compared with induction and maintenance phases. hnRNP K knockdown using short-hairpin RNA led to cell death in ATRA-sensitive NB4 and resistant NB4-R2 cells by apoptosis with SET cleavage. In addition, hnRNP K knockdown increased granulocytic differentiation in APL cells, mainly in NB4-R2 with ATRA. hnRNP K knockdown had an effect similar to that of treatment with U0126 (an meiosis-specific serine/threonine protein kinase/ERK inhibitor), mainly in NB4-R2 cells. SET knockdown in APL cells revealed that apoptosis induction in cells with hnRNP K knockdown occurred by SET cleavage rather than by reduction in SET protein. Transplantation of NB4-R2 cells into nude mice confirmed that arsenic trioxide (ATO) combined with U0126 has higher potential against tumor progression when compared to ATO. Therefore, hnRNP K/SET and ERK are potential therapeutic targets for both antineoplastic leukemia therapy and relapsed APL patients with ATRA resistance.

Topics: Animals; Arsenic Trioxide; Heterogeneous-Nuclear Ribonucleoprotein K; Humans; Leukemia, Promyelocytic, Acute; Mice; Mice, Nude; Tretinoin

Topics: Acute Disease; Humans; Leukemia, Promyelocytic, Acute; Pancreatitis; Tretinoin

Acute promyelocytic leukemia is a special subtype of acute myeloid leukemia. The incidence of early death and complications is high. An oral regimen of all-trans retinoic acid combined with the realgar-indigo naturalis formula (RIF) without chemotherapy has provided a new strategy for the treatment of these patients.. A 92-year-old male patient was admitted to the hospital due to fatigue and oral bleeding. He had no fever or lung infection. Routine blood test showed white blood cell count 1.0 ×109/L, hemoglobin 100 g/L, and platelets 21 × 109/L. Coagulation function indicated fibrinogen 1.02 g/L and D-dimer 2360 ng/mL. And 28% abnormal promyelocytes were observed in peripheral blood.. A bone marrow morphologic, immunophenotypic, cytogenetic, and molecular examination was performed. Routine bone marrow examination showed active proliferation of nucleated cells, with promyelocytes accounting for 91%; immunophenotyping revealed an early myeloid cell population, accounting for approximately 82.4% of all cells.. From February 15, 2020, 25 mg/m2 all-trans retinoic acid was orally administered daily. After the fusion gene result was obtained, oral administration of 60 mg/kg RIF daily began since February 18, 2020. The combination of the 2 agents was given until March 16, 2020. Oral administration of 25 mg/m2 retinoic acid daily began from March 20, 2020 for 2 weeks, and oral administration of 60 mg/kg RIF daily lasted for 4 weeks as the consolidation therapy. During the treatment, the proportion of promyelocytes in peripheral blood, white blood cell count, platelets, coagulation function, liver function, and QT interval were monitored.. Oral retinoic acid and oral RIF were given without chemotherapy and the patient achieved bone marrow remission after 1 month, and molecular remission was achieved 2 months later. In the early stage of acute promyelocytic leukemia, combined thrombocytopenia and disseminated intravascular coagulation may develop. Platelet and fresh frozen plasma infusion were proactively given until platelets were stabilized above 30 × 109/L, and the coagulation function returned to normal.. The regimen was safe and effective, and subsequent treatment did not require hospitalization, which helped to improve the patient's quality of life.

Topics: Administration, Oral; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Drugs, Chinese Herbal; Hematologic Tests; Humans; Leukemia, Promyelocytic, Acute; Male; Tretinoin

Differentiation therapy is attracting increasing interest in cancer as it can be more specific than conventional chemotherapy approaches, and it has offered new treatment options for some cancer types, such as treating acute promyelocytic leukaemia (APL) by retinoic acid. However, there is a pressing need to identify additional molecules which act in this way, both in leukaemia and other cancer types. In this work, we hence developed a novel transcriptional drug repositioning approach, based on both bioinformatics and cheminformatics components, that enables selecting such compounds in a more informed manner. We have validated the approach for leukaemia cells, and retrospectively retinoic acid was successfully identified using our method. Prospectively, the anti-parasitic compound fenbendazole was tested in leukaemia cells, and we were able to show that it can induce the differentiation of leukaemia cells to granulocytes in low concentrations of 0.1 μM and within as short a time period as 3 days. This work hence provides a systematic and validated approach for identifying small molecules for differentiation therapy in cancer.

Topics: Cheminformatics; Drug Repositioning; Fenbendazole; Humans; Leukemia, Promyelocytic, Acute; Tretinoin

Topics: Adolescent; Anthracyclines; Antineoplastic Agents; Antineoplastic Agents, Immunological; Arsenic Trioxide; Case-Control Studies; Child; Child, Preschool; Combined Modality Therapy; Female; Gemtuzumab; Hematopoietic Stem Cell Transplantation; Humans; Italy; Leukemia, Promyelocytic, Acute; Male; Neoplasm Recurrence, Local; Prognosis; Progression-Free Survival; Remission Induction; Retrospective Studies; Salvage Therapy; Treatment Outcome; Tretinoin; Young Adult

All-trans retinoic acid (ATRA) and pre-upfront arsenic trioxide (ATO) have revolutionized the therapy of acute promyelocytic leukemia (APL). However, internal tandem duplication of FMS-like tyrosine kinase 3 (FLT3-ITD) mutations is associated with increased risk of relapse. The aim of this study was to analyze the prognostic impact of FLT3-ITD on APL patients who received remission induction with ATRA, idarubicin (IDA) and/or ATO, followed by ATRA plus ATO along with anthracycline, as consolidation therapy. A total of 72 patients newly diagnosed with APL were included in this study. 83.3% of the patients achieved complete remission (CR) after induction therapy. FLT3-ITD mutations were detected in 16 (22.2%) patients and closely related to bcr-3 PML-RARa transcript (P<0.001). The 5-year overall survival (OS) rate was 100% in both FLT3-ITD

Topics: Adult; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Female; fms-Like Tyrosine Kinase 3; Gene Duplication; Humans; Idarubicin; Leukemia, Promyelocytic, Acute; Male; Mutation; Prognosis; Tretinoin; Young Adult

Topics: Adult; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Combined Modality Therapy; Female; Gene Rearrangement; Hematopoietic Stem Cell Transplantation; Heterogeneous-Nuclear Ribonucleoprotein Group C; High-Throughput Nucleotide Sequencing; Humans; Leukemia, Promyelocytic, Acute; Oncogene Proteins, Fusion; Promyelocytic Leukemia Protein; Proto-Oncogene Proteins c-bcl-2; Remission Induction; Retinoic Acid Receptor alpha; Sulfonamides; Transcription Factors; Tretinoin

Despite therapeutic advances, early death (ED) remains a major factor curtailing survival of acute promyelocytic leukemia (APL). Studies examining factors that cause early death (ED; within 30 days of admission) and the correlation of survival with the timing of administration of all-trans retinoic acid (ATRA) and hemostatic parameters are scarce. We performed a cohort analysis of nonselect patients with newly diagnosed APL who presented to the health care system in Hong Kong, where oral arsenic trioxide was used. From 1 January 2007 to 30 April 2020, 358 patients (median age, 47 [1-97] years) with newly diagnosed APL were identified. ED occurred in 56 patients (16%): 11 (3%) died in the first 2 days after admission (intracranial hemorrhage [ICH], n = 6; APL-differentiation syndrome [APL-DS], n = 4; infection, n = 1); 22 (6%) died within 3 to 7 days (ICH, n = 12; APL-DS, n = 8; infections, n = 2), and 23 (6%) died within 8 to 30 days (ICH, n = 7; APL-DS, n = 11; infection, n = 5). Factors significantly associated with ED by multivariate analysis included male sex (P = .01); presenting leukocyte count ≥10 × 109/L (P = .03); fibrinogen <1.5 g/L (P = .02); and ATRA administration >24 hours after hospital admission (P < .001). After a median follow-up of 47 (0-166) months, the 5- and 10-year overall survival (OS) was 68.6% and 61.2%, respectively. Excluding EDs, the 5- and 10-year post-30-day OS improved to 81.3% and 72.5%. Early administration of ATRA (<24 hours) and vigorous correction of hemostatic abnormalities, including hypofibrinogenemia, are key to reducing ED.

Topics: Arsenic Trioxide; Hospitals; Humans; Leukemia, Promyelocytic, Acute; Leukocyte Count; Male; Middle Aged; Tretinoin

To prevent early death, management of coagulopathy is important in patients with untreated acute promyelocytic leukemia (APL). This study aimed to clarify factors associated with in-hospital death in patients with coagulopathy during induction therapy for APL. We retrospectively identified patients with newly diagnosed APL who received induction therapy including all-trans retinoic acid (ATRA) and developed coagulopathy, using a nationwide inpatient database in Japan. Of 1115 eligible patients, 175 (15%) died at a median of 13 days (interquartile range, 7-30) after admission. In the multivariable analysis, compared with younger patients (aged < 40 years), the occurrence of in-hospital death was significantly more common among older patients (aged ≥ 40 and < 60 years: odds ratio = 2.58 [95% confidence interval: 1.29-5.19]; aged ≥ 60 and < 80 years: 7.66 [3.89-15.10]; aged ≥ 80 years: 16.83 [7.41-38.21]). Delayed initiation of ATRA and no conventional chemotherapy were significantly associated with in-hospital death (1.79 [1.16-2.76] and 2.40 [1.47-3.92], respectively). A total of 699 patients (63%) received anticoagulant therapies, but none of these was significantly associated with lower mortality. Although the present study was constrained by a lack of laboratory findings because of database limitations, the results showed that untreated patients with APL, especially the elderly, had a poor prognosis. Immediate administration of ATRA may reduce in-hospital mortality.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Blood Coagulation Disorders; Female; Hospital Mortality; Humans; Induction Chemotherapy; Japan; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Retrospective Studies; Risk Factors; Tretinoin

Retinoic acid inducible gene G (

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Biomarkers; Bone Marrow; Female; Gene Expression Regulation; Humans; Intracellular Signaling Peptides and Proteins; Leukemia, Promyelocytic, Acute; Male; Middle Aged; RNA, Messenger; Tretinoin; Young Adult

To investigate the expression of peptidylarginine deiminase 4 (PADI4) during the process of differentiation into granulocyte of NB4 cells induced by all-trans-retinoic acid (ATRA) and whether PADI4 is involved in the inflammatory cytokines expression.. Granulocyte differentiation model of NB4 cells induced by ATRA was established. The cell morphology changes were observed by Wright-Giemsa staining. The expression of cell differentiation marker CD11b was analyzed by flow cytometry. The mRNA and protein expression of PADI4 was detected by RT-PCR and Western blot, respectively. The expression of tumor necrosis factor (TNF) α and interleukin (IL) 1β was analyzed by ELISA, and also examined with the knockdown of PADI4 expression by siRNA.. After NB4 cells induced by ATRA, the cytoplasm increased and the ratio of nuclear to cytoplasmic was reduced. Nuclear dented, and rod-shaped nucleus, lobulated phenomenon increased (P<0.05). Flow cytometry analysis results showed that the cell surface molecule CD11b expression increased (P<0.01). RT-PCR and Western blot showed the expression of PADI4 increased at both transcriptional and translational levels during the process of the differentiation. ELISA showed TNF-α and IL-1β secretion increased in differentiated macrophages, while they could be inhibited by PADI4-specific siRNA.. During the differentiation into granulocyte of NB4 cells induced by ATRA, PADI4 expression increased. Furthermore, PADI4 appeared to play a critical role in inflammatory cytokines secretion.. PADI4对NB4细胞分化过程中炎性因子表达水平的影响.. 探讨全反式维甲酸（ATRA）诱导人急性早幼粒细胞白血病细胞株NB4向粒细胞分化过程中肽酰基精氨酸脱亚胺酶4（PADI4）的表达变化及其是否参与炎性因子的表达.. 建立ATRA诱导的NB4细胞分化模型，采用Wright-Giemsa染色观察细胞形态学变化；采用流式细胞术检测细胞表面分化抗原CD11b的表达；RT-PCR方法检测PADI4基因转录水平的表达；Western bolt方法检测PADI4翻译水平的表达；ELISA检测培养液中肿瘤坏死因子（TNF）-α和白细胞介素（IL）-1β的表达；siRNA技术干扰PADI4表达后ELISA检测TNF-α和IL-1β的表达.. ATRA诱导后NB4细胞胞浆增多，核浆比例降低，核有凹陷，杆状和分叶现象增多。流式细胞术检测结果显示细胞表面分子CD11b表达明显升高(P<0.01)。在分化模型中，RT-PCR及Western blot检测结果显示PADI4转录水平和翻译水平表达均明显升高(P<0.05)。ELISA方法检测培养液中TNF-α和IL-1β的表达水平明显升高(P<0.05)，而siRNA技术干扰PADI4表达后TNF-α和IL-1β的表达水平明显下降(P<0.05).. ATRA诱导NB4细胞向粒细胞分化过程中PADI4的表达升高，同时PADI4参与了NB4细胞分化过程中炎性因子的表达.

Topics: Cell Differentiation; Cell Line, Tumor; Cytokines; Granulocytes; Humans; Leukemia, Promyelocytic, Acute; Protein-Arginine Deiminase Type 4; Tretinoin

Topics: Central Nervous System; Central Nervous System Neoplasms; Humans; Leukemia, Promyelocytic, Acute; Recurrence; Tretinoin

All-trans retinoic acid (ATRA) serves as the backbone of the management of patients with acute promyelocytic leukemia (APL), with guidelines recommending the initiation of ATRA as soon as APL is suspected. As a regional referral center for patients with acute leukemia, those who are suspected of having APL are often transferred to our facility. However, many referring centers are unable to initiate treatment using ATRA. We conducted an exploratory analysis of the clinical availability of ATRA and the factors limiting access to this critical drug.. The United States was divided into 6 geographic regions: Northwest, Southwest, Central, Southeast, Northeast, and the Great Lakes. Twenty hospitals were randomly selected from states within each of these regions and were surveyed as to whether they typically treated patients with acute leukemia, the availability of ATRA at their institution, and reported reasons for not stocking ATRA (if not available).. Less than one-third of hospitals queried (31%) had ATRA in stock. Neither the size of the hospital nor the hospital's status as academic versus nonacademic (53% vs 31%; P=.08) influenced ATRA availability. Of the hospitals that referred patients with APL, only 14% (7/49) had ATRA readily available. Hospitals that treated patients with APL were more likely to have ATRA available than referring centers (58% vs 14%; P=.000002).. Nearly two-thirds of the hospitals surveyed that cared for patients with acute leukemia do not have ATRA immediately available. Moreover, the vast majority of hospitals that refer patients to other centers do not have ATRA. These findings should spur investigation into the impact of immediate ATRA availability on the morbidity and mortality of patients with APL. A call by hematologists nationwide to their formulary committees is warranted to ensure that this lifesaving medication is available to patients suspected of having APL.

Topics: Humans; Leukemia, Myeloid, Acute; Leukemia, Promyelocytic, Acute; Tretinoin

Topics: Anelloviridae; Antineoplastic Agents; Child; Female; Humans; Karyotype; Leukemia, Promyelocytic, Acute; Oncogene Proteins, Fusion; Oncogenic Viruses; Retinoic Acid Receptor alpha; Torque teno virus; Tretinoin

A 68-year-old male was diagnosed with acute promyelocytic leukemia (APL). A G-banding chromosomal analysis revealed the co-existence of two clones: one with del(20q) and t(15;17)(q22;q12) and another with del(20q) alone. During the remission of APL following treatment with all-trans-retinoic acid, del(20q) was persistently identified, indicating a diagnosis of cytogenetic abnormalities of undetermined significance (CCAUS) with isolated del(20q). Bicytopenia developed 48 months after the remission of APL. The presence of isolated del(20q) was detected in the G-banding analysis, whereas morphological dysplasia of hematopoietic cells was not confirmed. This case showed indolent progression from CCAUS after the remission of APL to clonal cytopenia of undetermined significance (CCUS). CCUS with isolated del(20q) persisted for 24 months without any finding of hematological malignancies. At the most recent follow-up, targeted capture sequencing showed the U2AF1 S34F mutation. Considerable attention needs to be paid in follow-ups for CCAUS with del(20q) after the treatment of leukemia.

Topics: Aged; Chromosome Aberrations; Clone Cells; Follow-Up Studies; Humans; Leukemia, Promyelocytic, Acute; Male; Remission Induction; Tretinoin

Pseudotumor cerebri (PTC), also known as idiopathic or benign intracranial hypertension, is characterized by elevated intracranial pressure without any evidence of organic central nervous system disorders. PTC is a rare but well-known adverse event associated with all-trans retinoic acid (ATRA) treatment. Persistent blindness in about 10% of affected patients is caused by PTC; therefore, prompt and accurate diagnosis is required. Recently, magnetic resonance imaging (MRI) findings, including empty sella, flattening of the posterior aspect of the globe, and distention of the perioptic subarachnoid space, have been found to be of high diagnostic value in PTC, but there apparently have been no reports about MRI findings in ATRA-induced PTC. We report here an 11-year-old boy with acute promyelocytic leukemia who developed ATRA-induced PTC during leukemia treatment. MRI findings beneficial for the diagnosis of PTC were observed.

Topics: Antineoplastic Agents; Child; Humans; Leukemia, Promyelocytic, Acute; Magnetic Resonance Imaging; Male; Prognosis; Pseudotumor Cerebri; Tretinoin

Patients with high-risk acute promyelocytic leukemia (APL) have inferior outcomes compared with patients with low-risk APL, predominantly due to higher risk of early mortality related to hemorrhage. The majority of regimens contain prolonged maintenance, but the impact of this phase is not clear in the era of all trans retinoic acid (ATRA) and arsenic trioxide (ATO). We present a retrospective analysis of 10 patients that were treated for high risk APL based on the consolidation treatment phase of APL 0406 study without subsequent maintenance. With a median follow up of 38 months, all patients remain in remission.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Disease-Free Survival; Female; Follow-Up Studies; Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Retrospective Studies; Risk Factors; Survival Rate; Tretinoin

Topics: Arsenic Trioxide; Arsenicals; China; Cost-Benefit Analysis; Humans; Leukemia, Promyelocytic, Acute; Tretinoin

Topics: Arsenic Trioxide; Blindness; Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Retinal Detachment; Tretinoin

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Child; Child, Preschool; Disease-Free Survival; Drug Tolerance; Female; France; Humans; Infant; Leukemia, Promyelocytic, Acute; Male; Retrospective Studies; Survival Rate; Tretinoin

In acute promyelocytic leukemia (APL), normal retinoid signaling is disrupted by an abnormal PML-RARα fusion oncoprotein, leading to a block in cell differentiation. Therapeutic concentrations of all-trans-retinoic acid (ATRA) can restore retinoid-induced transcription and promote degradation of the PML-RARα protein. Autophagy is a catabolic pathway that utilizes lysosomal machinery to degrade intracellular material and facilitate cellular re-modeling. Recent studies have identified autophagy as an integral component of ATRA-induced myeloid differentiation.. As the molecular communication between retinoid signaling and the autophagy pathway is not defined, we performed RNA sequencing of NB4 APL cells treated with ATRA and examined autophagy-related transcripts.. ATRA altered the expression of >80 known autophagy-related transcripts, including the key transcriptional regulator of autophagy and lysosomal biogenesis, TFEB (11.5-fold increase). Induction of TFEB and its transcriptional target, sequestosome 1 (SQSTM1, p62), is reduced in ATRA-resistant NB4R cells compared to NB4 cells. TFEB knockdown in NB4 cells alters the expression of transcriptional targets of TFEB and reduces CD11b transcript levels in response to ATRA.. We show for the first time that TFEB plays an important role in ATRA-induced autophagy during myeloid differentiation and that autophagy induction potentiates leukemic cell differentiation (Note: this study includes data obtained from NCT00195156, https://clinicaltrials.gov/show/NCT00195156).

Topics: Antineoplastic Agents; Autophagy; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Biopsy; Bone Marrow; Cell Differentiation; Cell Line, Tumor; Gene Expression Regulation, Leukemic; Gene Knockdown Techniques; Humans; Leukemia, Promyelocytic, Acute; Oncogene Proteins, Fusion; RNA Interference; RNA, Small Interfering; Signal Transduction; Tretinoin

Ubiquitin/ISG15-conjugating enzyme E2L6 (UBE2L6) is a critical enzyme in ISGylation, a post-translational protein modification that conjugates the ubiquitin-like modifier, interferon-stimulated gene 15 (ISG15), to target substrates. Previous gene expression studies in acute promyelocytic leukemia (APL) cells showed that all-trans-retinoic acid (ATRA) altered the expression of many genes, including UBE2L6 (200-fold) and other members of the ISGylation pathway. Through gene expression analyses in a cohort of 98 acute myeloid leukemia (AML) patient samples and in primary neutrophils from healthy donors, we found that UBE2L6 gene expression is reduced in primary AML cells compared with normal mature granulocytes. To assess whether UBE2L6 expression is important for leukemic cell differentiation-two cell line models were employed: the human APL cell line NB4 and its ATRA-resistant NB4R counterpart, as well as the ATRA-sensitive human AML HL60 cells along with their ATRA-resistant subclone-HL60R. ATRA strongly induced UBE2L6 in NB4 APL cells and in ATRA-sensitive HL60 AML cells, but not in the ATRA-resistant NB4R and HL60R cells. Furthermore, short hairpin (sh)RNA-mediated UBE2L6 depletion in NB4 cells impeded ATRA-mediated differentiation, suggesting a functional role for UBE2L6 in leukemic cell differentiation. In addition, ATRA induced ISG15 gene expression in NB4 APL cells, leading to increased levels of both free ISG15 protein and ISG15 conjugates. UBE2L6 depletion attenuated ATRA-induced ISG15 conjugation. Knockdown of ISG15 in NB4 APL cells inhibited ISGylation and also attenuated ATRA-induced differentiation. In summary, we demonstrate the functional importance of UBE2L6 in ATRA-induced neutrophil differentiation of APL cells and propose that this may be mediated by its catalytic role in ISGylation.

Topics: Cell Differentiation; Cell Line, Tumor; Gene Expression Regulation, Leukemic; Gene Knockdown Techniques; Humans; Leukemia, Promyelocytic, Acute; Neutrophils; Protein Processing, Post-Translational; Tretinoin; Ubiquitin-Conjugating Enzymes

Topics: Humans; Leukemia, Promyelocytic, Acute; Neoplasms; Syndrome; Tomography, X-Ray Computed; Tretinoin

Topics: Humans; Leukemia, Promyelocytic, Acute; Tretinoin

To investigate the efficacy and safety of arsenic trioxide combined with ATRA and chemo- therapy for treatment of relapsed acute promyelocytic leukemia (APL) patients.. The clinic data of 25 patients with relapse APL treated in our hospital from 1996 to 2013 were collected and analyzed. Among the 25 patients, 15 patients suffered first-time hematological relapse (HR), and the other 10 patients showed first-time molecular relapse (MR). The patients with first-time replase were treated with ATO+ATRA+Anthracycline re-induction chemotherapy. The clinical features, complete remission (CR) rate, overall survival (OS), disease-free survival (DFS) and adverse events after re-induction therapy were analyzed.. Fourteen of 15 hematological relapsed patients achieved the second-time hematological complete remission (CR2) after re-induction therapy except one patient died of bleeding complication during the re-induction. 8 of 14 patient showed molecular complete remission (CRm) after two cycles of therapy with this regimen. Totally, eleven out of the 14 HR patients were alive without disease till the last follow-up, and 3 of the 14 HR patients died because of bleeding complications. All of the 10 molecular relapsed patients received the second CRm after treated by the regimen. Among these 10 patients, 6 patients suffered only once relapse and continued with the molecular CR2 status, and for the other 4 patients with more than two-relapses, only 1 survived untill 89.3 months after achieved second-time CRm, and other 3 patients died because of bleeding complications.. For relapsed APL patients, the treatment with ATO+ATRA+chemotherapy regimen after relapse still shows encouraging efficacy, no matter whether or not the application of ATO in the previous regimens. In addition, patients with more than two molecular relapses show a poor prognosis.. 亚砷酸联合维甲酸及化疗治疗复发急性早幼粒细胞白血病的疗效分析.. 探讨亚砷酸(ATO)联合维甲酸（ATRA）及化疗治疗复发急性早幼粒细胞白血病(APL)的疗效及安全性.. 收集并总结分析中国医学科学院血液病医院自1996年至2013年收治的25例复发APL患者的临床资料,包括首次血液学复发15例，首次分子生物学复发10例，所有患者在首次复发时均采用亚砷酸+维甲酸+蒽环类方案再诱导化疗，分析再次缓解率、总生存及无病生存率，观察该方案治疗的不良反应.. 15例血液学复发患者采用该方案进行再诱导化疗，1例患者在再诱导过程中早期死亡，余14例患者均再次取得血液学完全缓解；其中8例患者经两个疗程治疗后再次取得分子学完全缓解。在14例患者中有3例患者再次复发后因出血并发症死亡，余11例均存活至末次随访。10例分子学复发患者经该方案治疗后均再次取得分子学缓解；其中，6例第1次分子学复发的患者，再次取得持续分子学缓解；4例2次以上分子学复发的患者，仅1例再次取得分子学缓解后存活至随访89.3个月，余3例最终血液学复发并死于出血并发症.. 对于复发APL患者，无论前期是否应用亚砷酸治疗，复发后应用亚砷酸联合维甲酸及化疗仍可取得较好疗效。2次以上分子学复发的患者预后较差.

Topics: Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Humans; Leukemia, Promyelocytic, Acute; Oxides; Remission Induction; Treatment Outcome; Tretinoin

Although it has been widely considered that all-trans retinoic acid (ATRA) is an efficient therapeutic agent for acute promyelocytic leukemia (APL), there is an urgent need for extending and examining new therapeutics in medicine. Dithiocarbamates (DTCs) are one of the recent important chemical synthetic compounds used in cancer therapy. The aim of this study was to evaluate the apoptosis-inducing effect of 2-nitro-1-phenylethylpiperidine-1-carbodithioate (2-NDC) as an active derivative from DTCs, in combination with ATRA on human APL NB4 cells. The viability of treated NB4 cells was measured by 3-(4,5-dimethyltiazol-2-yl)-2,5-diphenyltetrazolium bromide assay in various concentrations (10-120 µM). The proapoptotic effects of 2-NDC were investigated by acridine orange/ethidium bromide staining, DNA ladder formation, and flow cytometry. We also assessed the oxidative stress-inducing effect of 2-NDC and in combination with ATRA on the NB4 cells. The alteration in gene expression levels of Bax, Bcl2, and Survivin was measured through a real-time polymerase chain reaction. Furthermore, we redetected the interaction between 2-NDC and antiapoptotic proteins Bcl2 and Survivin via molecular docking. We found that 2-NDC induced apoptosis in NB4 cells in a time-dosage-dependent manner. Also, 2-NDC triggered apoptosis by expanding intracellular reactive oxygen species, combined with ATRA. Bax/Bcl2 ratio was modulated and Survivin was downregulated in NB4 cells upon 2-NDC treatment. Molecular docking studies indicated that 2-NDC binds to the baculovirus inhibitor of apoptosis protein repeat domain of Survivin and Bcl homology 3 domain of Bcl2 with various affinities. Based on the present observations, it seems that this derivative can be estimated as an appropriate candidate for future pharmaceutical evaluations.

Topics: Antineoplastic Agents; Apoptosis; Cell Cycle; Cell Line, Tumor; Cell Survival; DNA Damage; Down-Regulation; Drug Interactions; Humans; Leukemia, Promyelocytic, Acute; Molecular Docking Simulation; Proto-Oncogene Proteins c-bcl-2; Reactive Oxygen Species; Survivin; Thiocarbamates; Tretinoin

As a subtype of acute myeloid leukemia (AML), acute promyelocytic leukemia (APL) is characterized by a chromosomal translocation, most of which result in the production of a PML-RAR alpha fusion protein. Although the overall survival rate of APL patients has improved dramatically due to all-trans retinoic acid (ATRA) treatment, ATRA-resistance remains a clinical challenge in the management of APL. Therefore, alternative agents should be considered for ATRA-resistant APL patients. Here, we report that antimalaria drug primaquine phosphate (PRQ) exhibits an anti-leukemia effect on both ATRA-sensitive cell line NB4 and ATRA-resistant APL cell lines, NB4-LR2, NB4-LR1, and NB4-MR2. Moreover, PRQ significantly inhibited primary colony formation of untreated or relapsed APL patients. Further study showed that PRQ could induce the apoptosis of APL cells by inhibiting NF-κB signaling pathway. The in vivo study showed that PRQ significantly inhibited NB4-LR2 xenograft tumors growth. These results suggest that PRQ is a potential therapeutic agent for ATRA-resistant APL patients.

Topics: Adult; Animals; Apoptosis; Cell Line, Tumor; Cell Proliferation; Cell Survival; Drug Resistance, Neoplasm; Female; Humans; Leukemia, Promyelocytic, Acute; Male; Mice, Inbred BALB C; Mice, Nude; Middle Aged; NF-kappa B; Primaquine; Signal Transduction; Tretinoin; Tumor Stem Cell Assay; Xenograft Model Antitumor Assays

A 69-year-old woman with leukocytopenia and thrombocytopenia was referred to our hospital. Her bone marrow comprised 70.5% abnormal promyelocytes that were positive for myeloperoxidase/CD33/CD117 and CD13 (dim) and negative for CD2/CD34/CD56 and HLA-DR. Chromosome analysis of the bone marrow showed t (12;17;15) (p13;q21;q22), and fluorescence in situ hybridization revealed the PML-RARA fusion signal only on the derivative chromosome 15. The patient was diagnosed with acute promyelocytic leukemia (APL) with PML-RARA and was treated using all-trans retinoic acid (ATRA). In peripheral blood (PB), PML-RARA-positive polymorphonuclear cells (PMNs) appeared on the second week and became negative on the sixth week after treatment, whereas PML-RARA-negative PMNs started to increase in number on the sixth week. Molecular remission was confirmed on the 10th week. Quantitative evaluation of the differentiated leukemic cells of APL and recovered cells from normal hematopoiesis in PB can provide useful information for a safer induction therapy. No significant difference was noted in the kinetics of the leukemic cells under ATRA treatment as well as in the clinical features between our patient without RARA-PML and those with t (15;17), which is a cytogenetic evidence for the critical role of PML-RARA in the pathogenesis of APL.

Topics: Aged; Chromosomes, Human; Female; Humans; In Situ Hybridization, Fluorescence; Kinetics; Leukemia, Promyelocytic, Acute; Oncogene Proteins, Fusion; Translocation, Genetic; Tretinoin

Topics: Abdomen; Acute Kidney Injury; Aged, 80 and over; Anaplasma phagocytophilum; Antineoplastic Agents; Bone Marrow Examination; Diagnosis, Differential; Ehrlichiosis; Fibrin Fibrinogen Degradation Products; Humans; L-Lactate Dehydrogenase; Leukemia, Promyelocytic, Acute; Male; Pancytopenia; Thorax; Tomography, X-Ray Computed; Tretinoin

Telomerase (hTERT) reactivation and sustained expression is a key event in the process of cellular transformation. Therefore, the identification of the mechanisms regulating hTERT expression is of great interest for the development of new anticancer therapies. Although the epigenetic state of hTERT gene promoter is important, we still lack a clear understanding of the mechanisms by which epigenetic changes affect hTERT expression. Retinoids are well-known inducers of granulocytic maturation in acute promyelocytic leukemia (APL). We have previously shown that retinoids repressed hTERT expression in the absence of maturation leading to growth arrest and cell death. Exploring the mechanisms of this repression, we showed that transcription factor binding was dependent on the epigenetic status of hTERT promoter. In the present study, we used APL cells lines and publicly available datasets from APL patients to further investigate the integrated epigenetic events that promote hTERT promoter transition from its silent to its active state, and inversely. We showed, in APL patients, that the methylation of the distal domain of hTERT core promoter was altered and correlated with the outcome of the disease. Further studies combining complementary approaches carried out on APL cell lines highlighted the significance of a domain outside the minimal promoter, localized around 5 kb upstream from the transcription start site, in activating hTERT. This domain is characterized by DNA hypomethylation and H3K4Me3 deposition. Our findings suggest a cooperative interplay between hTERT promoter methylation, chromatin accessibility, and histone modifications that force the revisiting of previously proposed concepts regarding hTERT epigenetic regulation. They represent, therefore, a major advance in predicting sensitivity to retinoid-induced hTERT repression and, more generally, in the potential development of therapies targeting hTERT expression in cancers.

Topics: Cell Line, Tumor; Chromatin; Cluster Analysis; CpG Islands; DNA Methylation; Epigenesis, Genetic; Gene Expression Regulation, Leukemic; Genetic Loci; Genome, Human; Histone Code; Humans; Leukemia, Promyelocytic, Acute; Nucleosomes; Promoter Regions, Genetic; RNA, Messenger; Telomerase; Tretinoin

Acute promyelocytic leukemia is an oncologic emergency. The limited cases reported in the literature have led to poor understanding of the safety of management of acute promyelocytic leukemia during pregnancy.. Herein is an acute promyelocytic leukemia case of a 22-year-old young pregnant woman who had various social problems. The patient was diagnosed with acute promyelocytic leukemia in her the second trimester of her first pregnancy.. This drug regimen is controversial during pregnancy owing to the teratogenic effects and fatal retinoic acid syndrome especially in early gestation. In this case, patient was started the induction therapy of all-trans-retinoic acid treatment at her second trimester during her first pregnancy.. Our lady demonstrated the possibility of using all-trans-retinoic acid and arsenic trioxide and chemotherapy during second and third trimester with successful pregnancy outcomes.

Topics: Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Cytarabine; Female; Hematopoietic Stem Cell Transplantation; Humans; Idarubicin; Induction Chemotherapy; Leukemia, Promyelocytic, Acute; Pregnancy; Recurrence; Tretinoin; Young Adult

All-trans retinoic acid (ATRA) is an anti-cancer differentiation therapy agent effective for acute promyelocytic leukemia (APL) but not acute myeloid leukemia (AML) in general. Using the HL-60 human non-APL AML model where ATRA causes nuclear enrichment of c-Raf that drives differentiation and G1/G0 cell cycle arrest, we now observe that c-Raf in the nucleus showed novel interactions with several prominent regulators of the cell cycle and cell differentiation. One is cyclin-dependent kinase 2 (Cdk2). ATRA treatment caused c-Raf to dissociate from Cdk2. This was associated with enhanced binding of Cdk2 with retinoic acid receptor α (RARα). Consistent with this novel Raf/CDK2/RARα axis contributing to differentiation, CD38 expression per cell, which is transcriptionally regulated by a retinoic acid response element (RARE), is enhanced. The RB tumor suppressor, a fundamental regulator of G1 cell cycle progression or arrest, was also targeted by c-Raf in the nucleus. RB and specifically the S608 phosphorylated form (pS608RB) complexed with c-Raf. ATRA treatment induced S608RB-hypophosphorylation associated with G1/G0 cell cycle arrest and release of c-Raf from RB. We also found that nuclear c-Raf interacted with SMARCD1, a pioneering component of the SWI/SNF chromatin remodeling complex. ATRA treatment diminished the amount of this protein bound to c-Raf. The data suggest that ATRA treatment to HL-60 human cells re-directed c-Raf from its historically pro-proliferation functions in the cytoplasm to pro-differentiation functions in the nucleus.

Topics: Antineoplastic Agents; Cell Differentiation; Cell Division; G1 Phase Cell Cycle Checkpoints; HL-60 Cells; Humans; Leukemia, Promyelocytic, Acute; Phosphorylation; Proto-Oncogene Proteins c-raf; Retinoic Acid Receptor alpha; Tretinoin

The histone demethylase LSD1 is deregulated in several tumors, including leukemias, providing the rationale for the clinical use of LSD1 inhibitors. In acute promyelocytic leukemia (APL), pharmacological doses of retinoic acid (RA) induce differentiation of APL cells, triggering degradation of the PML-RAR oncogene. APL cells are resistant to LSD1 inhibition or knockout, but targeting LSD1 sensitizes them to physiological doses of RA without altering of PML-RAR levels, and extends survival of leukemic mice upon RA treatment. The combination of RA with LSD1 inhibition (or knockout) is also effective in other non-APL, acute myeloid leukemia (AML) cells. Nonenzymatic activities of LSD1 are essential to block differentiation, while RA with targeting of LSD1 releases a differentiation gene expression program, not strictly dependent on changes in histone H3K4 methylation. Integration of proteomic/epigenomic/mutational studies showed that LSD1 inhibitors alter the recruitment of LSD1-containing complexes to chromatin, inhibiting the interaction between LSD1 and the transcription factor GFI1.

Topics: Antineoplastic Agents; Catalysis; Cell Differentiation; Cell Line, Tumor; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Histone Demethylases; Histones; Humans; Leukemia, Myeloid, Acute; Leukemia, Promyelocytic, Acute; Oncogene Proteins, Fusion; Tretinoin; Tumor Cells, Cultured

Topics: Humans; Leukemia, Promyelocytic, Acute; Oncogene Proteins, Fusion; Retinoic Acid Receptor alpha; Translocation, Genetic; Tretinoin

To investigate the differentiation of acute promyelocytic leukemia (APL) cells induced by Tetrandrine targeting MUC1.. HL-60 cells at logarithmic growth phase were choosen as object of reaserch and were divided into four groups: control, ATRA, Tetrandrine and ATRA+Tetrandrine group. Cell morphologic changes in each group were observed by microscopy. The change of cell differentiation ability was analyzed by nitro-blue tetrazolium (NBT) reduction test. The expression of cell surface differentiation antigen CD11b was measured by flow cytometry. The expression of MUC1 protein was detected by Western blot.. The differentiation of HL-60 cell could be induced by Tetrandrine. The NBT reduction-positive rate of ATRA+Tetrandrine group was significantly higher than that in ATRA group and Tetrandrine group (P<0.05). The percentage of CD11b positive cells in ATRA+Tetrandrine group(43.62％±1.38％) was significantly higher than that in Tetrandrine group(15.25％±2.11％), ATRA group (28.84％±7.53％) and control group(8.16％±1.01％) (P<0.05). The content of MUC1 protein in Tetrandrine group was significantly lower than that in control group and ATRA group (P<0.05).. Tetrandrine and ATRA can synergize to promote the differentiation and maturation of HL-60 cells, and the mechanism may be related with MUC1 expression.. 汉防己甲素诱导HL-60细胞分化.. 探讨汉防己甲素(Tetrandrine)靶向黏蛋白1（MUC1）诱导急性早幼粒细胞白血病(APL)细胞分化.. 以HL-60细胞株作为研究对象，选取对数生长期细胞，分为空白对照、ATRA、汉防己甲素和ATRA+汉防己甲素，共4组。显微镜下观察各组细胞形态的变化；用NBT还原实验分析细胞分化能力的变化；采用流式细胞术检测细胞表面分化抗原CD11b表达的变化；采用Western blot 检测MUC1表达的变化.. 汉防己甲素可以诱导HL-60细胞分化； ATRA+汉防己甲素组NBT还原阳性率明显高于ATRA和汉防己甲素组（P＜0.05）；ATRA+汉防己甲素组CD11b+ 细胞百分率(43.62％±1.38％) 明显高于汉防己甲素(15.25％±2.11％)、ATRA(2184％±7.53％)和空白对照组(8.16％±1.01％)（P＜0.05）；汉防己甲素组MUC1蛋白量明显低于空白对照组和ATRA组（P＜0.05）.. 汉防己甲素体外能协同ATRA使HL-60细胞分化成熟，其作用机制可能与调控MUC1的表达有关.

Topics: Benzylisoquinolines; Cell Differentiation; HL-60 Cells; Humans; Leukemia, Promyelocytic, Acute; Tretinoin

Topics: Antineoplastic Agents; Arsenic Trioxide; Humans; Induction Chemotherapy; Leukemia, Promyelocytic, Acute; Molecular Targeted Therapy; Practice Guidelines as Topic; Tretinoin

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; COVID-19; COVID-19 Drug Treatment; Humans; Leukemia, Promyelocytic, Acute; Male; SARS-CoV-2; Tretinoin

Topics: Adult; Baltimore; Humans; Incidence; Leukemia, Promyelocytic, Acute; Tretinoin

MicroRNA (miRNA) expression has been implicated in leukaemia. In recent years, miRNAs have been under investigation for their potential as non-invasive biomarkers in acute promyelocytic leukaemia (APL). We investigated whether miR-638 in circulating leukaemia cells is a non-invasive biomarker in diagnosis, assessment of the treatment response and minimal residual disease (MRD) surveillance of APL.. Sixty cases of acute myeloid leukaemia (AML), including 30 cases of APL and 30 cases of non-APL AML, were selected. Thirty healthy controls were also selected. Bone marrow (BM) and peripheral blood (PB) samples were collected from APL patients at diagnosis and post-induction. Microarray analysis and quantitative real-time PCR (qRT-PCR) were performed for miRNA profiling and miR-638 expression analysis, respectively. For statistical analysis, Mann-Whitney U test, Wilcoxon Signed Rank test, receiver operating characteristic (ROC) curve analysis and Spearman's rho correlation test were used.. Both microarray and qRT-PCR data showed that miR-638 was significantly upregulated in BM after APL patients received induction therapy. Moreover, miR-638, which is specifically downregulated in APL cell lines, was upregulated after all-trans retinoic acid (ATRA)-induced myeloid differentiation. Receiver operating characteristic (ROC) curve analyses revealed that miR-638 could serve as a valuable biomarker for differentiating APL from controls or non-APL AML. Furthermore, miR-638 expression was sharply increased after induction therapy and complete remission (CR). An inverse correlation was observed between miR-638 and PML-RARα transcripts levels in BM samples, while a positive correlation was revealed between PB miR-638 and BM miR-638 levels in APL patients after induction therapy.. Our study suggested that miR-638 may serve as a potential APL biomarker for diagnosis and assessment of the response to targeted therapy, and PB miR-638 could be used for non-invasive MRD surveillance in APL.

Topics: Biomarkers, Tumor; Bone Marrow Cells; Female; Humans; Leukemia, Myeloid, Acute; Leukemia, Promyelocytic, Acute; Male; MicroRNAs; Middle Aged; Neoplasm, Residual; Neoplastic Cells, Circulating; Remission Induction; Tretinoin

Non-T cell activation linker (NTAL) is a lipid raft-membrane protein expressed by normal and leukemic cells and involved in cell signaling. In acute promyelocytic leukemia (APL), NTAL depletion from lipid rafts decreases cell viability through regulation of the Akt/PI3K pathway. The role of NTAL in APL cell processes, and its association with clinical outcome, has not, however, been established. Here, we show that reduced levels of NTAL were associated with increased all-trans retinoic acid (ATRA)-induced differentiation, generation of reactive oxygen species, and mitochondrial dysfunction. Additionally, NTAL-knockdown (NTAL-KD) in APL cell lines led to activation of Ras, inhibition of Akt/mTOR pathways, and increased expression of autophagy markers, leading to an increased apoptosis rate following arsenic trioxide treatment. Furthermore, NTAL-KD in NB4 cells decreased the tumor burden in (NOD scid gamma) NSG mice, suggesting its implication in tumor growth. A retrospective analysis of NTAL expression in a cohort of patients treated with ATRA and anthracyclines, revealed that NTAL overexpression was associated with a high leukocyte count (P = 0.007) and was independently associated with shorter overall survival (Hazard Ratio: 3.6; 95% Confidence Interval: 1.17-11.28; P = 0.026). Taken together, our data highlights the importance of NTAL in APL cell survival and response to treatment.

Topics: Adaptor Proteins, Signal Transducing; Adolescent; Adult; Aged; Animals; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Cell Differentiation; Cell Line, Tumor; Cell Proliferation; Cell Survival; Disease-Free Survival; Female; Gene Knockdown Techniques; Humans; Leukemia, Promyelocytic, Acute; Leukocyte Count; Male; Membrane Microdomains; Mice; Middle Aged; Retrospective Studies; Survival Analysis; Tretinoin; Xenograft Model Antitumor Assays; Young Adult

A 69-year-old man was referred to the hematology department for the evaluation of pancytopenia. He had been treated with radiation and epirubicin for hepatocellular carcinoma, and with docetaxel and pembrolizumab for lung adenocarcinoma. Bone marrow smears exhibited markedly increased promyelocytes, and polymerase chain reaction (PCR) study demonstrated chimeric fusion genes of

Topics: Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Carcinoma, Hepatocellular; Docetaxel; Epirubicin; Humans; Leukemia, Promyelocytic, Acute; Liver Neoplasms; Lung Neoplasms; Male; Neoplasms, Multiple Primary; Treatment Outcome; Tretinoin

Topics: Adult; Antineoplastic Agents; Arsenic Trioxide; Female; Humans; Leukemia, Promyelocytic, Acute; Pregnancy; Pregnancy Complications, Neoplastic; Treatment Outcome; Tretinoin; Young Adult

Neutrophils represent the first line of defense against pathogens using various strategies, such as phagocytosis, production of reactive oxygen species (ROS) and neutrophil extracellular traps (NETs) formation. Recently, an autophagy-independent role of autophagy related (

Topics: Apoptosis; Autophagy; Autophagy-Related Protein 5; Cell Differentiation; Cell Proliferation; Dimethylformamide; Flow Cytometry; Granulocytes; HL-60 Cells; Humans; Leukemia, Promyelocytic, Acute; Microtubule-Associated Proteins; Neutrophils; Phagocytosis; Reactive Oxygen Species; Tretinoin; Up-Regulation

This is a case report of a 68-year-old female referred to the SARS-CoV-2 ward with one week of intermittent fever and three days of progressive loss of vision. Laboratory work-up revealed severe coagulopathy, thrombocytopenia and hyperleukocytosis. MRI showed multiple ischaemic cortical lesions. Acute treatment with all-trans retinoic acid and cytoreduction was started and coagulation parameters corrected. Patients referred to pandemic wards must undergo stringent examination and be referred for further evaluation irrespective of suspected severe acute respiratory syndrome coronavirus-2 infection.

Topics: Aged; Betacoronavirus; Blindness; Coronavirus Infections; COVID-19; Cytoreduction Surgical Procedures; Female; Fever; Humans; Leukemia, Promyelocytic, Acute; Pandemics; Pneumonia, Viral; SARS-CoV-2; Tretinoin

Since the introduction of all-trans retinoic acid and, more recently, arsenic trioxide into the therapy of acute promyelocytic leukemia (APL), significant improvements in patient outcomes have been achieved, and this disease has become the most curable subtype of acute myeloid leukemia. However, while primary leukemia resistance has virtually disappeared, a sizable fraction of APL patients still die before or during induction therapy. Hemorrhagic death still remains the major problem during this early phase of treatment and, to a lesser extent, deaths due to infection, differentiation syndrome and other causes. Patients with APL typically present with a range of laboratory abnormalities consistent with the diagnosis of disseminated intravascular coagulation and hyperfibrinolysis. This APL-associated coagulopathy, as a result of a dysregulation of the hemostatic system due to the imbalance between procoagulant, anticoagulant and profibrinolytic mechanisms, may show a variety of clinical manifestations, ranging from minimal bleeding or localized thrombosis to lethal or life-threatening hemorrhages or thrombotic events that sometimes occur concomitantly. Hemorrhagic events are the most common cause of death associated with APL coagulopathy, but thrombosis, a less recognized and probably underestimated life-threatening manifestation of the thrombo-hemorrhagic syndrome, is also a non-negligible cause of morbidity and mortality in patients with APL. In this article, we aim to discuss recent advances in the knowledge of pathogenesis, predictors of thrombo-hemorrhagic events, management of coagulopathy associated with APL and the controversial issues that still persist.

Topics: Blood Coagulation Disorders; Disseminated Intravascular Coagulation; Hemorrhage; Humans; Leukemia, Promyelocytic, Acute; Tretinoin

Differentiation syndrome (DS) is the main life-threatening adverse event that occurs in acute promyelocytic leukemia (APL) patients treated with all-trans retinoic acid (ATRA). Cytokine imbalances have been reported to play role during the developing of acute promyelocytic leukemia differentiation syndrome (APL-DS). However, the relationship between the plasma cytokine levels and their prognostic value for the prediction of DS developing in patients with APL during the treatment with ATRA and anthracyclines has not been previously reported.. In this study, we followed an APL cohort (n = 17) over 7 days of ATRA therapy in DS (n = 6) and non-DS groups (n = 11). Interleukin (IL)-1β, IL-6, IL-8, IL-10, IL-12p70 and TNF-α were measured in the peripheral blood plasma from 17 patients with APL and 11 healthy adult controls by using the cytometric bead array method.. In non-DS patients, IL-8 plasma levels were significantly reduced in the seventh day of ATRA treatment (34.16; 6.99 to 147.11 pg mL. We demonstrated that the modulation of IL-8 following ATRA treatment may occur regardless of the development of DS and, therefore, does not appear to be a predictive biomarker to monitor the APL-DS.

Topics: Adult; Aged; Antineoplastic Agents; Biomarkers, Tumor; Cell Differentiation; Female; Humans; Interleukin-6; Interleukin-8; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Retrospective Studies; Syndrome; Treatment Outcome; Tretinoin; Young Adult

A 55-year-old woman developed acute promyelocytic leukaemia during treatment with all-trans-retinoic acid and arsenic trioxide. Initially, she presented with symptoms of epigastric pain, vomiting, and nausea, and she developed acute pancreatitis. She was treated with parenteral nutritional supplementation for 20 days. However, the patient continued to develop refractory hyponatraemia, hypotension, and apathy. Finally, the patient was diagnosed with Wernicke encephalopathy (WE) using head magnetic resonance imaging. The patient underwent high-dose intravenous thiamine administration, and her symptoms were alleviated. WE is a rare adverse event during acute pancreatitis therapy. Acute pancreatitis that is caused by all-trans-retinoic acid and arsenic trioxide is a rare complication of acute promyelocytic leukaemia during chemotherapy. Further study is essential to improve our comprehension of the risk factors for complications in patients with acute promyelocytic leukaemia, considering that the associated complications were potentially caused by multiple etiological factors. A better understanding of these risk factors may help to improve the prognosis of patients with acute promyelocytic leukaemia at an early stage.

Topics: Acute Disease; Arsenic Trioxide; Arsenicals; Female; Humans; Leukemia, Promyelocytic, Acute; Middle Aged; Oxides; Pancreatitis; Tretinoin; Wernicke Encephalopathy

The 2017 World Health Organization (WHO) classification states that acute promyelocytic leukemia (APL) always presents with strong myeloperoxidase staining. However, we herein report of a 40-year-old woman with the microgranular variant of acute promyelocytic leukemia presenting with weak myeloperoxidase (MPO) staining. The leukemic cells were morphologically similar to monocytic cells, showing distorted-shaped nuclei and weak MPO staining. However, flow cytometry revealed positivity of CD2, CD34, and human leucocyte antigen-DR (HLA-DR) and pointed toward a diagnosis of APL. PML-RARA mRNA detection finally led the patient to a definitive diagnosis. The patient achieved complete remission by induction chemotherapy including tretinoin, cytarabine and idarubicin, and no differentiation syndrome was observed.

Topics: Adult; Female; Flow Cytometry; Humans; Leukemia, Promyelocytic, Acute; Peroxidase; Staining and Labeling; Tretinoin

Topics: Cell Differentiation; Cell Line, Tumor; Cell Lineage; Cohort Studies; Gene Expression Profiling; Gene Expression Regulation, Leukemic; Glycolysis; Humans; Leukemia, Promyelocytic, Acute; Myeloid Cells; Oxidative Phosphorylation; Signal Transduction; Transcription, Genetic; Tretinoin

All‑trans retinoic acid (ATRA) and arsenic trioxide (As2O3) are currently first‑line treatments for acute promyelocytic leukemia (APL). However, a number of patients with APL are resistant to ATRA but still sensitive to As2O3, and the underlying mechanisms of this remain unclear. In the present study, two‑dimensional gel electrophoresis, mass spectrometry and other proteomic methods were applied to screen and identify the differentially expressed proteins between the retinoic acid‑sensitive cell lines and drug‑resistant cell lines. The results demonstrated that in retinoic acid‑resistant NB4‑R1 cells, the protein expression of cofilin‑1 was markedly increased compared with that in the drug‑sensitive NB4 cells. Subsequently, the effects of cofilin‑1 on As2O3‑induced apoptosis in NB4‑R1 cells were further investigated. The results revealed that cell viability was markedly suppressed and apoptosis was increased in the As2O3‑treated NB4‑R1 cells, with increased expression levels of cleaved‑poly (ADP‑ribose) polymerase and cleaved‑caspase 12. Cofilin‑1 expression was significantly decreased at both the mRNA and protein levels in the As2O3‑treated group compared with the control. Western blotting further revealed that As2O3 treatment decreased the cytoplasmic cofilin‑1 level but increased its expression in the mitochondrion. However, the opposite effects of As2O3 on the cytochrome C distribution were found in NB4‑R1 cells. This suggested that As2O3 can induce the transfer of cofilin‑1 from the cytoplasm to mitochondria and trigger the release of mitochondrial cytochrome C in NB4‑R1 cells. Moreover, cofilin‑1 knockdown by its specific short hairpin RNA significantly suppressed As2O3‑induced NB4‑R1 cell apoptosis and inhibited the release of mitochondrial cytochrome C. Whereas, overexpression of cofilin‑1 using a plasmid vector carrying cofilin‑1 increased the release of cytochrome C into the cytoplasm from the mitochondria in As2O3‑treated NB4‑R1 cells. In conclusion, cofilin‑1 played a role in As2O3‑induced NB4‑R1 cell apoptosis and it might be a novel target for APL treatment.

Topics: Antineoplastic Agents; Apoptosis; Arsenic Trioxide; Cell Death; Cofilin 1; Drug Resistance, Neoplasm; Humans; Leukemia, Promyelocytic, Acute; Mitochondria; Oxides; Proteomics; Proto-Oncogene Proteins c-bcl-2; Receptors, Retinoic Acid; Tretinoin; Tumor Cells, Cultured

A 53-year-old male presented with pancytopenia for 13 months. He had a past history of follicular lymphoma and hypopharyngeal cancer, which was treated via chemotherapy and radiotherapy. Bone marrow aspiration biopsy of the patient revealed a hypocellular marrow with 32% of hypergranular blasts without Auer bodies. There were also erythroid and megakaryocytic dysplasia in the bone marrow. Although the PML/RARA transcript was detected by fluorescence in situ hybridization (FISH) and reverse transcription polymerase chain reaction (RT-PCR), the G-banding karyotype analysis showed a complex karyotype without t (15;17). The PML/RARA fusion signal was identified on chromosome 15 by metaphase FISH. The patient was diagnosed of therapy-related acute promyelocytic leukemia (t-APL) with cryptic PML/RARA. He successfully attained molecular complete remission with all-trans retinoic acid (ATRA) and two courses of arsenic trioxide (ATO). He was subsequently administered nivolumab without ATRA maintenance therapy because of a progressing metastasis of a hypopharyngeal cancer to the lung. The patient had a relapse of t-APL following nine courses of nivolumab, 8 months after ending consolidation therapy with ATO. Reinduction therapy with ATRA was not effective for the relapsed t-APL that was accompanied by del (5q) and monosomy 7. Little has been previously reported on t-APL with cryptic PML/RARA. Therefore, the clinical course of this patient may provide useful insights about the characteristics of t-APL with cryptic PML/RARA.

Topics: Chromosomes, Human, Pair 15; Humans; In Situ Hybridization, Fluorescence; Karyotype; Leukemia, Promyelocytic, Acute; Male; Metaphase; Middle Aged; Oncogene Proteins, Fusion; Tretinoin

Topics: Arsenic Trioxide; Ear Canal; Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Recurrence; Sarcoma, Myeloid; Tretinoin

Acute promyelocytic leukemia (APL) is rare in patients with Down syndrome (DS). Cytotoxic chemotherapy combined with all-trans retinoic acid (ATRA) has been a standard treatment for APL, but is potentially intolerable for DS patients because of their vulnerability to cytotoxic agents. We report here a case of a 10-year-old girl with DS and APL successfully treated with a combination of ATRA and arsenic trioxide, a therapy emerging as a new standard for APL. She achieved molecular remission and completed the therapy without significant toxicities. ATRA/arsenic trioxide combination therapy would be a preferable option for DS patients with APL.

Topics: Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Child; Down Syndrome; Female; Humans; Leukemia, Promyelocytic, Acute; Tretinoin

Despite the success achieved in the treatment of acute lymphoblastic leukemia (ALL), the search for new drugs featuring selectivity against leukemia cells and effectiveness to prevent relapsed ALL is still highly desirable. Here, we described the synthesis of several novel 3-substituted and 3,6-disubstituted-2-carboalkoxy indoles followed by the elucidation of their mechanism of action and in vivo anti-leukemia efficacy. The synthesis of 3-substituted-2-carboalkoxy indoles relied on two Heck arylations of methyl acrylate and methyl cinnamates respectively, to generate β,β-disubstituted acrylates followed by an efficient Cadogan-Sundberg reaction of these latter intermediates. The method developed led to the synthesis of twenty-one novel functionalized indoles. Of these, indole 20 showed selective cytotoxicity against leukemia cells at the nanomolar scale, and, therefore, it was selected for the investigation of its mechanism of action. Indole 20 was found to target tubulin leading to G2/M cell cycle arrest, DNA damage and apoptosis. Indole 20 decreased β-tubulin protein in leukemia cells in a time-dependent manner and induced depolymerization of the microtubule network in Hela cells, thus fully characterizing its microtubule destabilizer activity. The connectivity map analysis of HL60 promyelocytic leukemia cells treated with indole 20 revealed a transcriptional profile similar to that of cells treated with prostaglandins, apparently due to the induction of cellular differentiation as addressed by the expression of CD11 and CD14 markers. Finally, indole 20 given intraperitoneally, at 10 mg/kg, 5x/week significantly prolonged the overall survival of NOD/SCID mice transplanted with RS4; 11 B-ALL cells.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cinnamates; G2 Phase Cell Cycle Checkpoints; HeLa Cells; HL-60 Cells; Humans; Indoles; Leukemia, Promyelocytic, Acute; Mice, Inbred NOD; Mice, SCID; Precursor Cell Lymphoblastic Leukemia-Lymphoma

While acute promyelocytic leukemia has a good prognosis with all-trans retinoic acid (ATRA) treatment, ATRA resistance is a major obstacle. It is now demonstrated that TRIBBLES 3 (TRIB3) stabilizes TWIST1, leading to ATRA resistance. Peptides that disrupt this interaction lead to the degradation of TWIST1 and overcome ATRA resistance.

Topics: Cell Cycle Proteins; Humans; Leukemia, Promyelocytic, Acute; Nuclear Proteins; Protein Serine-Threonine Kinases; Repressor Proteins; Tretinoin; Twist-Related Protein 1

In this work, we have exploited the unique properties of a chimeric archaeal-human ferritin to encapsulate, deliver and release cytochrome c and induce apoptosis in a myeloid leukemia cell line. The chimeric protein combines the versatility in 24-meric assembly and cargo incorporation capability of Archaeglobus fulgidus ferritin with specific binding of human H ferritin to CD71, the "heavy duty" carrier responsible for transferrin-iron uptake. Delivery of ferritin-encapsulated cytochrome C to the Acute Promyelocytic Leukemia (APL) NB4 cell line, highly resistant to transfection by conventional methods, was successfully achieved in vitro. The effective liberation of cytochrome C within the cytosolic environment, demonstrated by double fluorescent labelling, induced apoptosis in the cancer cells.

Topics: Apoptosis; Cell Line, Tumor; Cytochromes c; Ferritins; Humans; Leukemia, Promyelocytic, Acute; Nanostructures; Tretinoin

]Objective:To investigate the efficacy and safety of induction regimens containing arsenite, allo-transretinoic acid (ATRA) and anthracyclines of different doses as induction chemotherapy for acute promyelocytic leukemia (APL).. The clinical data of 129 consecutive hospitalized newly diagnosed APL patients from January 2011 to December 2017 were collected and retrospectively analyzed. Sixty-six patients received arsenite, ATRA and anthracyclines of low doses (low dose group), while other 63 patients received arsenite, ATRA and anthracyclines of standard doses (standard dose group), the efficacy and safety were compared and analyzed in 2 groups.. There were no statistically significant differences in terms of age, sex, routine blood indexes,LDH level, bone marrow promyelocyte count,prognostic stratification between patients in two groups (P>0.05). During the treatment, WBC count peak and its time point were not significantly different between two groups (P>0.05). Both induction regimens showed good efficacy, the PML-RARα gene conversion rate from positive into negative, the 2-year overall survival rate and disease-free survival rate in the low-dose group were similar to those in the standard dose group(P＞0.05). The recovery time of neutrophils and platelets in the low-dose group was 0 d and 11 d, respectively, which were statistically  significantly shorter than those in the standard dose group (3 d,15 d) (both P=0.000). The median value of platelet and erythrocyte transfusion in the low-dose group was 6.9 U and 4.2 U, respectively, which were statistically significantly lower than that in the standard dose group (8.4 U,6.8 U) (P=0.037，0.000). And the inpatient time in the low and the standard dose groups were 30.98 and 30.71 days, respectively (P=0.770).. For newly diagnosed patients with APL, the efficacy was similar between induction therapy containing arsenite,ATRA and low dose anthracyclines and the induction therapy containing arsenite, ATRA and standard dose anthracyclines, however, the former appears even safer.. 不同剂量蒽环类药物诱导治疗初诊急性早幼粒细胞白血病的疗效与安全性评价.. 探讨含亚砷酸、全反式维甲酸（ATRA）联合不同剂量蒽环类药物的诱导方案对初诊急性早幼粒细胞白血病（APL）患者的临床疗效和安全性.. 收集并回顾性分析2011年1月至2017年12月新诊断的129例APL患者病历资料，比较分析亚砷酸、ATRA联合小剂量蒽环类药物（小剂量组66例）与联合标准剂量蒽环类药物（标准剂量组63例）诱导治疗的疗效和安全性.. 2组患者起病时年龄、性别、血常规水平、LDH、骨髓早幼粒细胞比例、预后分层均无统计学差异（ P＞0.05）。治疗过程中，2组患者的WBC计数峰值及该数值出现的时间点无统计学差异（P＞0.05）。2种诱导治疗方案的疗效均良好，小剂量组与标准剂量组的 PML-RARα 基因转阴率、2年OS率和2年PFS率也均无统计学差异（P＞0.05）。 小剂量组的中性粒细胞数恢复时间与血小板恢复时间分别为0 d和11 d，与标准剂量组的3 d和15 d相比，均明显缩短（P=0.000）。小剂量组的血小板和红细胞输注量的中位数分别为6.9 U和4.2 U，与标准剂量组的8.4 U和6.8 U相比，差异有统计学意义（P=0.037，P=0.000）。小剂量组与标准剂量组的住院天数的中位数分别为30.98 d和30.71 d（P=0.770）.. 对于初诊APL患者，应用亚砷酸、ATRA联合小剂量蒽环类药物诱导治疗，与亚砷酸、ATRA联合标准剂量蒽环类药物相比，疗效相当，且更为安全.

Topics: Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Humans; Leukemia, Promyelocytic, Acute; Remission Induction; Retrospective Studies; Treatment Outcome; Tretinoin

To investigate the differentiation of acute promyelocytic leukemia (APL) cells induced by adenosine targeting Prx III.. HL-60 cells were divided into four groups: control group, all-trans retinoic acid (ATRA) group, adenanthin group and ATRA+adenanthin group. Cell morphologic changes were observed under optical microscope. The influence of adenanthin on the differentiation of HL-60 was observed by nitro blue tetrazolium chloride (NBT) test. Cell surface differentiation antigens CD11b expression was measured by flow cytometry. The protein expression of Prx III was detected by immunohistochemical assay.. Adenanthin could induce the differentiation of HL-60 cells; the NBT reduction positive rate in ATRA+adenanthin group was significantly higher than that in ATRA group and adenanthin group (P＜0.05). The percentage of CD11b positive cells in ATRA+adenanthin group (43.62％±1.38％) was higher than that in adenanthin group (28.15％±1.78％), ATRA group (36.72％±1.33％) and control group (7.99％±1.78％) (P＜0. 05). The content of Prx Ⅲ protein in adenanthin group was significantly higher than that in control group and ATRA group (P＜0.05).. Adenanthin and ATRA have a synergistic effect on the differentiation and maturation of HL-60 cells, and its mechanism may be related with regulation of Prx III expression.. 腺花素通过靶向 Prx III 诱导急性早幼粒白血病细胞分化的研究.. 探讨腺花素（Adenanthin）靶向Prx III 诱导急性早幼粒白血病（acute promyelocyticleukemia，APL）细胞分化.. 以HL-60细胞株作为研究对象，取对数生长期细胞，分为对照、全反式维甲酸（ATRA）、Adenanthin和ATRA+Adenanthin，共4组。观察各组细胞形态的变化；用NBT还原实验分析细胞分化能力的变化；流式细胞术检测细胞表面分化抗原CD11b的表达变化；采用Western blot 检测Prx III表达的变化.. Adenanthin可诱导HL-60细胞分化；ATRA+Adenanthin组NBT还原阳性率明显高于ATRA组和Adenanthin组（P＜0.05）；ATRA+Adenanthin组CD11b阳性细胞百分率（43.62％±1.38％）均明显高于Adenanthin组（28.15％±1.78％）、ATRA组（36.72％±1.33％）及空白对照组（7.99％±1.78％）（P＜0.05）；Adenanthin组Prx Ⅲ蛋白水平明显高于空白对照组及ATRA组（P＜0.05）.. 腺花素能协同ATRA使HL-60细胞分化成熟，其作用机制可能与调控 Prx III的表达有关.

Topics: Cell Differentiation; Diterpenes, Kaurane; HL-60 Cells; Humans; Leukemia, Promyelocytic, Acute; Peroxiredoxin III; Tretinoin

The detection of PML/RARA or variant RARA rearrangements is critical for the diagnosis and treatment of patients with newly diagnosed acute promyelocytic leukemia (APL). While most cases of APL harboring the PML/RARA fusion respond to all-trans retinoic acid (ATRA), some variant RARA rearrangements are ATRA insensitive. Herein, we report a 27-year-old male with newly diagnosed, rapidly progressive APL and a rarely described STAT5B/RARA fusion with known resistance to ATRA therapy. While the PML/RARA dual-color dual-fusion fluorescence in situ hybridization (FISH) probe study was negative, the RARA break-apart probe study revealed an atypical RARA rearrangement in 95% of nuclei. A next generation sequencing assay, mate-pair sequencing, was subsequently performed to further characterize the RARA rearrangement and identified the RARA gene fusion partner STAT5B.

Topics: Adult; Gene Fusion; Humans; In Situ Hybridization, Fluorescence; Leukemia, Promyelocytic, Acute; Male; Retinoic Acid Receptor alpha; STAT5 Transcription Factor; Tretinoin

Topics: Humans; Leukemia, Promyelocytic, Acute; Oncogene Proteins, Fusion; Retinoic Acid Receptor alpha; STAT3 Transcription Factor; Tretinoin

To date, only one subtype of acute myeloid leukemia (AML), acute promyelocytic leukemia (APL) can be effectively treated by differentiation therapy utilizing all-trans retinoic acid (ATRA). Non-APL AMLs are resistant to ATRA. Here we demonstrate that the acetyltransferase GCN5 contributes to ATRA resistance in non-APL AML via aberrant acetylation of histone 3 lysine 9 (H3K9ac) residues maintaining the expression of stemness and leukemia associated genes. We show that inhibition of GCN5 unlocks an ATRA-driven therapeutic response. This response is potentiated by coinhibition of the lysine demethylase LSD1, leading to differentiation in most non-APL AML. Induction of differentiation was not correlated to a specific AML subtype, cytogenetic, or mutational status. Our study shows a previously uncharacterized role of GCN5 in maintaining the immature state of leukemic blasts and identifies GCN5 as a therapeutic target in AML. The high efficacy of the combined epigenetic treatment with GCN5 and LSD1 inhibitors may enable the use of ATRA for differentiation therapy of non-APL AML. Furthermore, it supports a strategy of combined targeting of epigenetic factors to improve treatment, a concept potentially applicable for a broad range of malignancies.

Topics: Apoptosis; Bone Marrow; Cell Differentiation; Cell Line, Tumor; Cell Membrane; Drug Resistance, Neoplasm; Epigenesis, Genetic; Genotype; HEK293 Cells; Histone Demethylases; Histones; HL-60 Cells; Humans; Leukemia, Myeloid, Acute; Leukemia, Promyelocytic, Acute; Leukocytes, Mononuclear; p300-CBP Transcription Factors; Tretinoin

Acute promyelocytic leukemia (APL) manifesting during pregnancy is a very rare but highly challenging gestational complication in part due to its associated profound coagulopathy. We present the case of a 23-year-old Gravida 3 Para 2002 woman admitted to our hospital at 26 weeks of gestation for severe pre-eclampsia with documentation of intrauterine fetal demise (IUFD), thrombocytopenia, and placental abruption. A peripheral blood smear revealed promyelocytes with azure granules, highly concerning for APL. Additional peripheral blood studies confirmed APL. Placental examination also revealed circulating blasts in decidual vessels and scattered blast entrapment in diffuse perivillous fibrinoid deposits, but none in the chorionic villi. Treatment for APL was initiated immediately and she is in complete molecular remission. Our case underscores the importance of close collaboration among obstetric, hematology, and pathology teams in the care of patients with pre-eclampsia, thrombocytopenia, and postpartum coagulopathy. We also describe five additional cases of gestations complicated by hematologic malignancies identified upon a 10-year institutional retrospective review.

Topics: Abruptio Placentae; Antineoplastic Agents; Disseminated Intravascular Coagulation; Female; Fetal Death; Humans; Leukemia, Promyelocytic, Acute; Postpartum Period; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Neoplastic; Retrospective Studies; Treatment Outcome; Tretinoin; Young Adult

为进一步规范我国儿童急性早幼粒细胞白血病（APL）的诊断和治疗，国家卫生健康委员会组建了国家卫生健康委儿童白血病专家委员会（简称专家委员会）。根据近年来国内外APL突破性的研究进展，专家委员会制定了"儿童急性早幼粒细胞白血病诊疗规范（2018年版）"，已于2018年10月8日在国家卫生健康委网站颁布。本文将对此诊疗规范进行解读，旨在更新临床医生对儿童APL的认识和理解，更好地指导临床治疗。.

Topics: Antineoplastic Agents; Asian People; Child; Humans; Leukemia, Promyelocytic, Acute; Practice Guidelines as Topic; Tretinoin

To investigate the effect of chromosomal karyotype on the prognosis of patients with acute promyelocytic leukemia (APL) in condition of the maintenance treatment based on arsenic trioxide.. The patients with acute promyelocytic leukemia for last 12 years in our hospital were retrospectively collected. The patients mainly treated with arsenic trioxide in maintenance protocol were selected and followed up. All the patients were divided into 3 groups according to cytogenetic data: single t (15; 17) group, t (15; 17) with additional chromosomal abnormality (ACA) group, and normal karyotype group. Then, the prognostic significance of ACAs and complex karyotype were investigated in APL patients.. There were 57 cases in the single t (15; 17) group, in which 8 cases died in the first month after induction treatment with early mortality rate of 14%. There were 21 patients in t (15; 17) with ACA group, in which 4 cases died in the first month with early mortality rate of 19%. There were 15 cases in normal chromosome group, in which 5 cases died in the first month with the early mortality rate of 33.3%. There was no statistical difference in the early mortality among 3 groups. All the remaining 76 patients achieved complete hematological remission. These patients were followed up. The median follow-up time was 43.9 months. Among them, only 2 patients in single t (15; 17) group and 1 patient in t (15; 17) with ACA group relapsed. No patient relapsed in normal karyotype group. The relapse rate was 3.5% in single t (15; 17) group and 4.2% in t (15; 17) with ACA group, respectively. There was no statistical difference in the overall survival and disease-free survival rates among 3 groups. Further analysis showed that the patients with complex chromosome karyotypes had lower relapse-free survival rates, but overall survival rates were not significantly different in 3 group.. In general, ACA can not affect the prognosis of patients with acute promyelocytic leukemia in condition of the maintenance treatment based on arsenic trioxide, but the complex chromosomal karyotype may reduce the relapse-free survival rates.. 以亚砷酸为主的维持治疗下染色体核型对急性早幼粒细胞白血病患者预后的影响.. 探讨在以亚砷酸为主的维持治疗体系下染色体核型对急性早幼粒细胞白血病患者的预后影响.. 回顾性收集12年内本院住院治疗的急性早幼粒细胞白血病患者，并选取其中以亚砷酸为主的方案维持治疗且可随访的患者，分为单纯 t (15; 17)组，t (15; 17)伴有附加染色体异常组，正常核型组并探讨附加染色体异常对患者预后的影响，同时进一步探讨复杂核型对预后的意义.. 单纯t (15; 17)组患者共57例，早期死亡8例，其早期死亡率为14.0%。附加染色体异常组患者21例，其早期死亡4例，死亡率19.0%。正常染色体组15例，早期死亡5例，其死亡率33.3%， 3组间早期死亡率无统计学差异。其余76例患者均达到完全血液学缓解。对76例患者进行长期随访，中位随访43.9个月，其中单纯t (15; 17)组患者复发2例，复发率3.5%，附加染色体异常组患者复发1例，复发率4.2%，正常染色体组无病例复发。3组间总生存率、无病生存率无统计学差异。进一步分析显示，复杂染色体核型的患者无复发生存率较低，但总体生存率未显示显著区别.. 以亚砷酸为主的维持治疗体系，附加染色体异常总体上不影响急性早幼粒细胞白血病患者的预后，但是复杂染色体核型可能会降低患者的无复发生存率.

Topics: Arsenic Trioxide; Humans; Karyotype; Leukemia, Promyelocytic, Acute; Prognosis; Remission Induction; Retrospective Studies; Treatment Outcome; Tretinoin

We report a 55-year-old man who began undergoing hemodialysis for polycystic kidney disease 17 years ago. Because pancytopenia and susceptibility to infection were identified, a bone marrow biopsy was performed, resulting in a diagnosis of acute promyelocytic leukemia (APL). All-trans retinoic acid (ATRA) treatment was initiated, but promyelocytic leukemia/retinoic acid receptor alpha gene fusion without remission was identified by fluorescence in situ hybridization. We administered ATRA/arsenic trioxide (ATO) combination therapy for therapy-resistant APL and confirmed molecular genetic remission. The ATRA/ATO combination therapy was continued, obtaining complete remission 2 years after commencement of treatment. Cystic infections continued during ATRA/ATO combination therapy, similar to infections before APL morbidity, and there were no adverse events leading to treatment discontinuation. ATRA/ATO combination therapy is considered a safe and effective treatment for therapy-resistant APL patients on hemodialysis.

Topics: Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Humans; In Situ Hybridization, Fluorescence; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Polycystic Kidney Diseases; Remission Induction; Renal Dialysis; Treatment Outcome; Tretinoin

To study the clinical effect of the SCMC APL-2010 regimen in the treatment of acute promyelocytic leukemia (APL) in children.. A retrospective analysis was performed for the clinical data of 44 children with APL who received treatment with the SCMC APL-2010 regimen between April 2010 and July 2016. The Kaplan-Meier survival analysis was used to evaluate event-free survival (EFS) rate and overall survival (OS) rate.. Of the 44 children with APL, 42 (95%) achieved a complete remission (CR) after one course of treatment and 1 achieved CR after two courses of treatment, with an overall CR rate of 98%. The 9-year EFS and OS rates were 96%±3% and 97.7%±2.2% respectively. As for adverse events, 41 (93%) had infection, 29 (66%) had granulocyte reduction, 12 (27%, 1 died) had differentiation syndrome, 16 (36%) had liver dysfunction, 12 (27%) had adverse gastrointestinal reactions, and 7 (16%) had QT prolongation, 1 (2%) had orchitis, and no secondary neoplasm was observed.. Children with APL receiving the SCMC APL-2010 regimen have a good prognosis and can achieve a long-term survival, while treatment-related infection is commonly seen.

Topics: Antineoplastic Combined Chemotherapy Protocols; Child; Disease-Free Survival; Humans; Leukemia, Promyelocytic, Acute; Male; Remission Induction; Retrospective Studies; Treatment Outcome; Tretinoin

Topics: Chromosomes, Human, Pair 15; Chromosomes, Human, Pair 17; Cytogenetics; Humans; In Situ Hybridization, Fluorescence; Leukemia, Promyelocytic, Acute; Oncogene Proteins, Fusion; Retinoic Acid Receptor alpha; Tretinoin

Topics: Apoptosis; Cell Differentiation; Cell Line, Tumor; Humans; Leukemia, Promyelocytic, Acute; RNA, Long Noncoding; Tretinoin

Objective To investigate the effect of all-trans retinoic acid (ATRA) on cell differentiation in nuclear localization signal-retinoic acid receptor-α (NLS-RARα)-overexpressing leukemia cells. Methods Lentivirus was used to infect NB4 and U937 cells to overexpress NLS-RARα. Fluorescent microscope, real-time PCR and Western blot analysis were performed to measure the mRNA and protein expression of NLS-RARα, CD11b and CEBPβ. Modified Wright staining was used to observe the cell morphology. Results NLS-RARα was overexpressed successfully after the lentivirus infection. Overexpressed NLS-RARα could repress the expression of CD11b and CEBPβ. NLS-RARα could be degraded by ATRA in a concentration- and time-dependent manner; ATRA promoted cell differentiation in both negative control cells and NLS-RARα-overexpressing cells. Conclusion ATRA promotes the differentiation of human leukemia cells by degrading NLS-RARα protein.

Topics: Cell Differentiation; Humans; Leukemia, Promyelocytic, Acute; Nuclear Localization Signals; Retinoic Acid Receptor alpha; Tretinoin; U937 Cells

Chronic lymphocytic leukemia (CLL) is known to be associated rarely with myeloid malignancies such as acute myelogenous leukemia. In this article, we report an extremely rare occurrence of acute promyelocytic leukemia in a patient with CLL. A 71-year-old man first presented to our clinic with a diagnosis of CLL and worsening motor neuropathy symptoms. It was suspected that his CLL might be contributing to the neuropathy as a paraneoplastic syndrome, and he was treated with rituximab monotherapy in weekly doses for the 1st month and monthly treatments thereafter. By the end of his sixth monthly course of rituximab, the patient noted significant improvement in neuropathy symptoms but reported experiencing a new-onset worsening fatigue. He had new-onset cytopenias (white blood cells 1.6k/µL, hemoglobin 11.7g/dL, and platelet count 77k/µL). A bone marrow examination was performed; it showed a high percentage of progranulocytes (21%), which stained positive for myeloperoxidase (MPO) and demonstrated a fine granular pattern on the promyelocytic leukemia (PML) oncogenic domain immunofluorescence test. The diagnosis of acute promyelocytic leukemia was confirmed by fluorescence in situ hybridization, which showed a PML/RARα rearrangement in 46% of interphases. Flow cytometry was consistent with immunophenotype of acute promyelocytic leukemia and minimal residual CLL (0.07%). The patient was started promptly on all-trans-retinoic acid and arsenic trioxide induction regimen. Molecular remission was achieved after the first consolidation cycle. The patient is currently past his fourth consolidation cycle of all-trans-retinoic acid/arsenic trioxide and continues to be in complete remission. Our case illustrates that it is important for the physicians to be aware of coexistent hematologic and solid tumor malignancies in CLL, and maintain a low threshold for diagnostic testing based on grounds of low clinical suspicion.

Topics: Aged; Antineoplastic Agents; Arsenic Trioxide; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Promyelocytic, Acute; Male; Rituximab; Tretinoin

Topics: Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Female; Humans; Leukemia, Promyelocytic, Acute; Male; Point-of-Care Systems; Prospective Studies; Syndrome; Tretinoin; Ultrasonography

As a classic differentiation agent, all-trans retinoic acid (ATRA) has been widely used in the treatment of acute promyelocytic leukemia (APL). However, the clinical application of ATRA has strict limitations, for its severe side effects due to the accumulation of peripheral blood leukocytes. The scaffold protein RACK1 (Receptor for activated C kinase 1), which regulates multiple signaling pathways, has been proposed to contribute to the survival of leukemic progenitors. But it remains unclear whether it is also involved in the oncogenic growth of APL. In the present study, we demonstrate that silencing of endogenous RACK1 expression synergized with ATRA to promote the death of NB4 and HL-60 APL cells without effect on cell differentiation induced by ATRA. Interestingly, RACK1 knockdown combined with ATRA treatment mainly induces apoptosis. It is distinct to the necrotic cell death induced by idarubicin in combination with ATRA, a regimen extensively used in the clinic to prevent neutrophil accumulation. Further exploration revealed that the lysosome-autophagy pathway is likely to be responsible for the anti-apoptotic role of RACK1. Taken together, our findings indicate that RACK1 is essential in maintaining the malignant features of APL, and targeting RACK1 may have promising therapeutic implications in the treatment of APL.

Topics: Antineoplastic Agents; Apoptosis; Autophagy; Cell Differentiation; Humans; Leukemia, Promyelocytic, Acute; Neoplasm Proteins; Receptors for Activated C Kinase; Signal Transduction; Tretinoin; Tumor Cells, Cultured

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Child; Child, Preschool; Female; Hematologic Diseases; Humans; Leukemia, Promyelocytic, Acute; Male; Tretinoin

Fatty acid oxidation dependency of leukemia cells has been documented in recent studies. Pharmacologic inhibition of fatty acid oxidation, thereby, displays significant effects in suppressing leukemia. 2-Bromopalmitate, a palmitate analogue, was initially identified as an inhibitor of fatty acid oxidation, and recently recognized as an inhibitor of protein palmitoylation. However, the effects of 2-Bromopalmitate on leukemia and its cellular targets remain obscure. Herein, we discover in cultured cell lines, a transplantable mouse model, and primary blasts that 2-Bromopalmitate presents synergistic differentiation induction with all-trans retinoic acid in acute promyelocytic leukemia. Moreover, 2-Bromopalmitate overcomes all-trans retinoic acid resistance in all-trans retinoic acid-resistant cells and leukemic mice. Mechanistically, 2-Bromopalmitate covalently binds at cysteine 105 and cysteine 174 of retinoic acid receptor alpha (RARα) and stabilizes RARα protein in the presence of all-trans retinoic acid which is known to induce RARα degradation, leading to enhanced transcription of RARα-target genes. Mutation of both cysteines largely abrogates the synergistic effect of 2-Bromopalmitate on all-trans retinoic acid-induced differentiation, demonstrating that 2-Bromopalmitate promotes all-trans retinoic acid-induced differentiation through binding RARα. All-trans retinoic acid-based regimens including arsenic trioxide or chemotherapy, as preferred therapy for acute promyelocytic leukemia, induce adverse events and irreversible resistance. We expect that combining all-trans retinoic acid with 2-Bromopalmitate would be a promising therapeutic strategy for acute promyelocytic leukemia, especially for overcoming all-trans retinoic acid resistance of relapsed acute promyelocytic leukemia patients.

Topics: Drug Delivery Systems; Drug Resistance, Neoplasm; Humans; Leukemia, Promyelocytic, Acute; Neoplasm Proteins; Palmitates; Retinoic Acid Receptor alpha; Tretinoin; Xenograft Model Antitumor Assays

Differentiation syndrome (DS) is a life-threatening complication arising during retinoid treatment of acute promyelocytic leukemia (APL). Administration of all-trans retinoic acid leads to significant changes in gene expression, among the most induced of which is transglutaminase 2, which is not normally expressed in neutrophil granulocytes. To evaluate the pathophysiological function of transglutaminase 2 in the context of immunological function and disease outcomes, such as excessive superoxide anion, cytokine, and chemokine production in differentiated NB4 cells, we used an NB4 transglutaminase knock-out cell line and a transglutaminase inhibitor, NC9, which inhibits both transamidase- and guanosine triphosphate-binding activities, to clarify the contribution of transglutaminase to the development of potentially lethal DS during all-trans retinoic acid treatment of APL. We found that such treatment not only enhanced cell-surface expression of CD11b and CD11c but also induced high-affinity states; atypical transglutaminase 2 expression in NB4 cells activated the nuclear factor kappa (κ)-light-chain-enhancer of the activated B-cell pathway, driving pathogenic processes with an inflammatory cascade through the expression of numerous cytokines, including tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1β), and monocyte chemoattractant protein 1. NC9 decreased the amount of transglutaminase 2, p65/RelA, and p50 in differentiated NB4 cells and their nuclei, leading to attenuated inflammatory cytokine synthesis. NC9 significantly inhibits transglutaminase 2 nuclear translocation but accelerates its proteasomal breakdown. This study demonstrates that transglutaminase 2 expression induced by all-trans retinoic acid treatment reprograms inflammatory signaling networks governed by nuclear factor κ-light-chain-enhancer of activated B-cell activation, resulting in overexpression of TNF-α and IL-1β in differentiating APL cells, suggesting that atypically expressed transglutaminase 2 is a promising target for leukemia treatment.

Topics: Antineoplastic Agents; CD11 Antigens; Cell Differentiation; Cell Line, Tumor; Cytokines; Gene Expression Regulation, Leukemic; Gene Knockdown Techniques; GTP-Binding Proteins; Humans; Inflammation Mediators; Leukemia, Promyelocytic, Acute; Macrophage-1 Antigen; Neoplasm Staging; NF-kappa B; Phagocytosis; Protein Glutamine gamma Glutamyltransferase 2; Signal Transduction; Transglutaminases; Tretinoin

Out of 956, there were 95 (10%) CD56+ APL patients treated with PETHEMA ATRA and chemotherapy. CD56+ expression was associated with high WBC, BCR3 isoform, and co-expression of CD2, CD34, CD7, HLA-DR, CD15, and CD117 antigens. CD56+ vs CD56- APL presented higher induction death rate (16% vs 8%, p = .02) and 5-years cumulative incidence of relapse (33% versus 10%, p = .006), irrespectively of the Sanz score (low-risk 47% versus 5%, p < .001; intermediate 23% versus 7%, p < .001; and high-risk 42% versus 21%, p = .007). In the multivariate analysis, CD56 + (p < .0001), higher relapse-risk score (p = .001), and male gender (p = .05) retained the independent predictive value. CD56+ APL also showed a greater risk of CNS relapse (6% versus 1%, p < .001) and lower 5-year OS (75% versus 83%, p = .003). The AIDA-based LPA2012 trial, with an intensified consolidation schedule for CD56+ APL, will elucidate whether an intensified consolidation schedule could mitigate the relapse rate in this setting.

Topics: Adolescent; Adult; Aged; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; CD56 Antigen; Child; Child, Preschool; Female; Gene Expression; Humans; Kaplan-Meier Estimate; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Prognosis; Recurrence; Treatment Outcome; Tretinoin; Young Adult

The specific prognostic factors and the long-term effects of different treatment options in APL remain unclear. In this retrospective study, 70 APL patients were treated with ATRA + DNR/DA or ATRA + ATO regimens for induction therapy and DA or ATRA + ATO for consolidation and maintenance therapy. The prognostic factors and treatment effects on outcome were analyzed. Results showed that the 5-year OS in low-intermediate risk and high risk groups were 95.63% and 100%, and the 5-year RFS were 95.34% and 100%, respectively, the early mortality rate was 4.28%. No significant difference was found on OS and RFS with different regimens, but side-effects and treatment-related mortality rates were lower in ATRA + ATO group. CD34 expression, FLT3-ITD mutation and PML-RARA isoform had no significance on OS and RFS. In conclusion, cytogenetic and molecular abnormalities had no influence on effect of APL patients; ATRA + ATO sequential maintenance may alleviate complications, treatment-related mortality, and the previously high risk factors.

Topics: Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Consolidation Chemotherapy; Female; Humans; Leukemia, Promyelocytic, Acute; Maintenance Chemotherapy; Male; Prognosis; Recurrence; Retreatment; Retrospective Studies; Survival Analysis; Time Factors; Treatment Outcome; Tretinoin

In acute promyelocytic leukemia (APL), all-trans retinoic acid (ATRA) treatment induces granulocytic differentiation and maturation. MicroRNAs play pivotal roles in formation of the leukemic phenotype. Previously, microRNA-382-5p (miR-382-5p) was upregulated in acute myeloid leukemia (AML) with t(15;17). In the present study, we found that miR-382-5p expression was elevated with ATRA-induced differentiation of APL. To investigate the potential functional role of miR-382-5p in APL differentiation, an APL cell line was transfected with miR-382-5p mimics, inhibitors, or negative control (NC). The results showed in APL cell line NB4 that miR-382-5p downregulation upon ATRA treatment was a key event in the drug response. Mechanistic investigations revealed that miR-382-5p targeted the ATRA-regulated tumor suppressor gene PTEN through direct binding to its 3' UTR. Enforced expression of miR-382-5p or specific PTEN inhibitors inhibited ATRA-induced granulocytic differentiation via regulation of the cell cycle regulator cyclinD1. Conversely, PTEN overexpression promoted differentiation and enhanced sensitivity of NB4 cell line to physiological levels of ATRA. Finally, we found that PTEN overexpression restored PML nuclear bodies (NBs). Taken together, these results demonstrated that up-regulated miR-382-5p in NB4 cell line inhibited granulocytic differentiation through the miR-382-5p/PTEN axis, uncovering PTEN as a critical element in the granulocytic differentiation program induced by ATRA in APL.

Topics: Antineoplastic Agents; Cell Differentiation; Cyclin D1; HL-60 Cells; Humans; Leukemia, Promyelocytic, Acute; MicroRNAs; PTEN Phosphohydrolase; THP-1 Cells; Tretinoin

Acute promyelocytic leukemia (APL) is one of the most fatal hematological malignancies. APL during pregnancy is a rare comorbidity and can lead to adverse outcomes, such as maternal and/or fetal death, without timely and appropriate management. Medical management for APL during pregnancy remains challenging. We reported 2 patients with no regular prenatal visits who were diagnosed with APL during pregnancy. One presented with typical hematological abnormalities related to infection, while the other presented with intracranial hemorrhage, which is rare. Although supportive measures and chemotherapy were administered after APL was diagnosed, these two patients had completely different outcomes. The pregnancy outcomes of APL patients depend greatly on the timely diagnosis and appropriate management of the disease. Physicians should pay more attention to APL during pregnancy and thus may save more maternal and fetal lives. Further study of the management of APL during pregnancy is warranted. Abbreviations: AML: acute myeloid leukemia; APL: acute promyelocytic leukemia; WBC: white blood cell; RBC: red blood cell; Hb: hemoglobin; PT: prothrombin time; TT: thrombin time; APTT: activated partial thromboplastin time; TP: total protein; ALB: albumin; AST: aspartate transaminase; ALT: alanine aminotransferase; LDH: lactate dehydrogenase; ATRA: all-trans retinoic acid; ICH: intracranial hemorrhage; DIC: disseminated intravascular coagulation.

Topics: Adult; Age of Onset; Antineoplastic Agents; Female; Humans; Leukemia, Promyelocytic, Acute; Pregnancy; Pregnancy Complications, Neoplastic; Prognosis; Tretinoin; Young Adult

Topics: Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Blood Transfusion; Hospitalization; Humans; Leukemia, Promyelocytic, Acute; Treatment Outcome; Tretinoin

Essential for cell survival, the 90 kD Heat Shock Proteins (HSP90) are molecular chaperons required for conformational stabilization and trafficking of numerous client proteins. Functional HSP90 is required for the stability of AKT, a serine-threonine kinase phosphorylated in response to growth factor stimulation. AKT plays a crucial regulatory role in differentiation, cell cycle, transcription, translation, metabolism and apoptosis. Acute promyelocytic leukaemia (APL) is characterized by the presence of the promyelocytic leukaemia/retinoic acid receptor alpha (PML/RARA) fusion protein, which deregulates expression of several genes involved in differentiation and apoptosis. Here, we report inhibition of HSP90AA1 and HSP90AB1 isomer transcription in blasts isolated from patients with APL, associated with reduction of HSP90 protein expression and loss of control on AKT protein phosphorylation. We show that in vitro treatment of PML/RARA expressing cells with all-trans retinoic acid (ATRA) up-regulates HSP90 expression and stabilizes AKT. Addition of the HSP90-inhibitor 17-(allylamino)-17-demethoxygeldanamycin in combination with ATRA, blocks upregulation of AKT protein, indicating that HSP90 is necessary for ATRA action on AKT. This is the first report proving that expression of HSP90 isomers are directly and differentially repressed by PML/RARA, with critical results on cellular homeostasis of target proteins, such as AKT, in APL blasts.

Topics: Benzoquinones; HEK293 Cells; Histones; HSP90 Heat-Shock Proteins; Humans; Lactams, Macrocyclic; Leukemia, Promyelocytic, Acute; Oncogene Proteins, Fusion; Promoter Regions, Genetic; Promyelocytic Leukemia Protein; Proto-Oncogene Proteins c-akt; Retinoic Acid Receptor alpha; RNA, Messenger; Transfection; Tretinoin; Tumor Cells, Cultured; Up-Regulation

In non-acute promyelotic leukemia (APL)- non myelocytic leukemia (AML), identification of a signaling signature would predict potentially actionable targets to enhance differentiation effects of all-trans-retinoic acid (RA) and make combination differentiation therapy realizable. Components of such a signaling machine/signalsome found to drive RA-induced differentiation discerned in a FAB M2 cell line/model (HL-60) were further characterized and then compared against AML patient expression profiles. FICZ, known to enhance RA-induced differentiation, was used to experimentally augment signaling for analysis. FRET revealed novel signalsome protein associations: CD38 with pS376SLP76 and caveolin-1 with CD38 and AhR. The signaling molecules driving differentiation in HL-60 cluster in non-APL AML

Topics: Antineoplastic Agents; Apoptosis; Biomarkers, Tumor; Carbazoles; Cell Differentiation; Drug Resistance, Neoplasm; Drug Synergism; Drug Therapy, Combination; Gene Expression Regulation, Neoplastic; HL-60 Cells; Humans; Leukemia, Myeloid, Acute; Leukemia, Promyelocytic, Acute; Signal Transduction; Tretinoin

Organophosphonates are a group of chemical agents which have high bioactivity. In the present study, we aimed to investigate the anticancer activity of the synthesized β-lactam derivatives of α-amino phosphonates on solid tumor and human leukemic cell lines. The results show that one of these compounds, Diethyl [(3-phenoxy-2-oxo-4-phenyl-azetidine-1-yl)-phenyl-methyl]-phosphonate, is a potent anticancer agent which especially shows anti-leukemic activity. Flow cytometry study showed that this chemical agent causes the G1 phase cell cycle arrest and consequently apoptosis in NB4 cell line as an acute promyelocytic leukemia model. In fact, this agent induces cell differentiation and apoptosis, at low and high concentrations, respectively. Its combination with All-Trans Retinoic Acid shows a higher percentage of cells in the terminal differentiation stage. This evidence suggested that diethyl phosphonate might be a proper candidate for chemo-differentiation therapy in acute promyelocytic leukemia and even in other types of acute myeloid leukemia.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Differentiation; Cell Line, Tumor; Flow Cytometry; G1 Phase Cell Cycle Checkpoints; Humans; Leukemia, Promyelocytic, Acute; Organophosphonates; Tretinoin

To perform a retrospective analysis of the prognostic relevance of clinicopathologic parameters in a well-documented cohort of patients treated with all-trans-retinoic acid (ATRA)-based induction regimens in order to discover which indicators can predict a high risk of early death (ED) and patient survival.. We analyzed data of 288 newly diagnosed adult acute promyelocytic leukemia patients in Hangzhou, China. The median follow-up time was 32 months (range, 6-78 months).. The 3-year disease-free and overall survival rates were 90.83% and 91.69%, respectively. In the multivariable analysis, older age (≥ 60 years) was the only independent risk factor for ED (hazard ratio [HR] = 15.057; P = .004). High white blood cell count was not a risk factor for ED (P = .055), but it was for relapse (HR = 2.7; P = .009). FLT3 mutation (HR = 3.9; 95% confidence interval, 1.4 to 10; P = .007) and older age (≥ 60 years) (HR = 5.3; 95% confidence interval, 2.4 to 11; P < .001) were prognostic factors for poorer disease-free and overall survival. Interestingly, CD15 negativity (HR = 0.23; P = .049) was a prognostic factor for relapse. The ED rate was 5.9% (17/288 patients).. The perceived impact of the identification of these high-risk factors should be described in order to decide whether any modifications to treatment strategy should be entertained.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Death; Female; Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Prognosis; Retrospective Studies; Survival Rate; Tretinoin

Topics: Aged; Arsenic Trioxide; Biopsy, Needle; Drug Eruptions; Follow-Up Studies; Humans; Immunohistochemistry; Leukemia, Promyelocytic, Acute; Male; Remission, Spontaneous; Risk Assessment; Treatment Outcome; Tretinoin

Distinct types of PML-RARα hybrid transcripts viz bcr-1, bcr-2 and bcr-3 result from translocation between chromosomes 15 and 17 t(15;17) in Acute Promyelocytic Leukemia patients. We aimed to determine the frequencies of the PML-RARα transcripts and FLT3-ITD mutations in APL patients to evaluate their prognostic implications and also to analyze their impact on disease outcome.. RT-PCR and Rq-PCR were adopted for transcript typing and quantitation of PML-RARα transcripts while FLT3-ITD was detected by PCR in APL patients.. PML-RARα bcr-1, bcr-2 and bcr-3 transcripts were found in 26, 3 and 16 cases respectively. 64.4% patients achieved complete remission, 22.2% expired early wherein majority of the cases expressed bcr-3 transcript (p = 0.03). 50% relapse rate was observed in patients with bcr-3 transcripts. Multivariate analysis showed expression of bcr-3 transcript associated with early death (p = 0.027) and increased relapse risk (P = 0.046). Patients expressing bcr-3 hybrid transcript showed lowest OS of 28.0 months (± 5.26) (p = 0.027). FLT3-ITD mutation was detected in 5 (11.1%) patients and presence of these mutations was not associated either with PML-RARα transcripts or with disease outcome.. bcr-3 transcript has a more lethal outcome and is also associated with frequent relapse risk in APL patients of our region.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Arsenic Trioxide; Child; Chromosome Breakpoints; Disease-Free Survival; Female; Humans; India; Kaplan-Meier Estimate; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Multivariate Analysis; Oncogene Proteins, Fusion; RNA, Messenger; Treatment Outcome; Tretinoin; Young Adult

Genetic mutations on PML-RARα in acute promyelocytic leukemia (APL) are reported to associate with arsenic trioxide (ATO) or all-trans retinoic acid (ATRA) resistance. Here we performed a retrospective analysis of APL patients and identified that the patient with S214L mutation on the PML moiety of PML-RARα showed resistance to both ATO and ATRA. Super-resolution microcopy was used to examine the structural response of PML bodies in wild-type or the S214L mutant cells upon drug treatment. Different protein density and fluidity were identified with the S214L mutant PML bodies by single particle quantification and FRAP analysis. We discovered that altered SUMOylation and ubiquitination might contribute to the drug resistance. Taken together, we have revealed that the S214L mutation on PML-RARα disrupted the organization of PML body and dynamics changes, perturbing structural responses to ATRA and subsequent oncoprotein degradation. Our findings shed new light on the structural alterations of PML bodies and mechanisms of APL drug resistance.

Topics: Antineoplastic Agents; Arsenic Trioxide; Drug Resistance, Neoplasm; HEK293 Cells; Humans; Leukemia, Promyelocytic, Acute; Oncogene Proteins, Fusion; Point Mutation; Sumoylation; Tretinoin

With the introduction of arsenic trioxide and all-trans retinoic acid, the prognosis of acute promyelocytic leukemia has greatly improved. However, all-trans retinoic acid resistance is still unresolved in acute promyelocytic leukemia relapsed patients. In this study, the clinical achievable concentration of 7-hydroxystaurosporine synergized with all-trans retinoic acid to induce terminal differentiation in all-trans retinoic acid resistant acute promyelocytic leukemia cell lines. Though 7-hydroxystaurosporine is a PKC inhibitor, PKC might not be involved in the combination-induced differentiation since other PKC selective inhibitors, Gö 6976 and rottlerin failed to cooperate with all-trans retinoic acid to trigger differentiation. The combination significantly enhanced the protein level of CCAAT/enhancer binding protein β and/or PU.1 as well as activated MEK/ERK. U0126 (MEK specific inhibitor) not only suppressed the combination-induced differentiation but also restored the protein level of CCAAT/enhancer binding protein β and/or PU.1. However, RAF-1 inhibitor had no inhibitory effect on MEK activation and the combination-induced differentiation. Therefore, the combination overcame differentiation block via RAF-1 independent MEK/ERK modulation of the protein level of CCAAT/enhancer binding protein β and/or PU.1. These findings may provide a preclinical rationale for the potential role of this combination in the treatment of all-trans retinoic acid resistant acute promyelocytic leukemia patients.

Topics: Antineoplastic Agents; Cell Line, Tumor; Drug Resistance, Neoplasm; Enzyme Activation; Humans; Leukemia, Promyelocytic, Acute; MAP Kinase Kinase 1; MAP Kinase Signaling System; Mitogen-Activated Protein Kinases; Proto-Oncogene Proteins c-raf; Staurosporine; Tretinoin

Topics: Animals; Arsenic; fms-Like Tyrosine Kinase 3; Leukemia, Myeloid, Acute; Leukemia, Promyelocytic, Acute; Mice; Tretinoin

The RARG gene is a member of the nuclear hormone receptor superfamily and shares high homology with RARA and RARB. RARA is involved in translocation with PML in acute promyelocytic leukaemia (APL). Little is known about RARB or RARG rearrangement. RARG fusions were reported in only five APL patients and the partner genes were NUP98, PML and CPSF6. Here, we report NPM1 as a new partner gene of RARG and identify a unique NPM1-RARG-NPM1 chimeric fusion for the first time in an old male with morphological and immunophenotypical features of hypergranular APL but lacking response to all-trans retinoic acid (ATRA) and arsenic trioxide (As

Topics: Aged; Arsenic Trioxide; Drug Resistance, Neoplasm; Gene Fusion; Humans; Leukemia, Myeloid, Acute; Leukemia, Promyelocytic, Acute; Male; Nuclear Proteins; Nucleophosmin; Receptors, Retinoic Acid; Retinoic Acid Receptor gamma; Tretinoin

Although targeted therapies have proven effective and even curative in human leukaemia, resistance often ensues. IDH enzymes are mutated in ~20% of human AML, with targeted therapies under clinical evaluation. We here characterize leukaemia evolution from mutant IDH2 (mIDH2)-dependence to independence identifying key targetable vulnerabilities of mIDH2 leukaemia that are retained during evolution and progression from early to late stages. Mechanistically, we find that mIDH2 leukaemia are metastable and vulnerable at two distinct levels. On the one hand, they are characterized by oxidative and genotoxic stress, in spite of increased 1-carbon metabolism and glutathione levels. On the other hand, mIDH2 leukaemia display inhibition of LSD1 and a resulting transcriptional signature of all-trans retinoic acid (ATRA) sensitization, in spite of a state of suppressed ATRA signalling due to increased levels of PIN1. We further identify GSH/ROS and PIN1/LSD1 as critical nodes for leukaemia maintenance and the combination of ATRA and arsenic trioxide (ATO) as a key therapeutic modality to target these vulnerabilities. Strikingly, we demonstrate that the combination of ATRA and ATO proves to be a powerfully synergistic and effective therapy in a number of mouse and human mIDH1/2 leukemic models. Thus, our findings pave the way towards the treatment of a sizable fraction of human AMLs through targeted APL-like combinatorial therapies.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Disease Models, Animal; Humans; Isocitrate Dehydrogenase; Leukemia, Myeloid, Acute; Leukemia, Promyelocytic, Acute; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutation; Neoplasms, Experimental; Tretinoin; Tumor Cells, Cultured; U937 Cells

Acute promyelocytic leukemia is infrequent among patients aged ≥75 years old, a population that is rarely eligible for clinical protocols. This study aims to analyze the treatment strategies and clinical outcomes of very old APL patients reported to the international PETHEMA registry. Between 1997 and 2017, among 2501 APL cases registered 120 were ≥75 years old. Treatment approaches were: AIDA regimen, 79 patients; ATRA alone, 23; 16, supportive care (SC) and 2, other strategies. Patients treated with AIDA were younger, had better ECOG and lower leukocytes. Complete remission (CR) was achieved in 65% of AIDA-group vs. 45% in the ATRA-group, being infections followed by bleeding the most frequent causes of induction death. Patients in CR after AIDA showed 3-year DFS of 73%. Our real-life series of very old APL patients provides a reference basis for future treatment strategies aiming to improve clinical outcomes in this challenging population.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cohort Studies; Female; Follow-Up Studies; Humans; Idarubicin; Leukemia, Promyelocytic, Acute; Male; Neoplasm Recurrence, Local; Registries; Remission Induction; Survival Rate; Treatment Outcome; Tretinoin

To study the effect of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) combination treatment on apoptosis of acute promyelocytic leukemia cells (NB4), inflammation and prognosis. The effect of ATRA - ATO combination on the proliferation of NB4 was determined using MTT assay. Apoptosis of NB4 cells was assessed with TUNEL assay. The effect of ATRA-As2O3 combination on the expressions of IL-6 and TNF-α in NB4 cells was determined using ELISA kits, while its effect on the quality of life of 25 acute promyelocytic leukemia patients admitted to our hospital was scored, as an index of prognosis. The combination treatment with ATRA and ATO significantly inhibited the proliferation of NB4 cells and promoted their apoptosis, relative to the model group. In addition, the combination treatment reduced serum IL-6 and TNF-α levels in patients with acute promyelocytic leukemia, and improve their quality of life and survival. Combination treatment with ATRA and ATO significantly inhibits the proliferation of NB4 cells and promotes their apoptosis, and reduces inflammatory responses in patients with acute promyelocytic leukemia, while improving their quality of life and prognosis.

Topics: Apoptosis; Arsenic Trioxide; Cell Line, Tumor; Cell Proliferation; Down-Regulation; Humans; Interleukin-6; Leukemia, Promyelocytic, Acute; Prognosis; Quality of Life; Tretinoin; Tumor Necrosis Factor-alpha

The combination of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) has proven to be the most effective therapy for patients with acute promyelocytic leukemia (APL). The majority of the morbidity and mortality from APL therapy occur during the induction phase. The objective of the current study was to identify the risk factors associated with transfer to the intensive care unit (ICU) and endotracheal intubation during induction therapy in patients with APL.. The authors analyzed the clinical characteristics of 187 patients with newly diagnosed APL who were treated with ATRA and ATO with or without gemtuzumab ozogamicin. The authors documented the percentage change in body weight from baseline to the maximum recorded weight during induction or to the day of ICU transfer.. A total of 18 patients (10%) who initiated therapy with ATRA and ATO on a regular hospital floor required transfer to the ICU after a median of 12 days of induction therapy. The median volume of transfusions was 4350 mL (range, 60-30,750 mL). The volume of transfusions was the main factor associated with the risk of ICU transfer (odds ratio, 4.1; P < .001). Of the 18 patients transferred to the ICU, 10 patients (5%) required intubation. An increase in the total volume of transfusions, increase in weight ≥10% during induction therapy, and a plasma albumin level ≤3.2 g/dL at the time of diagnosis were found to be associated with an increased risk of endotracheal intubation.. Large volumes of blood product transfusions and unrecognized fluid overload during induction are associated with ICU transfer and endotracheal intubation in patients with APL. These can be prevented by limiting the amount of transfusions, careful monitoring for subtle signs of fluid overload, and early intervention with aggressive diuretic therapy.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Blood Component Transfusion; Female; Gemtuzumab; Humans; Induction Chemotherapy; Intensive Care Units; Intubation, Intratracheal; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Patient Transfer; Retrospective Studies; Risk Factors; Serum Albumin; Tretinoin; Water-Electrolyte Imbalance; Young Adult

Topics: Female; Humans; Leukemia, Promyelocytic, Acute; Pregnancy; Tretinoin

The resistance to differentiation therapy and early death caused by fatal bleeding endangers the health of a significant proportion of patients with acute promyelocytic leukemia (APL). This study aims to investigate the molecular mechanisms of all-. The important role of TWIST1 in APL leukemogenesis was first determined by gain- and loss-of-function assays. We then performed. We found that the epithelial-mesenchymal transition (EMT)-inducing transcription factor TWIST1 is highly expressed in APL cells and is critical for leukemic cell survival. TWIST1 and TRIB3 were highly coexpressed in APL cells compared with other subtypes of acute myeloid leukemia cells. We subsequently demonstrated that TRIB3 could bind to the WR domain of TWIST1 and contribute to its stabilization by inhibiting its ubiquitination. TRIB3 depletion promoting TWIST1 degradation reverses resistance to induction therapy and improves sensitivity to ATRA. On the basis of a detailed functional screen of synthetic peptides, we discovered a peptide analogous to the TWIST1 WR domain that specifically represses APL cell survival by disrupting the TRIB3/TWIST1 interaction.. Our data not only define the essential role of TWIST1 as an EMT-TF in patients with APL but also suggest that disrupting the TRIB3/TWIST1 interaction reverses induction therapy resistance and blocks rapid progression of APL early death.

Topics: Adolescent; Adult; Aged; Animals; Antineoplastic Agents; Bone Marrow; Cell Cycle Proteins; Cell Line, Tumor; Cell Survival; Disease Progression; Drug Resistance, Neoplasm; Epithelial-Mesenchymal Transition; Female; Gene Expression Profiling; Gene Expression Regulation, Leukemic; Gene Knockdown Techniques; HEK293 Cells; Humans; Leukemia, Promyelocytic, Acute; Male; Mice; Middle Aged; Nuclear Proteins; Peptidomimetics; Protein Binding; Protein Serine-Threonine Kinases; Protein Stability; Remission Induction; Repressor Proteins; RNA, Small Interfering; Tissue Array Analysis; Tretinoin; Twist-Related Protein 1; Ubiquitination; Xenograft Model Antitumor Assays; Young Adult

Acute promyelocytic leukemia (APL) is characterized by arrested differentiation of promyelocytes. Patients treated with all-trans retinoic acid (ATRA) alone experience relapse, while patients treated with ATRA and arsenic trioxide (ATO) are often relapse-free. This suggests sustained changes have been elicited by the combination therapy. To understand the lasting effects of the combination therapy, we compared the effects of ATRA and ATO on NB4 and ATRA-resistant NB4-MR2 APL cells during treatment versus post treatment termination. After treatment termination, NB4 cells treated with ATRA or ATO reverted to non-differentiated cells, while combination-treated cells remained terminally differentiated. This effect was diminished in NB4-MR2 cells. This suggests combination treatment induced more permanent changes. Combination treatment induced higher expression of target genes (e.g., transglutaminase 2 and retinoic acid receptor beta), which in NB4 cells was sustained post treatment termination. To determine whether sustained epigenetic changes were responsible, we quantified the enrichment of histone modifications by chromatin immunoprecipitation, and CpG methylation by bisulfite-pyrosequencing. While ATRA and combination treatment induced similar histone acetylation enrichment, combination treatment induced greater demethylation of target genes, which was sustained. Therefore, sustained demethylation of target genes by ATRA and ATO combination treatment is associated with lasting differentiation and gene expression changes.

Topics: Apoptosis; Arsenic Trioxide; Cell Differentiation; Cell Line, Tumor; Chemokine CCL2; CpG Islands; Demethylation; GTP-Binding Proteins; Humans; Leukemia, Promyelocytic, Acute; Promoter Regions, Genetic; Protein Glutamine gamma Glutamyltransferase 2; Receptors, Retinoic Acid; Transcriptome; Transglutaminases; Tretinoin

Despite advances in the treatment of acute promyelocytic leukemia (APL) with all-trans-retinoic acid (ATRA), its underlying mechanism has not been fully elucidated. The oncogenic microRNA cluster miR-17-92 modulates multiple cellular processes, including survival, proliferation, and apoptosis. However, the role of miR-17-92 and its regulation has not yet been documented for APL.. We analyzed miR-17-92 expression in APL samples and cell lines by qRT-PCR. The expression of c-Myc was measured by western blot. Cell differentiation was assessed by measuring the surface CD11b antigen expression by flow cytometry analysis.. We observed that miR-17-92 was upregulated in APL compared with healthy donors. Furthermore, we demonstrated that expressions of c-Myc and miR-17-92 are markedly suppressed during ATRA-induced NB4 cell differentiation. Importantly, we also demonstrated that miR-17-92 is directly regulated by c-Myc during the granulocytic differentiation of APL cells. Finally, the overexpression of miR-17-5p blocks ATRA-induced differentiation.. We report abnormal expression of the miR-17-92 cluster in APL cells, which is responsible for the differentiation block in blast cells in APL. In addition, we identified miR-17-92 as a target gene of c-Myc during ATRA-induced granulocytic differentiation.

Topics: Antineoplastic Agents; Cell Differentiation; Cell Line, Tumor; Gene Expression Regulation, Leukemic; Humans; Leukemia, Promyelocytic, Acute; MicroRNAs; Proto-Oncogene Proteins c-myc; RNA, Long Noncoding; Tretinoin

Despite the high probability of cure of patients with acute promyelocytic leukemia (APL), mechanisms of relapse are still largely unclear. Mutational profiling at diagnosis and/or relapse may help to identify APL patients needing frequent molecular monitoring and early treatment intervention. Using an NGS approach including a 31 myeloid gene-panel, we tested BM samples of 44 APLs at the time of diagnosis, and of 31 at relapse. Mutations in PML and RARA genes were studied using a customized-NGS-RNA panel. Patients relapsing after ATRA-chemotherapy rarely had additional mutations (P = .009). In patients relapsing after ATRA/ATO, the PML gene was a preferential mutation target. We then evaluated the predictive value of mutations at APL diagnosis. A median of two mutations was detectable in 9/11 patients who later relapsed, vs one mutation in 21/33 patients who remained in CCR (P = .0032). This corresponded to a significantly lower risk of relapse in patients with one or less mutations (HR 0.046; 95% CI 0.011-0.197; P < .0001). NGS-analysis at the time of APL diagnosis may inform treatment decisions, including alternative treatments for cases with an unfavorable mutation profile.

Topics: Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Bone Marrow; Clone Cells; Disease Progression; Drug Resistance, Neoplasm; High-Throughput Nucleotide Sequencing; Humans; Leukemia, Promyelocytic, Acute; Mutation; Neoplasm Proteins; Neoplastic Stem Cells; Oncogene Proteins, Fusion; Promyelocytic Leukemia Protein; Protein Domains; Recurrence; Remission Induction; Reproducibility of Results; Retinoic Acid Receptor alpha; RNA, Messenger; RNA, Neoplasm; Tretinoin

Increasingly, acute promyelocytic leukemia (APL) is treated with a combination of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). This study characterizes bone marrow findings after ATRA/ATO therapy.. Bone marrow biopsies from 16 patients treated with ATRA/ATO and seven patients treated with ATRA/chemotherapy (CTX) for APL were evaluated.. In ATRA/ATO cases, the marrow was likely to be hypercellular (79%) with a decreased myeloid:erythroid (M:E) ratio (88%), megaloblastoid maturation of erythroid precursors (100%), erythroid atypia (75%), and increased (88%) and atypical (75%) megakaryocytes. Significant myeloid atypia was only seen in extensive residual disease. The ATRA/CTX cases were less likely to be hypercellular (38%), have a M:E ratio of 1:1 or less (0%), exhibit significant erythroid atypia (0%), or have increased (0%) or atypical (38%) megakaryocytes.. Bone marrow biopsies from patients treated with ATO have unusual but characteristic features. Despite variability in marrow findings, clinical outcomes were uniformly favorable.

Topics: Adolescent; Adult; Aged; Arsenic Trioxide; Biopsy; Bone Marrow; Bone Marrow Cells; Erythroid Cells; Female; Humans; Karyotype; Leukemia, Promyelocytic, Acute; Male; Megakaryocytes; Middle Aged; Myeloid Cells; Myeloid Progenitor Cells; Treatment Outcome; Tretinoin; Young Adult

Differentiation syndrome (DS), previously known as retinoic acid syndrome or ATRA (all-trans retinoic acid) or ATO (arsenic trioxide) syndrome, is a life-threatening complication of the therapy with differentiating agents in patients with acute promyelocytic leukemia (APL). The latter is a rare subtype of acute myeloid leukemia and represents a hematological emergency. The clinical manifestations of DS, after induction therapy with differentiating agents, include unexplained fever, acute respiratory distress with interstitial pulmonary infiltrates, unexplained hypotension, peripheral edema, congestive heart failure and acute renal failure. The therapy is based on early intravenous administration of high-dose dexamethasone, in order to counteract the cytokine storm responsible for the DS. Among the supportive measures for the management of DS, furosemide (in 87% of patients) and dialysis (12% of patients) are used to manage acute renal failure, peripheral and pulmonary edema. We describe a case of acute renal failure, treated with haemodialysis, in a young patient with APL and an early and severe DS after induction therapy. This is a rare condition, not well known among nephrologists, where early recognition and treatment are crucial for the prognosis.

Topics: Acute Kidney Injury; Adult; Antineoplastic Agents; Arsenic Trioxide; Dexamethasone; Edema; Fever of Unknown Origin; Humans; Hypotension; Induction Chemotherapy; Leukemia, Promyelocytic, Acute; Male; Renal Dialysis; Respiratory Distress Syndrome; Syndrome; Tretinoin

Treatment outcome in older patients with acute promyelocytic leukemia (APL) is lower compared with younger patients, mainly because of a higher induction death rate and postremission non-relapse mortality (NRM). This prompted us to design a risk- and age-adapted protocol (Programa Español de Tratamientos en Hematología (PETHEMA)/HOVON LPA2005), with dose reduction of consolidation chemotherapy. Patients aged ⩾60 years reported to the PETHEMA registry and were treated with all-trans retinoic acid (ATRA) plus anthracycline-based regimens according to three consecutive PETHEMA trials that were included. We compared the long-term outcomes of the LPA2005 trial with the preceding PETHEMA trials using non-age-adapted schedules (LPA96&LPA99). From 1996 to 2012, 389 older patients were registered, of whom 268 patients (69%) were eligible. Causes of ineligibility were secondary APL (19%), and unfit for chemotherapy (11%). Median age was 67 years, without relevant differences between LPA2005 and LPA96&LPA99 cohorts. Overall, 216 patients (81%) achieved complete remission with no differences between trials. The 5-year NRM, cumulative incidence of relapse, disease-free survival and overall survival in the LPA2005 vs the LPA96&99 were 5 vs 18% (P=0.15), 7 vs 12% (P=0.23), 87 vs 69% (P=0.04) and 74 vs 60% (P=0.06). A less intensive front-line regimen with ATRA and anthracycline monochemotherapy resulted in improved outcomes in older APL patients.

Topics: Aged; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Female; Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Recurrence; Remission Induction; Risk Factors; Treatment Outcome; Tretinoin

Retinoic acid (RA) in association with chemotherapy or with arsenic trioxide (ATO) results in high cure rates of acute promyelocytic leukemia (APL). We show that RA-induced differentiation of human leukemic cell lines and primary blasts dramatically increases their sensitivity to endoplasmic reticulum (ER) stress-inducing drugs at doses that are not toxic in the absence of RA. In addition, we demonstrate that the PERK pathway, triggered in response to ER stress, has a major protective role. Moreover, low amounts of pharmacologically induced ER stress are sufficient to strongly increase ATO toxicity. Indeed, in the presence of ER stress, ATO efficiently induced apoptosis in RA-sensitive and RA-resistant APL cell lines, at doses ineffective in the absence of ER stress. Our findings identify the ER stress-related pathways as potential targets in the search for novel therapeutic strategies in AML.

Topics: Antineoplastic Agents; Apoptosis; Arsenic Trioxide; Cell Differentiation; Cell Line; Cell Line, Tumor; Endoplasmic Reticulum Stress; HEK293 Cells; Humans; Leukemia, Promyelocytic, Acute; Tretinoin

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Biomarkers, Tumor; Child; Child, Preschool; Chromosome Breakpoints; Female; Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Neoplasm Recurrence, Local; Prognosis; Promyelocytic Leukemia Protein; Retinoic Acid Receptor alpha; Tretinoin; Young Adult

All-trans retinoic acid (ATRA) has demonstrated notable success in the treatment of acute promyelocytic leukemia (APL) by inducing granulocytic differentiation. The underlying mechanisms of ATRA therapeutic effects have not been entirely clarified. Here, we reported that the regulation of neddylation, a ubiquitination-like post-translational modification, was involved in the treatment of ATRA on APL. Treating APL cells with ATRA led to the degradation of UBA3, a subunit of neddylation E1. Lysosome-autophagy pathway but not proteasome pathway was responsible for the degradation of UBA3. Neddylation suppression in APL cells was capable of inducing apoptosis, differentiation and proliferation inhibition, suggesting a pivotal role of neddylation in APL cells. ATRA treatment also led to UBA3 degradation in primary APL cells. Taken together, our findings indicated that neddylation was important to maintain the malignant features of APL cells, and suppression of neddylation was involved in the effects of ATRA on APL cells.

Topics: Antineoplastic Agents; Apoptosis; Autophagy; Cell Differentiation; Gene Expression Regulation, Neoplastic; Humans; Leukemia, Promyelocytic, Acute; NEDD8 Protein; Prognosis; Protein Processing, Post-Translational; Tretinoin; Tumor Cells, Cultured; Ubiquitin-Activating Enzymes

Retinoic acid (RA) has broad clinical applications for the treatment of various cancers, particularly acute promyelocytic leukemia. However, RA-based therapy is limited by relapse in patients associated with RA resistance, the mechanism of which is poorly understood. Here, we suggest a new molecular mechanism of RA resistance by a repressor, named RA resistance factor (RaRF). RaRF suppressed transcriptional activity of the RA receptor (RAR) by directly interacting with and sequestering RAR to the nucleolus in response to RA. RaRF was highly expressed in RA-resistant leukemia cells and its expression was strongly correlated with RA sensitivity. MCL1 was upregulated by RA treatment upon RaRF depletion, accompanying leukemic myeloblast differentiation, which is negatively regulated by ectopic RaRF expression. Collectively, we propose that RaRF may be a factor in the resistance mechanism and thus a potential target for leukemia therapy using RA.

Topics: Cell Differentiation; Cell Line, Tumor; Cell Nucleolus; Datasets as Topic; Drug Resistance, Neoplasm; Gene Expression Regulation, Leukemic; Granulocyte Precursor Cells; Humans; Kaplan-Meier Estimate; Leukemia, Promyelocytic, Acute; Myeloid Cell Leukemia Sequence 1 Protein; Receptors, Retinoic Acid; Repressor Proteins; Tretinoin; Up-Regulation

Topics: Antigens, CD; Antineoplastic Combined Chemotherapy Protocols; Arsenicals; Bone Marrow; Diabetes Mellitus, Type 2; Humans; Idarubicin; Immunophenotyping; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Neoplasms, Multiple Primary; Remission Induction; Tretinoin

Topics: Child; Female; Hearing Loss; Humans; Leukemia, Promyelocytic, Acute; Tinnitus; Tretinoin

Emerging evidences have shown that long non-coding RNAs (lncRNAs) play critical roles in cancer development and cancer therapy. LncRNA Nuclear Enriched Abundant Transcript 1 (NEAT1) is indispensable during acute promyelocytic leukemia (APL) cell differentiation induced by all-trans retinoic acid (ATRA). However, the precise mechanism of NEAT1 upregulation has not been fully understood. In this study, we performed chromatin immunoprecipitation and luciferase reporter assays to demonstrate that C/EBP family transcription factor C/EBPβ bind to and transactivate the promoter of lncRNA NEAT1 through the C/EBPβ binding sites both around -54 bp and -1453 bp upstream of the transcription start site. Moreover, the expression of C/EBPβ was increased after ATRA treatment, and the binding of C/EBPβ in the NEAT1 promoter was also dramatically increased. Finally, knockdown of C/EBPβ significantly reduced the ATRA-induced upregulation of NEAT1. In conclusion, C/EBPβ directly activates the expression of NEAT1 through binding to the promoter of NEAT1. Knockdown of C/EBPβ impairs ATRA-induced transcriptional activation of NEAT1. Our data indicate that C/EBPβ contributes to ATRA-induced activation of NEAT1 during APL cell differentiation. Our results enrich our knowledge on the regulation of lncRNAs and the regulatory role of C/EBPβ in APL cell differentiation.

Topics: CCAAT-Enhancer-Binding Protein-beta; Cell Differentiation; Cell Line, Tumor; Gene Knockdown Techniques; Humans; Leukemia, Promyelocytic, Acute; Promoter Regions, Genetic; Protein Binding; Protein Biosynthesis; RNA, Long Noncoding; Transcriptional Activation; Tretinoin; Up-Regulation

Topics: Adult; Anti-Inflammatory Agents; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Cardiovascular Agents; Chest Pain; Drug Substitution; Echocardiography; Electrocardiography; Humans; Idarubicin; Leukemia, Promyelocytic, Acute; Male; Myocarditis; Pericarditis; Remission Induction; Tretinoin

The success of all-trans retinoic acid (ATRA) in differentiation therapy for patients with acute promyelocytic leukemia (APL) highly encourages researches to apply a new combination therapy based on ATRA. Therefore, research strategies to further sensitize cells to retinoids are urgently needed. In this study, we showed that Dihydromyricetin (DMY), a 2,3-dihydroflavonol compound, exhibited a strong synergy with ATRA to promote APL NB4 cell differentiation. We observed that DMY sensitized the NB4 cells to ATRA-induced cell growth inhibition, CD11b expression, NBT reduction and myeloid regulator expression. PML-RARα might not be essential for DMY-enhanced differentiation when combined with ATRA, while the enhanced differentiation was dependent on the activation of p38-STAT1 signaling pathway. Taken together, our study is the first to evaluate the synergy of DMY and ATRA in NB4 cell differentiation and to assess new opportunities for the combination of DMY and ATRA as a promising approach for future differentiation therapy.

Topics: Antineoplastic Agents; Cell Differentiation; Cell Line, Tumor; Drug Synergism; Flavonols; Humans; Leukemia, Myeloid, Acute; Leukemia, Promyelocytic, Acute; MAP Kinase Signaling System; Oncogene Proteins, Fusion; Proteolysis; Signal Transduction; STAT1 Transcription Factor; Tretinoin

Untreated acute promyelocytic leukaemia (APL) is a rapidly lethal blood cancer. Conventional treatment consists of all-trans retinoic acid and chemotherapy. Standard chemo-therapy-containing treatments necessitate the use of blood products. This is a case report of typical APL in a 32-year-old female patient, who due to religious conviction refused supportive therapy with blood products. A treatment regimen consisting of all-trans retinoic acid and arsenic trioxide was successful without the use of blood transfusions.

Topics: Adult; Antineoplastic Agents; Arsenic Trioxide; Female; Humans; Leukemia, Promyelocytic, Acute; Religion and Medicine; Treatment Outcome; Treatment Refusal; Tretinoin

Topics: Adult; Antineoplastic Agents; Base Sequence; Carrier Proteins; Cell Differentiation; Chromosomes, Human, Pair 1; Chromosomes, Human, Pair 17; DNA-Binding Proteins; Humans; Leukemia, Promyelocytic, Acute; Male; Neoplastic Stem Cells; Nuclear Proteins; Oncogene Proteins, Fusion; Retinoic Acid Receptor alpha; Transcription Factors; Translocation, Genetic; Tretinoin; Tumor Cells, Cultured

Topics: Adult; Antineoplastic Agents; Bone Diseases; Humans; Leukemia, Promyelocytic, Acute; Male; Pain; Pain Management; Treatment Outcome; Tretinoin

To investigate the factors affecting the early-death, overall survival (OS) and relapse-free survival (RFS) of acute promyelocytic leukemia (APL) patients.. The clinical and laboratorial charachteristics of 176 APL patients in our center were analyzed retrospectively during January 2002 to Mar 2016. The risk factors of early death and factors affecting OS and RFS of patients were analyzed.

Topics: Antineoplastic Combined Chemotherapy Protocols; Arsenicals; Humans; Leukemia, Promyelocytic, Acute; Oxides; Prognosis; Retrospective Studies; Tretinoin

The acute promyelocytic leukemia (APL) is a rare disease. However, if diagnosed early and treated immediately high cure rates can be achieved. Signs of hematopoietic insufficiency such as cytopenias or leucocytosis can be present at first presentation of the patients. Moreover, hemorrhagic diatheses due to coagulpathy are present in approximately 80 % of cases and contribute substatially to the high early death rate in APL patients, which has been reported as high as 30 % in population based studies. In case of initial suspicion of APL treatment with all-trans retinoic acid (ATRA) should be initated immediately to reduce the risk of fatal bleeding events and confirmation or exclusion of the PML-RARA transcript should not be awaited before start of ATRA treatment. While patients with a low or intermediate risk of relapse are treated with a combination of ATRA and arsenic trioxide (ATO), those with high risk of relapse still receive a combination regimen consisting of ATRA, anthracyclines and cytosine-arabinosid. However, treatment strategies are under clinical investigation aiming at reducing the administration of conventional chemotherapy in high risk APL patients. With the current treatment approaches cure rates of approximately 90 % of the patients with low or intermeditae risk APL can be achieved. Nevertheless, particularly the high initial death rate warrants further clinical and pathiobiologic studies to identify targets and means to decrease hemorrhagic complications in patients with APL.. Die APL ist eine sehr seltene Erkrankung. Ihre hohen Heilungschancen können verspielt werden, wenn sie nicht frühzeitig bei entsprechenden klinischen Symptomen und laborchemischen Veränderungen differenzialdiagnostisch berücksichtigt wird. KLINISCHE PRäSENTATION:  Neben Zeichen der hämatopoetischen Insuffizienz wie mehr oder weniger stark ausgeprägten Zytopenien oder Leukozytose (bei der varianten Form) sind lebensbedrohliche Blutungskomplikationen typische Symptome bereits bei Erstdiagnose. Intrakranielle und pulmonale Blutungen sind die häufigsten hämorrhagischen Todesursachen.. Bei Verdacht auf APL muss neben der rasch verfügbaren morphologischen Diagnostik umgehend der Nachweis der Translokation t(15;17) bzw. der Fusionsgene PML/RARA mittels molekularzytogenetischer Verfahren erfolgen. THERAPIE DER AKUTEN PROMYELOZYTENLEUKäMIE:  Die Therapie muss wegen fataler hämorrhagischer Blutungskomplikationen schon bei Verdacht auf das Vorliegen einer APL mit ATRA eingeleitet werden, auch wenn die Diagnose APL noch nicht genetisch belegt ist. Patienten mit Leukozytenwerten von < 10 000/µl werden mit einer Kombination aus ATRA und ATO behandelt, während die Standardtherapie bei höheren Leukozytenwerten noch aus ATRA und Anthrazyklin- plus Cytosinarabinosid-haltiger konventioneller Chemotherapie besteht. In klinischen Studien werden auch für diese Patientenpopulation Therapieprotokolle untersucht, die den Einsatz konventioneller Chemotherapeutika zugunsten von ATRA und ATO zurücknehmen.. Nach wie vor ist die Rate an den in der Mehrzahl hämorrhagisch bedingten Frühtodesfällen ein relevantes klinisches Problem. Neben einer besseren Aufklärung des Pathomechanismus der hämorrhagischen Diathese stellen klinische Fortbildungsprogramme, die die Aufmerksamkeit bez. der APL erhöhen und die Bildung regionaler Kompetenznetzwerke unter Involvierung von in Diagnostik und Therapie erfahrenen Hämatologen eine Möglichkeit dar, die immer noch hohe Frühtodesrate zu reduzieren.

Topics: Antineoplastic Agents; Arsenic Trioxide; Arsenicals; Humans; Leukemia, Promyelocytic, Acute; Oxides; Rare Diseases; Tretinoin

Acute promyelocytic leukemia (APL) is a curable subtype of acute myeloid leukemia. APL is currently treated with combination of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) resulting in the induction of apoptosis and differentiation of the leukemic cells. Differentiation syndrome (so-called ATRA syndrome) is the main life-threatening complication of induction therapy with these differentiating agents.. Herein, we report the case of a 49-year-old woman diagnosed with APL with, concomitantly, a bulky cutaneous lesion of 10 cm diameter with a red-to-purple background and a necrotic center, localized on her abdomen.. After 10 days of treatment, the cutaneous lesion became purulent. Fluorescence in situ hybridization (FISH) analysis performed on this pus confirmed the presence of malignant features in the involved granulocytes proving their origin from the differentiation of leukemic APL cells, as all the analyzed nuclei showed 2 promyelocytic leukemia (PML)-retinoic acid receptor-a (RARA) fusions signals.. The association by ATRA and ATO was continued.. Eventually, the evolution was favorable with healing in three weeks.. This case report therefore highlights the differentiation phenomenon of promyelocytic blasts within promyelocytic sarcoma with the ATRA-ATO combination and the efficacy of this drug association in resolving both the malignant sarcoma and a secondary local infection.

Topics: Abdomen; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Cell Differentiation; Female; Humans; Induction Chemotherapy; Leukemia, Promyelocytic, Acute; Middle Aged; Oxides; Sarcoma, Myeloid; Suppuration; Tretinoin

Topics: Adolescent; Adult; Aged; Female; Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Registries; Survival Rate; Tretinoin; Young Adult

Acute promyelocytic leukemia (APL) is a medical emergency because of associated lethal early bleeding, a condition preventable by prompt diagnosis and therapeutic intervention. The mechanisms underlying the hemostatic anomalies of APL are not completely elucidated. RNA-sequencing-based characterization of APL (n = 30) was performed and compared to that of other acute myeloid leukemia (n = 400) samples and normal promyelocytes. Perturbations in the transcriptome of coagulation and fibrinolysis-related genes in APL extend beyond known culprits and now include Thrombin, Factor X and Urokinase Receptor. Most intriguingly, the Podoplanin (PDPN) gene, involved in platelet aggregation, is aberrantly expressed in APL promyelocytes and is the most distinctive transcript for this disease. Using an antibody panel optimized for AML diagnosis by flow cytometry, we also found that PDPN was the most specific surface marker for APL, and that all-trans retinoic acid therapy rapidly decreases its expression. Functional studies showed that engineered overexpression of this gene in human leukemic cells causes aberrant platelet binding, activation and aggregation. PDPN-expressing primary APL cells, but not PDPN-negative primary leukemias, specifically induce platelet binding, activation and aggregation. Finally, PDPN expression on leukemia cells in a xenograft model was associated with thrombocytopenia and prolonged bleeding time in vivo. Together our results suggest that PDPN may contribute to the hemostatic perturbations found in APL.

Topics: Adult; Aged; Animals; Female; Flow Cytometry; Hemorrhage; Humans; Leukemia, Promyelocytic, Acute; Male; Membrane Glycoproteins; Mice; Middle Aged; Platelet Aggregation; Thrombocytopenia; Transcriptome; Tretinoin

Despite All-trans retinoic acid (ATRA) has transformed acute promyelocytic leukemia (APL) from the most fatal to the most curable hematological cancer, there remains a clinical challenge that many high-risk APL patients who fail to achieve a complete molecular remission or relapse and become resistant to ATRA. Herein, we report that 5-(4-methoxyphenethyl)-[1, 3] dioxolo [4, 5-j] phenanthridin-6(5H)-one (ZYH005) exhibits specific anticancer effects on APL and ATRA-resistant APL in vitro and vivo, while shows negligible cytotoxic effect on non-cancerous cell lines and peripheral blood mononuclear cells from healthy donors. Using single-molecule magnetic tweezers and molecule docking, we demonstrate that ZYH005 is a DNA intercalator. Further mechanistic studies show that ZYH005 triggers DNA damage, and caspase-dependent degradation of the PML-RARa fusion protein. As a result, APL and ATRA-resistant APL cells underwent apoptosis upon ZYH005 treatment and this apoptosis-inducing effect is even stronger than that of arsenic trioxide and anticancer agents including 5-fluorouracil, cisplatin and doxorubicin. Moreover, ZYH005 represses leukemia development in vivo and prolongs the survival of both APL and ATRA-resistant APL mice. To our knowledge, ZYH005 is the first synthetic phenanthridinone derivative, which functions as a DNA intercalator and can serve as a potential candidate drug for APL, particularly for ATRA-resistant APL.

Topics: Animals; Apoptosis; Arsenic Trioxide; Caspases; Cell Line, Tumor; Cell Proliferation; DNA Damage; Drug Resistance, Neoplasm; Humans; Intercalating Agents; Leukemia, Promyelocytic, Acute; Mice; Molecular Docking Simulation; Oncogene Proteins, Fusion; Phenanthridines; Promyelocytic Leukemia Protein; Proteolysis; Retinoic Acid Receptor alpha; Tretinoin; Xenograft Model Antitumor Assays

For patients who have acute promyelocytic leukemia (APL) in second complete remission (CR2), optimal postremission strategies remain undefined.. The role of an oral arsenic trioxide (As. Seventy-three patients with APL in first relapse (R1) were studied. Oral As. For patients with relapsed APL, As

Topics: Administration, Oral; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Ascorbic Acid; Chemical and Drug Induced Liver Injury; Combined Modality Therapy; Disease-Free Survival; Female; Headache; Hematopoietic Stem Cell Transplantation; Hong Kong; Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Neoplasm Recurrence, Local; Prospective Studies; Remission Induction; Risk Factors; Severity of Illness Index; Survival Analysis; Time Factors; Transplantation, Autologous; Tretinoin; Young Adult

Life on Earth is constantly exposed to electromagnetic fields (EMFs) and the effects induced by EMFs on biological systems have been extensively studied producing different and sometimes contradictory results. Extremely low-frequency electromagnetic fields (ELF-EMFs) have shown to play a role in regulating cell proliferation and differentiation, although how EMFs influence these processes remains unclear. Human acute promyelocytic leukemia (APL) cells are characterized by the arrest of differentiation at the promyelocytic stage due to epigenetic perturbations induced by PML/RARα fusion protein (Promyelocytic Leukemia protein - PML/Retinoic Acid Receptor alpha - RARα). Therapeutic administration of all-trans retinoic acid (ATRA) re-establishes the leukemogenic mechanism re-inducing the normal differentiation processes.. We studied the effects of ELF-EMFs (50 Hz, 2 mT) on the ATRA-mediated granulocytic differentiation process of APL NB4 cells (a cell line established from the bone marrow of a patient affected by the acute promyelocytic leukemia) by monitoring cellular proliferation and morphology, nitrob lue tetrazolium (NBT) reduction and the expression of differentiation surface markers. Finally, we investigated mechanisms focusing on reactive oxygen species (ROS) generation and related molecular pathways.. ELF-EMF exposure decreases cellular proliferation potential and helps ATRA-treated NB4 cells to mature. Furthermore, the analysis of ROS production and the consequent extracellular signal regulated kinases (ERK1/2) phosphorylation suggest that a changed intracellular oxidative balance may influence the biological effects of ELF-EMFs.. These results indicate that the exposure to ELF-EMF promotes ATRA-induced granulocytic differentiation of APL cells.

Topics: Bone Marrow Cells; Cell Differentiation; Cell Line; Cell Proliferation; Electromagnetic Fields; Humans; Leukemia, Promyelocytic, Acute; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Phosphorylation; Reactive Oxygen Species; Tetradecanoylphorbol Acetate; Tretinoin

During cell division, a large number of nuclear proteins are released into the cytoplasm due to nuclear envelope breakdown. Timely nuclear import of these proteins following exit from mitosis is critical for establishment of the G1 nuclear environment. Dysregulation of post-mitotic nuclear import may affect the fate of newly divided stem or progenitor cells and may lead to cancer. Acute promyelocytic leukemia (APL) is a malignant disorder that involves a defect in blood cell differentiation at the promyelocytic stage. Recent studies suggest that pharmacological concentrations of the APL therapeutic drugs, all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), affect post-mitotic nuclear import of the APL-associated oncoprotein PML/RARA. In the present study, we have investigated the possibility that ATRA and ATO affect post-mitotic nuclear import through interference with components of the nuclear import machinery. We observe reduced density and impaired integrity of nuclear pore complexes after ATRA and/or ATO exposure. Using a post-mitotic nuclear import assay, we demonstrate distinct import kinetics among different nuclear import pathways while nuclear import rates were similar in the presence or absence of APL therapeutic drugs.

Topics: Active Transport, Cell Nucleus; Antineoplastic Agents; Arsenic Trioxide; Arsenicals; Cell Line; Cell Nucleus; Humans; Kinetics; Leukemia, Promyelocytic, Acute; Mitosis; Nuclear Envelope; Nuclear Pore; Oxides; Permeability; Tretinoin

Acute promyelocytic leukemia (APL) was considered to be one of the most lethal forms of leukemia in adults before the introduction of the vitamin A metabolite all-trans retinoic acid (ATRA). Surprisingly, it has been confirmed that FICZ (6-Formylindolo (3, 2-b) carbazole) enhances ATRA-induced differentiation. Moreover, a number of studies have demonstrated that anti CD44 monoclonal antibody (mAb) induces to bring back differentiation blockage the leukemic stem cells. The level of differentiation markers including CD11b and CD11c in NB4 cells was assessed by flow cytometry. The induction of apoptosis was also evaluated. We estimated the induction potential of a triple compound of ATRA-FICZ, anti-CD44 maps. The cells showed the gradually increased expression levels of CD11b and CD11c. A mixture of a "CD44 mAb, ATRA and FICZ effectively promoted granulocytic maturation resulting in increased rates of apoptosis. The differences in expression of CD11b and CD11c at 5 μg/ml and 10 μg/ml were significant. These phenomena were highest at 10 μg/ml CD44 mAb concentrations. Synergistic induction differentiation and apoptosis of APL cells by using a co-treatment with novel triple compound are more effective for eradicating blasts and controlling the metastasis. Our results show that the addition of anti-CD44 mAb improves "ATRA-FICZ"-induced differentiation and has potential to reduce usual chemotherapy based treatments. Taken together, this compound may lead to novel clinical applications of differentiation-based approaches for APL and other types of leukemia. Further clinical studies would be recommended to clarify the clinical efficacy.

Topics: Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Carbazoles; CD11b Antigen; CD11c Antigen; Cell Differentiation; Cell Line, Tumor; Dose-Response Relationship, Immunologic; Drug Synergism; Humans; Hyaluronan Receptors; Leukemia, Promyelocytic, Acute; Tretinoin

Topics: Adult; Aged; Antineoplastic Agents; Arsenic Trioxide; Disease Progression; Disseminated Intravascular Coagulation; Drug Substitution; Humans; Leukemia, Promyelocytic, Acute; Male; Treatment Outcome; Tretinoin

We report a rare case of hypercalcemia and acute pancreatitis in a subject with acute promyelocytic leukemia (APL) and pulmonary tuberculosis, during all-trans-retinoic acid (ATRA) treatment. Both associated complications were potentially due to several causes. A careful monitoring and exclusion of all causative factors must be addressed. Further research is necessary to improve our understanding of risk factors for these complications in patients with (APL). Studying these patterns may help us to improve outcomes for all children and young adults with hematologic malignancies.

Topics: Acute Disease; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Causality; Febrile Neutropenia; Humans; Hypercalcemia; Leukemia, Promyelocytic, Acute; Male; Mercaptopurine; Methotrexate; Middle Aged; Models, Biological; Pancreatitis; Pleural Effusion; Prednisone; Pulmonary Aspergillosis; Risk Factors; Tretinoin; Tuberculosis, Pulmonary; Vincristine

Topics: Humans; Leukemia, Promyelocytic, Acute; Membrane Glycoproteins; Platelet Aggregation; Thrombocytopenia; Tretinoin

Since tumor growth requires reactivation of telomerase (hTERT), this enzyme is a challenging target for drug development. Therefore, it is of great interest to identify telomerase expression and activity regulators. Retinoids are well-known inducers of granulocytic maturation associated with hTERT repression in acute promyelocytic leukemia (APL) blasts. In a maturation-resistant APL cell line, we have previously identified a new pathway of retinoid-induced hTERT transcriptional repression independent of differentiation. Furthermore, we reported the isolation of a cell variant resistant to this repression. Those cell lines could serve as unique tools to identify new telomerase regulators.. Using a microarray approach we identified the long non-coding RNA, H19 as a potential candidate playing a role in telomerase regulation. Expression of H19, hTERT, and hTR were examined by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). Telomerase activity was quantified by quantitative telomeric repeats amplification protocol (qTRAP). In vitro and in vivo assays were performed to investigate H19 function on telomerase expression and activity.. We showed both in retinoid-treated cell lines and in APL patient cells an inverse relationship between the expression of H19 and the expression and activity of hTERT. Exploring the mechanistic link between H19 and hTERT regulation, we showed that H19 is able to impede telomerase function by disruption of the hTERT-hTR interaction.. This study identifies a new way of telomerase regulation through H19's involvement and thereby reveals a new function for this long non-coding RNA that can be targeted for therapeutic purpose.

Topics: Cell Line, Tumor; Cell Proliferation; Cell Survival; Down-Regulation; Gene Expression Regulation, Neoplastic; Humans; Leukemia, Promyelocytic, Acute; MicroRNAs; RNA, Long Noncoding; Telomerase; Tretinoin

Leukaemia cutis or cutaneous infiltration of neoplastic myeloid or lymphoid cells is usually seen in the acute myelomonocytic and acute monocytic variants of acute myeloid leukaemia. Here, we report a case of acute promyelocytic leukaemia who achieved remission, presenting with skin lesions, the biopsy of which revealed leukaemia cutis, heralding the relapse of the disease. After establishing the diagnosis with bone marrow analysis, the patient was started on daunorubicin chemotherapy along with arsenic trioxide and all-trans retinoic acid. Afterwards, the skin lesions resolved, and the patient is planned for consolidation with bone marrow transplantation.

Topics: Antibiotics, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Biopsy; Consolidation Chemotherapy; Daunorubicin; Female; Humans; Leukemia, Promyelocytic, Acute; Leukemic Infiltration; Oxides; Skin; Tretinoin

Topics: Administration, Oral; Adolescent; Adult; Antineoplastic Agents; Arsenic; Cohort Studies; Female; Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Treatment Outcome; Tretinoin; Young Adult

Acute promyelocytic leukemia (APL) is a subtype of acute myeloid leukemia (AML). All-trans retinoic acid (ATRA) is the first-choice therapy for the treatment of this disease, but has been associated with side effects, the most serious of which is retinoic acid syndrome (RAS). RAS is characterized by unexplained fever, dyspnea, pulmonary infiltrate, leukocytosis and nephropathy. Genital ulcers have been described in some cases, but only two cases of oral ulcers related to this syndrome have been described in the literature. This paper describes the third case of oral ulceration related to ATRA in a 32-year-old white man with diagnosis of APL. Clinicians should know the side effects of ATRA and identify oral ulcers resulting from this therapy. The prompt identification of these ulcers enables the institution of appropriate treatment and can therefore contribute to continuation of the patient's cancer treatment.

Topics: Adult; Antineoplastic Agents; Humans; Leukemia, Promyelocytic, Acute; Lip Diseases; Male; Tretinoin; Ulcer

Retinoic acid (RA) and arsenic target the t(15;17)(q24;q21) PML/RARA driver of acute promyelocytic leukemia (APL), their combination now curing over 95% patients. We report exome sequencing of 64 matched samples collected from patients at initial diagnosis, during remission, and following relapse after historical combined RA-chemotherapy treatments. A first subgroup presents a high incidence of additional oncogenic mutations disrupting key epigenetic or transcriptional regulators (primarily WT1) or activating MAPK signaling at diagnosis. Relapses retain these cooperating oncogenes and exhibit additional oncogenic alterations and/or mutations impeding therapy response (RARA, NT5C2). The second group primarily exhibits FLT3 activation at diagnosis, which is lost upon relapse together with most other passenger mutations, implying that these relapses derive from ancestral pre-leukemic PML/RARA-expressing cells that survived RA/chemotherapy. Accordingly, clonogenic activity of PML/RARA-immortalized progenitors ex vivo is only transiently affected by RA, but selectively abrogated by arsenic. Our studies stress the role of cooperating oncogenes in direct relapses and suggest that targeting pre-leukemic cells by arsenic contributes to its clinical efficacy.

Topics: 5'-Nucleotidase; Animals; Antineoplastic Agents; Arsenic Trioxide; Drug Resistance, Neoplasm; fms-Like Tyrosine Kinase 3; Humans; Leukemia, Promyelocytic, Acute; Male; Mice; Mutation; Promyelocytic Leukemia Protein; Recurrence; Retinoic Acid Receptor alpha; Tretinoin

Staphylococcus aureus as a pathogen in human gestational membranes, a rather rare phenomenon, has recently been the focus of several researches. S. aureus forms biofilms on these membranes and potentially causes chorioamnionitis in pregnant women. We report a case of persistent methicillin-resistant S. aureus (MRSA) bacteremia owing to placental infection, causing chorioamnionitis and preterm birth. A 29-year-old Japanese woman at the 27th gestational week was diagnosed with acute promyelocytic leukemia and underwent all-trans retinoic acid therapy. Soon after hospitalization, the patient presented with persistent MRSA bacteremia of unknown origin. Despite various antimicrobial therapies, she experienced 12 MRSA bacteremia episodes over 6 weeks. However, after child birth, MRSA bacteremia disappeared without any complications. A pathologic examination of her placenta revealed placenta abscess, resulting in a diagnosis of MRSA-associated chorioamnionitis. Molecular analysis proved that a single MRSA strain (SCCmec Type IVa), which tested negative for Panton-Valentine leukocidin and toxic shock syndrome toxin-1, caused the obstinate infection. We should be aware that persistent MRSA bacteremia in pregnant women can originate from placental abscess.

Topics: Abdominal Abscess; Adult; Bacteremia; Bacterial Toxins; Chorioamnionitis; Exotoxins; Female; Humans; Leukemia, Promyelocytic, Acute; Leukocidins; Methicillin-Resistant Staphylococcus aureus; Pancytopenia; Placenta; Pregnancy; Staphylococcal Infections; Tretinoin

The synergistic effect of arsenic (As) and all-trans retinoic acid in acute promyelocytic leukemia (APL) has been well documented. However, several major issues impeding the efficient delivery of these drugs for APL therapy remain unsolved. The low solubility of retinoic acid in physiological solutions makes drug delivery cumbersome, and the high systemic cytotoxicity of arsenic trioxide leads to unwanted side effects. In the present study, a new organo-arsenic molecule was synthesized via template-directed ring-opening esterification of an epoxy arsenic hydride (2-chloro-1,3,2-dioxaarsolane, CDA) under a nucleophilic attack exposing the hydroxyl terminus. The additional single step conjugation with retinoic acid (RA) and polyethylene glycol (PEG) yielded the amphiphilic prodrug PEG-As-RA that readily self-assembles into nanoparticles in the aqueous phase. The assembled nanoparticles containing both arsenic and RA exhibit high water solubility and good biocompatibility. In addition, they are highly stable in physiological buffers and are efficiently taken up by human APL cells. In vivo imaging results showed that the nanoparticles are characterized by prolonged blood circulation, and release both RA and As via hydrolysis to provide combination therapy for human APL. This novel organo-arsenic molecule conjugated with RA offers a new approach to the treatment of APL.

Topics: Antineoplastic Agents; Arsenic; Arsenicals; Humans; Leukemia, Promyelocytic, Acute; Oxides; Prodrugs; Tretinoin

Circular RNAs (circRNAs) are a novel class of powerful regulators in gene expression and participate in the pathogenesis of many diseases, including cancer. However, little is known about the roles of circRNAs in the development and treatment of acute promyelocytic leukemia (APL). Here we report the expression profiling and function of circRNAs in APL, including their dynamic regulation during all-trans retinoic acid (ATRA)-induced differentiation. We performed two independent ribosomal RNA-minus RNA-sequencing (Ribo-minus RNA-seq) experiments with and without RNase R treatment on APL patient-derived NB4 cells and identified a total of 4313 circRNAs, including 1098 newly identified circRNAs. Detailed analysis showed that circRNAs expressed in APL cells were mostly exon-derived, not by-products during splicing, and could be distinguished from hematopoietic stem cells, neutrophils and lymphocytes. The true presence and stability of circRNAs were verified both in NB4 cells and primary APL patient samples. Moreover, we conducted a time-series analysis of circRNAs on ATRA-treated NB4 cells and uncovered 508 circRNAs with dynamic expression during ATRA treatment, including 246 upregulated and 262 downregulated. Further evidence demonstrated that the majority of circRNAs were regulated independently of their host linear mRNAs. Detailed functional experiments demonstrated that circ-HIPK2, one of the differentially expressed circRNAs, significantly influenced ATRA-induced differentiation of APL cells. Further mechanistic studies revealed that circ-HIPK2 was located in cytoplasm and served as a sponge for differentiation-associated miR-124-3p. Finally, circ-HIPK2 expression in APL patients was significantly lower than that in normal peripheral mononuclear cells and other subtypes of AML, indicating its potential role as an APL biomarker. Our study indicates the biological functions of circRNAs in the development and treatment of APL, and provides a comprehensive circRNA resource for future studies.

Topics: Base Sequence; Biomarkers, Tumor; Cell Differentiation; Cell Line, Tumor; Gene Expression Regulation, Leukemic; Genome, Human; HEK293 Cells; Humans; Leukemia, Promyelocytic, Acute; MicroRNAs; Reproducibility of Results; RNA, Circular; RNA, Messenger; Tretinoin

The introduction of all-trans retinoic acid (ATRA) has made acute promyelocytic leukemia (APL) a curable disease; however, early death prior to the completion of treatment remains a problem. In quantitative evaluation of response to ATRA treatment, lymphocytes must be excluded as they do not originally have t(15;17). We categorized peripheral blood leukocytes by nuclear morphology into polymorphonuclear cells (PMNs) comprising segmented granulocytes, and non-polymorphonuclear cells (NPMs) which includes lymphocytes, monocytes, band cells, and immature myeloid cells. We consecutively evaluated the ratio of t(15;17)-positive cells using fluorescence in situ hybridization in eight newly diagnosed patients with APL. We confirmed the differentiation of APL cells until cytogenetic complete remission; the association of a decrease of t(15;17)-positive NPMs and an increase of t(15;17)-positive PMNs was followed by a decrease of t(15;17)-positive PMNs. The kinetic pattern of t(15;17)-positive NPMs and PMNs was consistent in most patients, irrespective of leukocyte counts at diagnosis, additional chromosomal changes, and ATRA with or without chemotherapies. Kinetic analysis enables us to evaluate treatment response and the recovery of normal hematopoiesis in individuals.

Topics: Adult; Aged; Aged, 80 and over; Cell Transformation, Neoplastic; Female; Humans; In Situ Hybridization, Fluorescence; Karyotype; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Promyelocytic Leukemia Protein; Retinoic Acid Receptor alpha; Translocation, Genetic; Tretinoin

Topics: Aged, 80 and over; Humans; Leukemia, Promyelocytic, Acute; Male; Oncogene Proteins, Fusion; Tretinoin

Topics: Antineoplastic Combined Chemotherapy Protocols; Arsenic; Humans; Leukemia, Promyelocytic, Acute; Tretinoin

All-trans retinoic acid (ATRA) has been used for the treatment of acute promyelocytic leukemia (APL). However, its molecular mechanisms of action are unclear. Ubiquitin-specific protease 48 (USP48) is a deubiquitinase enzyme that can post-translationally remove ubiquitin molecules from substrates. In the present study, the role of USP48 in ATRA-induced differentiation of APL cells was studied. The expression of USP48 decreased following ATRA treatment. Functionally, overexpression of USP48 using electroporation-mediated delivery inhibited the proliferation of APL cells and promoted ATRA-mediated differentiation. The inverse observations were made upon siRNA-mediated knockdown of USP48. Furthermore, the expression of USP48 was increased in the nucleus upon ATRA exposure for ≤24 h, suggesting that USP48 was translocated into the nucleus. Interestingly, regulation of p65, a substrate of USP48, did not contribute to the downstream mechanism of ATRA-induced differentiation of APL cells. In addition, upstream mechanistic studies demonstrated that the expression of USP48 was regulated by microRNA-301a-3p. In conclusion, the present study highlights the function of USP48 in the ATRA-induced granulocytic differentiation of APL cells and provides a theoretical basis for identifying novel targets for differentiation therapy of APL.

Topics: Cell Differentiation; Cell Line, Tumor; Cell Nucleus; Gene Expression Regulation, Neoplastic; HL-60 Cells; Humans; Leukemia, Promyelocytic, Acute; MicroRNAs; THP-1 Cells; Tretinoin; Ubiquitin-Specific Proteases; Up-Regulation

Translocations of retinoic acid receptor-α (

Topics: Animals; Bone Marrow Cells; Humans; Leukemia, Promyelocytic, Acute; Mice; Nuclear Proteins; Oncogene Proteins, Fusion; Receptors, Cytoplasmic and Nuclear; Receptors, Retinoic Acid; Repressor Proteins; Retinoic Acid Receptor alpha; Signal Transduction; Translocation, Genetic; Tretinoin; Whole Genome Sequencing

Topics: Adult; Antineoplastic Agents; Humans; Inclusion Bodies; Leukemia, Promyelocytic, Acute; Male; Neutrophils; Tretinoin

To analyze the correlation of ATO therapeutic dose with the relapse of patients with acute promyelocytic leukemia (APL) and to investigate the optimal dose and courses of ATO.. The clinical data of 102 patients with APL from January 2008 to June 2015 were analyzed retrospectively. The clinical characteristics of APL patients in relapsed group and maintained remission group were compared. According to ATO dose in 2 years recommended in chinese guideline as criteria of grouping, the patients were divided into ATO high and low dose groups, then the relapse rate in groups was compared. The cut-off value of ATO dose was analyzed by ROC curve.. Univariate analysis showed that the relapse rate in high ATO and low ATO groups on 2 year treatment was 2.5% and 17.7% respectively (P<0.05); multiple variate analysis demonstrated that the ATO dose>22.4 mg/kg on 2 year treatment was independent preventive factor for the relapse of APL (OR=0.119, P<0.05). The ROC curve showed that the cut-off value of ATO dose on 2 year treatment was 8.765 mg/kg. The relapse rate of APL in group of ATO dose >8.765 mg/kg group was significantly lower than that in group of ATO dose <8.765 mg/kg.. The relapse of APL relates with used ATO dose, sufficient use of ATO dose can decrease the relapse rate of APL.

Topics: Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Humans; Leukemia, Promyelocytic, Acute; Oxides; Recurrence; Retrospective Studies; Tretinoin

Prolonged therapy with all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) is highly effective in newly diagnosed acute promyelocytic leukemia (APL) but there is limited data on the efficacy of this regimen in the relapse setting. We report here on 22 APL patients treated with prolonged ATRA-ATO therapy at the time of disease relapse. Twenty patients obtained molecular complete remission (CRm) after 2 cycles (90%). Of these, two patients underwent hematopoietic stem cell transplant (HSCT) while the remaining proceeded to receive additional cycles (up to a total of 5) of ATRA-ATO. With a median follow-up of 58 months from the time of relapse (range: 21-128 months), the 4-year OS probability was 0.85 (95% CI 0.61-0.94), DFS was 0.74 (95% CI 0.49-0.88), and EFS 0.68 (95% CI 0.45-0.83). Two patients were resistant to ATRA-ATO salvage and five relapsed at a median of 19 months. Of these, four died due to progressive disease while three relapsed achieved a new CRm after further salvage therapy. This experience confirms the potentially curative effect of prolonged ATRA-ATO therapy in relapsed APL, especially in patients with long first complete remission.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Combined Modality Therapy; Disease-Free Survival; Drug Administration Schedule; Drug Evaluation; Female; Follow-Up Studies; Hematopoietic Stem Cell Transplantation; Humans; Kaplan-Meier Estimate; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Oxides; Proportional Hazards Models; Recurrence; Remission Induction; Retrospective Studies; Salvage Therapy; Treatment Outcome; Tretinoin; Young Adult

Long non‑coding RNAs (lncRNAs) are crucial factors in acute promyelocytic leukemia (APL) cell differentiation. However, their expression patterns and regulatory functions during all‑trans‑retinoic acid (ATRA)‑induced APL differentiation remain to be fully elucidated. The profile of dysregulated lncRNAs between three bone marrow (BM) samples from patients with APL post‑induction and three BM samples from untreated matched controls was examined with the Human Transcriptome Array 2.0. The dysregulated lncRNA expression of an additional 27 APL BM samples was validated by reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) analysis. The lncRNA functions were predicted through co‑expressed messenger RNA (mRNA) annotations. Co‑expressed lncRNA‑mRNA networks were constructed to analyze the functional pathways. In total, 825 lncRNAs and 1,218 mRNAs were dysregulated in the treated APL BM group, compared with the untreated APL BM group. The expression of 10 selected lncRNAs was verified by RT‑qPCR analysis. During APL differentiation, NONHSAT076891 was the most upregulated lncRNA, whereas TCONS_00022632‑XLOC_010933 was the most downregulated. Functional analysis revealed that several lncRNAs may exert activities in biological pathways associated with ATRA‑induced APL differentiation through cis and/or trans regulation of mRNAs. The findings of the present study assist in explaining the contributions of lncRNAs in APL myeloid differentiation and improve current knowledge on the potential mechanisms regarding dysregulated lncRNA expression in ATRA‑induced APL differentiation.

Topics: Adult; Aged; Antineoplastic Agents; Biomarkers, Tumor; Case-Control Studies; Cell Differentiation; Computational Biology; Female; Follow-Up Studies; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Gene Regulatory Networks; Genome, Human; Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Prognosis; RNA, Long Noncoding; Transcriptome; Tretinoin; Young Adult

The prognosis of acute promyelocytic leukemia (APL) has been improved by the combination of all-trans retinoic acid (ATRA) with chemotherapy. Nonetheless, relapse occurs in a certain proportion of patients, mostly within three to four years after treatment. We herein report a patient treated with ATRA and chemotherapy achieving remission who relapsed approximately 17 years after the treatment. A literature review identified 5 additional reported cases of APL relapse after more than 10 years. None of them presented with generally established risk factors for relapse, such as a high leukocyte count. The potential for late relapse of APL occurring more than 10 years after treatment should be recognized.

Topics: Antineoplastic Agents; Chronic Disease; Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Prognosis; Recurrence; Remission Induction; Risk Factors; Time Factors; Treatment Outcome; Tretinoin

At present, acute promyelocytic leukemia (APL) is the most curable form of acute myeloid leukemia and can be treated using all-trans retinoic acid and arsenic trioxide. However, the current treatment of APL is associated with some issues such as drug toxicity, resistance and relapse. Therefore, other strategies are necessary for APL treatment. In the present study, we investigated the effects of salinomycin (SAL) on APL cell lines NB4 and HL-60 and determined its possible mechanisms. We observed that SAL inhibited cell proliferation, as determined by performing Cell Counting Kit-8 (CCK-8) assay, promoted cell apoptosis, as determined based on morphological changes, and increased Annexin V/propidium iodide (PI)-positive apoptotic cell percentage. Treatment with SAL increased Bax/Bcl-2 and cytochrome c expression and activated caspase-3 and -9, thus leading to poly(ADP-ribose) polymerase (PARP) cleavage and resulting in cell apoptosis. These results revealed that SAL induced cell apoptosis through activation of the intrinsic apoptosis pathway. The present study is the first to show that SAL induced the differentiation of APL cells, as determined based on mature morphological changes, increased NBT-positive cell and CD11b-positive cell percentages and increased CD11b and C/EBPβ levels. Furthermore, SAL decreased the expression of β-catenin and its targets cyclin D1 and C-myc. Results of immunofluorescence analysis revealed that SAL markedly decreased the β-catenin level in both the nucleus and cytoplasm. Combination treatment with SAL and IWR-1, an inhibitor of Wnt signaling, synergistically triggered SAL-induced differentiation of APL cells. These findings demonstrated that SAL effectively inhibited cell proliferation accompanied by induction of apoptosis and promotion of cell differentiation by inhibiting Wnt/β-catenin signaling. Collectively, these data revealed that SAL is a potential drug for treatment of APL.

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Arsenic Trioxide; Arsenicals; Cell Differentiation; Cell Line, Tumor; Drug Resistance, Neoplasm; Drug Synergism; Humans; Imides; Leukemia, Promyelocytic, Acute; Oxides; Pyrans; Quinolines; Tretinoin; Wnt Signaling Pathway

Arsenic trioxide (ATO) and all-trans retinoic acid (ATRA) combination safely cures fatal acute promyelocytic leukemia, but their mechanisms of action and efficacy are not fully understood. ATRA inhibits leukemia, breast, and liver cancer by targeting isomerase Pin1, a master regulator of oncogenic signaling networks. Here we show that ATO targets Pin1 and cooperates with ATRA to exert potent anticancer activity. ATO inhibits and degrades Pin1, and suppresses its oncogenic function by noncovalent binding to Pin1's active site. ATRA increases cellular ATO uptake through upregulating aquaporin-9. ATO and ATRA, at clinically safe doses, cooperatively ablate Pin1 to block numerous cancer-driving pathways and inhibit the growth of triple-negative breast cancer cells and tumor-initiating cells in cell and animal models including patient-derived orthotopic xenografts, like Pin1 knockout, which is substantiated by comprehensive protein and microRNA analyses. Thus, synergistic targeting of Pin1 by ATO and ATRA offers an attractive approach to combating breast and other cancers.

Topics: Animals; Antineoplastic Agents; Arsenic Trioxide; Cell Proliferation; Female; Fibroblasts; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Leukemia, Promyelocytic, Acute; Magnetic Resonance Spectroscopy; Mice; Mice, Inbred BALB C; Mice, Knockout; Neoplasm Transplantation; Neoplasms; NIMA-Interacting Peptidylprolyl Isomerase; Proteomics; Signal Transduction; Tretinoin

Although the cure rate of acute promyelocytic leukemia (APL) has exceeded 90%, the relapse/refractory APL that resistant to all-trans retinoic acid (ATRA) or ATO was still serious concern. Matrine (MAT) could improve the differentiation ability of ATRA-resistant APL cells. This study aimed to explore how the APL-specific fusion protein was degraded in ATRA-resistant APL with the application of MAT and ATRA.. ATRA-sensitive (NB4) and ATRA-resistant (NB4-LR1) cell lines were used. Nitroblue tetrazolium reduction assay and flow cytometry were used to detect the differentiation ability. The activity of ubiquitin-proteasome and autophagy-mediated pathways in both cells treated with ATRA with or without MAT were compared in protein and mRNA level (Western blot analysis, qRT-PCR), the Fluorescent substrate Suc-LLVY-AMC detection was used to detect the activity of proteasome, and electron microscope for observing autophagosome. MG 132(proteasome inhibitor), rapamycin (autophagy activator), hydroxychloroquine (lysosomal inhibitor) and STI571 [retinoic acid receptor alpha (RARα) ubiquitin stabilizer] were used as positive controls. The effect of MAT was observed in vivo using xenografts.. MAT improved the sensitivity of NB4-LR1cells to ATRA treatment, which was consistent with the expression of PML-RARα fusion protein. MAT promoted the ubiquitylation level in NB4-LR1. MG 132 induced the decrease in RARα in both cell lines, and hampered the differentiation of NB4 cells. MAT also promoted the autophagy in NB4-LR1 cells, with an increase in microtubule-associated protein 1 light chain3 (LC3)-II and LC3-II/LC3-I ratio and exhaustion of P62. The expression of LC3II increased significantly in the MAT and ATRA + MAT groups in combination with lysosomal inhibitors. A similar phenomenon was observed in mouse xenografts. MAT induced apoptosis and differentiation.. Autophagy and ubiquitin-mediated proteolytic degradation of PML/RARα fusion protein are crucial in MAT-induced differentiation sensitivity recovery of NB4-LR1 cells.

Topics: Alkaloids; Animals; Antineoplastic Agents; Autophagy; CCAAT-Enhancer-Binding Proteins; Cell Differentiation; Cell Line, Tumor; Drug Resistance, Neoplasm; Humans; Leukemia, Promyelocytic, Acute; Male; Matrines; Mice; Mice, Inbred BALB C; Mice, Nude; Oncogene Proteins, Fusion; Proto-Oncogene Proteins c-myc; Quinolizines; STAT1 Transcription Factor; Tretinoin; Ubiquitin; Ubiquitination