tretinoin and Disseminated-Intravascular-Coagulation

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

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

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

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) 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

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

Topics: Anticoagulants; Antithrombins; Benzamidines; Chondroitin Sulfates; Dalteparin; Dermatan Sulfate; Disseminated Intravascular Coagulation; Gabexate; Guanidines; Heparin; Heparitin Sulfate; Humans; Protease Inhibitors; Protein C; Recombinant Proteins; Thrombomodulin; 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: Anticoagulants; Disseminated Intravascular Coagulation; Gabexate; Heparin; Humans; Leukemia; Platelet Transfusion; Serine Proteinase Inhibitors; Thrombocytopenia; Tretinoin; Vitamin K Deficiency

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

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

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

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

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

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

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

Topics: Animals; Disseminated Intravascular Coagulation; Endothelium, Vascular; Epoprostenol; Hemolytic-Uremic Syndrome; Humans; Plasma Exchange; Prednisolone; Purpura, Thrombotic Thrombocytopenic; 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

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

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

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

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

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

Topics: Disseminated Intravascular Coagulation; Enoxaparin; Heparin, Low-Molecular-Weight; Humans; Leukemia, Promyelocytic, Acute; 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

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

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) 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

Topics: Disseminated Intravascular Coagulation; Humans; Induction Chemotherapy; Leukemia, Promyelocytic, Acute; Thrombomodulin; 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

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

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

Topics: Adult; Aged; Antineoplastic Agents; Arsenic Trioxide; Disease Progression; Disseminated Intravascular Coagulation; Drug Substitution; Humans; Leukemia, Promyelocytic, Acute; Male; Treatment Outcome; Tretinoin

Recombinant human soluble thrombomodulin (rTM) is a newly developed anti-coagulant approved for treatment of disseminated intravascular coagulation (DIC) in Japan. rTM exerts anti-inflammatory and cytoprotective functions via its lectin-like and epidermal growth factor-like domains, respectively. In this study, we retrospectively reviewed the treatment of 21 consecutive patients with coagulopathy, complicated by acute promyelocytic leukemia (APL), with all-trans retinoic acid (ATRA) with or without combination with rTM. Surprisingly, none of the 14 rTM-treated patients developed retinoic acid (RA)-related differentiation syndrome (DS). The co-culture of vascular endothelial cell-derived EA.hy926 and APL-derived NB4 cells in the presence of RA increased production of tumor necrosis factor alpha (TNF-α) in culture media, in parallel with activation of p38 mitogen-activated protein kinase and increased levels of intracellular adhesion molecule 1 (ICAM1) in EA.hy926 cells. This was also associated with increased levels of the phosphorylated forms of VE-cadherin and enhanced vascular permeability of EA.hy926 monolayers. Importantly, addition of rTM to this co-culture system inhibited the RA-induced phosphorylation of p38 and VE-cadherin and decreased ICAM1 and vascular permeability in EA.hy926 cells, without a decrease inthe levels of TNF-α. Taken together, use of rTM may be a promising treatment strategy to prevent DS in APL patients who receive ATRA.

Topics: Adult; Aged; Antineoplastic Agents; Apoptosis; Biomarkers, Tumor; Cell Differentiation; Cell Proliferation; Coculture Techniques; Disseminated Intravascular Coagulation; Female; Follow-Up Studies; Humans; Immunoenzyme Techniques; In Vitro Techniques; Japan; Leukemia, Promyelocytic, Acute; Male; Middle Aged; p38 Mitogen-Activated Protein Kinases; Prognosis; Recombinant Proteins; Respiratory Distress Syndrome; Retrospective Studies; Survival Rate; Thrombomodulin; Tretinoin; Tumor Cells, Cultured

The microgranular variant (M3v) of acute promyelocytic leukemia (APL) is rare, and the diagnosis can be delayed due to variability in how this condition presents. M3v blasts often have folded nuclei, but unlike traditional APL blasts, they often possess faint granules without Auer rods. In addition, microgranular APL often presents with an elevated or normal white blood cell count in contrast with the leukopenia seen in traditional APL. In APL, delayed diagnosis can lead to early death from disseminated intravascular coagulation (DIC), which is the main cause of mortality in an otherwise treatable, and often curable, leukemia. We describe a 19-year-old male with microgranular APL who presented with leukopenia and many blasts resembling non-APL AML blasts with an unexpected immunophenotypic pattern. He was treated for DIC and initiated on all-trans-retinoic acid and arsenic trioxide; he achieved complete molecular remission after induction therapy. Suspicion for APL should always remain high in the presence of clinical manifestations of the disease in order that appropriate treatment can be initiated rapidly to prevent early death.

Topics: Arsenic Trioxide; Arsenicals; Bone Marrow; Disseminated Intravascular Coagulation; Flow Cytometry; Humans; Immunophenotyping; Leukemia, Promyelocytic, Acute; Leukopenia; Male; Oxides; Treatment Outcome; Tretinoin; Young Adult

Topics: Antineoplastic Agents; Arsenic Trioxide; Arsenicals; Disseminated Intravascular Coagulation; Forkhead Box Protein O3; Forkhead Transcription Factors; Humans; Leukemia, Promyelocytic, Acute; Oncogene Proteins, Fusion; Oxides; Tretinoin

Early death (ED) occurs in 10-30% of patients with acute promyelocytic leukemia (APL). Is all-trans retinoic acid (ATRA) promptly given and does it decrease overall early mortality? ATRA was administered within 24h of morphological suspicion in only 44% of the 120 consecutive patients treated in the four collaborating centers. Absence of disseminated intravascular coagulation (p=0.012) and admission to a non-university-affiliated hospital (p=0.032) were independent predictors of ATRA delay. ED occurred in 17% of patients, and was independently correlated only with ICU admission (p=0.002). Our results do not demonstrate that prompt (versus delayed) ATRA administration decreases overall early death.

Topics: Adult; Aged; Antineoplastic Agents; Cohort Studies; Disseminated Intravascular Coagulation; Female; Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Patient Admission; Patient Transfer; Survival Analysis; Time-to-Treatment; Tretinoin; United States

Differentiation syndrome is a life-threatening complication of therapy that is carried out with agents used for acute promyelocytic leukemia. Its physiopathology comprehends the production of inflammatory mediators by differentiating granulocytes, endothelial and alveolar cells due to stimulation by all-trans retinoic acid and leading to sustained systemic inflammation.. Treatment with high cut-off continuous veno-venous hemodialysis (HCO-CVVHD) was performed to reduce the circulating mediators of systemic inflammation.. After 52 h of treatment, an important reduction was observed in inflammatory mediators (IL-1β: from 10 to 2 pg/ml; IL-8: from 57 to 40 pg/ml; TNF-α: from 200 to 105 pg/ml; IL-6: from 263 to 91 pg/ml), as well as in anti-inflammatory mediators (IL-10: from 349 to 216 pg/ml).. HCO-CVVHD should be explored as a part of treatment in systemic inflammation states other than sepsis (e.g., differentiation syndrome). Furthermore, its immunomodulatory effects could be particularly useful in immunocompromised patient treated with corticosteroids.

Topics: Acute Kidney Injury; Adult; Anticoagulants; Antineoplastic Combined Chemotherapy Protocols; Calcium Citrate; Capillary Leak Syndrome; Cell Differentiation; Disseminated Intravascular Coagulation; Fatal Outcome; Hemofiltration; Humans; Idarubicin; Immunomodulation; Inflammation; Inflammation Mediators; Leukemia, Promyelocytic, Acute; Male; Membranes, Artificial; Molecular Weight; Permeability; Prednisolone; Respiratory Insufficiency; Serum Albumin; Syndrome; Tretinoin

Topics: Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Disseminated Intravascular Coagulation; Hemorrhage; Humans; Leukemia, Promyelocytic, Acute; Oxides; Remission Induction; Secondary Prevention; Survival Rate; Time Factors; Treatment Failure; Tretinoin

Topics: Adult; Anthracyclines; Anticoagulants; Antineoplastic Combined Chemotherapy Protocols; Chest Pain; Disseminated Intravascular Coagulation; Female; Heparin; Humans; Leukemia, Promyelocytic, Acute; Magnetic Resonance Imaging; Myocardial Infarction; Neutropenia; Remission Induction; Stroke Volume; Thrombosis; Tretinoin; Ultrasonography

Acute promyelocytic leukemia (APL) is frequently associated, often from the earliest phases, with a life-threatening coagulation/bleeding syndrome; disseminated intravascular coagulation (DIC) is described in majority of patients. We report a case of 49-year-old male, without cardiovascular risk factors, who suddenly developed ischemic stroke and splenic infarction as presenting symptoms of APL and related DIC. The patient was immediately treated with all-trans retinoic acid (ATRA) and the alterations of hemocoagulation parameters promptly returned in normal range. The coagulation/bleeding syndrome of the onset of APL is associated with high mortality; both diagnostic and therapeutic approaches require special and timely consideration of this condition. Treatment with ATRA is essential.

Topics: Antineoplastic Agents; Disseminated Intravascular Coagulation; Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Stroke; Tretinoin

There are very limited reports about childhood acute promyelocytic leukemia (APL), especially about arsenic trioxide (ATO) treatment in both induction and post-remission regimens. 35 newly diagnosed APL patients received ATO treatment in our center and the clinical course as well as the outcome of them was investigated. The dose of intravenous ATO was 0.15-0.17 mg/kg per day, only one patient got 0.33 mg/kg per day, maximum dose was 10 mg per day in induction therapy with minimal chemotherapy treatment (CT) for hyperleukocytosis. Anthracycline or anthracycline-based CT was used for consolidation therapy and followed by 0.10-0.15 mg/kg per day ATO treatment in maintenance therapy. The continuous detection for morphology of bone marrow and PML-RARa were necessary for administrating CT or not. 3 patients died during induction therapy for intracranial hemorrhage, leukocytosis and septic shock. Total of 30 patients achieved complete remission (CR) and were followed-up for 10-108 months. The overall survival (OS) for all patients was 82.7%, whereas the OS for patients obtained CR was 95.8%. The event-free survival for 5 years was 80.3%. Disseminated intravascular coagulation could be under control to reduce induction mortality with adequate supportive care, especially in the first 2 weeks. The side effects of ATO were mild and transient. This regimen of ATO treatment both in induction and post-remission therapy was effective and safe for childhood APL to get long-term survival.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Bone Marrow; Child; Child, Preschool; China; Disseminated Intravascular Coagulation; Female; Humans; Incidence; Leukemia, Promyelocytic, Acute; Male; Oxides; Retrospective Studies; Treatment Outcome; Tretinoin

To explore the expression of CD34 in patients with acute promyelocytic leukemia (APL) and investigate the clinical and laboratory features of CD34(+) APL patients.. 262 APL patients diagnosed by chromosome analysis and/or fusion gene examination in the last five years were retrospectively analyzed in this study. To survey the expression of CD34 in those patients, all the cases were divided into two groups (CD34(+) APL vs. CD34(-) APL). The clinical features including age, gender, abnormal values of the peripheral hemogram before treatment, the complete remission (CR) rate and the incidence of DIC and laboratory data such as the results of morphology, immunology, cytogenetics and molecular biology (MICM) between those two groups were compared.. Of the 262 APL patients, 38 (14.5%) cases were positive for CD34 expression. There were no statistically significant differences between CD34(+) APL and CD34(-) APL groups in gender and age (P > 0.05). Before treatment, the median level of WBC in CD34(+) APL was 25.92 x 10(9)/L, which was significantly higher than that of CD34(-) APL (5.3 x 10(9)/L, P < 0.05). CD34(+) APL by morphology classification were mostly of the subtypes M3b and M3v (65.8%), while these subtypes in CD34(-) APL (40.3%) were significantly less (P < 0.01). There were no statistically significant differences between the two groups compared in respect of complete remission (CR) rate and the incidence of DIC (P > 0.05). The expression level of CD34 in APL had correlation to the expression level of CD2, CD7 and CD117; the latter three phenotypes in CD34(+) APL were significantly higher than those in CD34(-) APL (P < 0.01). No significant difference was found between those two groups by chromosome analysis, but there was more PML-RAR-alpha transcript short form in CD34(+) APL than that in CD34(-) APL (P < 0.05).. CD34(+) acute promyelocytic leukemia is a unique subtype of APL with different biological characteristics.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antigens, CD34; Antigens, CD7; Antineoplastic Agents; CD2 Antigens; Child; Disseminated Intravascular Coagulation; Female; Humans; Immunophenotyping; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Nuclear Proteins; Phenotype; Promyelocytic Leukemia Protein; Proto-Oncogene Proteins c-kit; Receptors, Retinoic Acid; Remission Induction; Retinoic Acid Receptor alpha; Retrospective Studies; Transcription Factors; Translocation, Genetic; Tretinoin; Tumor Suppressor Proteins; Young Adult

In this study, we show that all-trans retinoic acid (ATRA) treatment leads to a rapid decrease in telomerase activity, which was associated with the reduction in myeloblasts and occurs before the appearance of myelocytes, in a patient with acute promyelocytic leukemia (APL). Microarray analysis by ATRA treatment for 48 hr in peripheral blood mononuclear cells (in vivo) and in cultured bone marrow mononuclear cells (in vitro) from a patient with APL revealed upregulation of CD11b, CD11c, CCAAT enhancer binding protein epsilon, Rb1, Mad, and tumor necrosis factor-related genes; and downregulation of hTERT, c-Myc, WT1, bcl-2, and eukaryotic translation elongation factor 1alpha2. The results might offer the potential to define the molecular mechanism underlying ATRA-induced granulocytic differentiation in patients with APL, and provide clues to identify novel molecular therapeutic targets.

Topics: Antigens, Differentiation; Cell Differentiation; Child; Disseminated Intravascular Coagulation; Enzyme Activation; Female; Gene Expression Profiling; Gene Expression Regulation, Leukemic; Granulocytes; Humans; Leukemia, Promyelocytic, Acute; Leukocytes, Mononuclear; Oligonucleotide Array Sequence Analysis; Remission Induction; Reverse Transcriptase Polymerase Chain Reaction; RNA; Telomerase; Tretinoin; Tumor Cells, Cultured

Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia (AML) and is rare in children (< 10% of childhood AML). It tends to bleed with disseminated intravascular coagulation (DIC) and intracranial hemorrhage complication is often fatal. We report a 12-year-old child with APL who suffered a subdural hemorrhage and initially presented with a subtle headache mistaken as the side effect of all-trans-retinoic acid (ATRA). Blood component therapy and a pediatric dosage of ATRA (25 mg/m2/day) combined with idarubicin as induction chemotherapy were administered in the first week, but the bleeding diathesis persisted and DIC profiles showed no improvement. The patient then developed photophobia, neck stiffness, and constant headache. Evidence of increased intracranial pressure (IICP) and persistent bleeding from previous venous puncture sites were also noticed clinically. DIC and life-threatening IICP were beyond control until the ATRA dosage was increased to adult levels (45 mg/m2/day). This case suggests that the ATRA dosage for pediatric APL patients must be modified according to clinical condition. Emergency brain imaging should be considered in APL patients with signs of IICP to distinguish intracranial lesions from ATRA complications.

Topics: Child; Disseminated Intravascular Coagulation; Headache; Hematoma, Subdural; Humans; Leukemia, Promyelocytic, Acute; Male; Partial Thromboplastin Time; Prothrombin Time; Tretinoin

All-trans retinoic acid (ATRA) has been introduced to the management of acute promyelocytic leukemia (APL) as a differentiation treatment. This drug not only causes complete remission, but also improves disseminated intravascular coagulation (DIC) without adding anticoagulants in APL. We have attempted to determine whether ATRA is effective against DIC in rat models induced by tissue factor (TF) or lipopolysaccharide (LPS), because the anticoagulant effect of ATRA has been considered to induce thrombomodulin upregulation and TF downregulation on endothelial cells as well as on APL cells. In male Wistar rats, DIC was induced by a 4-h infusion of thromboplastin (3.75 U/kg) or lipopolysaccharide (30 mg/kg). The rats were given ATRA orally each day at a dose of 100 mg/kg per day for 1 week before the injection of TF or LPS in ATRA treatment groups, or given low molecular weight heparin (LMWH) 10 min before the injection of TF or LPS (200 U/kg, bolus intravenously) in LMWH treatment groups. No significant changes in hemostatic parameters or markers of organ dysfunction were caused by the ATRA administration, while DIC was significantly improved by LMWH in the TF-induced model. DIC was significantly improved by both ATRA and LMWH in the LPS-induced model. These findings suggested that ATRA was useful for treating DIC only in the LPS-induced model, and that drug efficacy should be carefully assessed because the agents used to induce DIC considerably influenced the outcome.

Topics: Animals; Disease Models, Animal; Disseminated Intravascular Coagulation; Keratolytic Agents; Lipopolysaccharides; Male; Rats; Rats, Wistar; Thromboplastin; Tretinoin

Disseminated intravascular coagulation in humans is frequently associated with Gram-negative bacterial sepsis. Therefore, to examine the role and time frame of the in vivo induction of tissue factor (TF) by bacterial endotoxin, a reverse transcription polymerase chain reaction and a solid-phase ELISA assay were developed to monitor the in vivo production in rabbits, of TF mRNA and TF antigen by peripheral blood leukocytes (PBL).. : Healthy rabbits were injected intravenously with either 1, 10 or 50 microg/kg of Salmonella endotoxin. Blood samples were obtained both before endotoxin administration and at various time points thereafter, up to 24 h. Some experiments were also done to determine whether all-trans retinoic acid would ameliorate the signs of the endotoxin-induced disseminated intravascular coagulation.. PBL counts dropped significantly within 2 h of rabbits receiving the endotoxin, recovering to baseline levels by 24 h. Platelet counts decreased gradually over this same time frame. Fibrin deposition was noted in renal glomerular capillaries at 24 h. An increase (P<0.001) in PBL-associated TF mRNA levels was observed 2 h post-endotoxin (10 microg/kg, n = 8), followed by a gradual decline over the subsequent 24 h. The average increase in TF mRNA at 2 h was approximately 4.6-fold (P<0.001) over that seen at time 0. The amount of mononuclear cell associated TF antigen demonstrated a peak at 2 h post-endotoxin (10 microg/kg, n = 13), with levels approximately 9.6-fold greater than (P<0.001) baseline. Pre-treatment of rabbits with all-trans retinoic acid significantly (P<0.001) ameliorated the PBL-associated increase in TF mRNA and TF antigen levels.. These results suggest that low dose endotoxin (10 microg/kg) faithfully reproduces the non-overt activation of coagulation observed in primates and human volunteers, supporting the hypothesis that TF expression is involved in the in vivo initiation and propagation of disseminated intravascular coagulation. Moreover, all-trans retinoic acid may be effective in modulating in vivo the TF transcription induced by endotoxin.

Topics: Animals; Antithrombin III; Blood Cell Count; Disseminated Intravascular Coagulation; Drug Evaluation, Preclinical; Endotoxemia; Fibrin; Fibrinogen; Gene Expression Regulation; Kidney Glomerulus; Leukocytes; Lipopolysaccharides; Male; Rabbits; RNA, Messenger; Thrombocytopenia; Thromboplastin; Tretinoin

Acute promyelocytic leukemia (APL) in pregnancy poses serious danger to both the mother and fetus. Cytotoxic chemotherapy may cause teratogenicity to the fetus. APL is unique because it is usually associated with a coagulopathy that markedly increases the risk for the mother and fetus. A 21 year old lady with APL in her third trimester of pregnancy was treated with oral tretinoin. Tretinoin reversed the coagulopathy and normalised her blood counts without causing cytotoxic damage associated with cancer chemotherapy. Fetal distress occurred at 37 weeks of gestation and an emergency caesarean section was performed without complications and no blood transfusion support was needed as her coagulopathy and thrombocytopenia had resolved. A remission was achieved with only tretinoin induction. She subsequently had consolidation and maintenance chemotherapy. The mother and baby remain well at 4 years from completion of chemotherapy. A total of 10 pregnancies associated with APL have been reported in the current literature. Premature delivery and a fetal arrhythmia were the only complications. Although retinoin is considered teratogenic, its use so far in second and third trimester has been safe.

Topics: Antineoplastic Agents; Disseminated Intravascular Coagulation; Female; Heart Rate, Fetal; Humans; Leukemia, Promyelocytic, Acute; Malaysia; Pregnancy; Pregnancy Complications; Pregnancy Trimester, Third; Premature Birth; Tretinoin; Young Adult

Anticoagulant drugs such as heparin are often administered to patients with disseminated intravascular coagulation (DIC) who are also being treated for their underlying disease. The pathophysiology of DIC is so varied that treatment with medications other than anticoagulants may be useful. All-trans retinoic acid (ATRA), which is used for the treatment of acute promyelocytic leukemia (APL), improves DIC in APL. In vitro studies have reported that ATRA caused downregulation of tissue factor and upregulation of thrombomodulin (TM) on endothelial cells as well as APL cells. We examined the effect of ATRA in an endotoxin-induced rat DIC model. DIC was induced in male Wistar rats with a 4-h sustained infusion of endotoxin at a dose of 30 mg/kg. ATRA (20 mg/day) was given every day for 1 week before the injection of endotoxin. ATRA improved the increase in thrombin-antithrombin III (TAT) complex and D-dimer in this model. Fibrin deposition in renal glomeruli was inhibited by ATRA administration, with an increase in the intensity of immunohistochemical TM staining. These findings suggest that ATRA has beneficial effects in the endotoxin-induced rat DIC model. The mechanism may be an upregulation of TM expression on endothelial cells.

Topics: Animals; Antithrombin III; Disseminated Intravascular Coagulation; Endotoxins; Fibrin Fibrinogen Degradation Products; Kidney Glomerulus; Male; Rats; Rats, Wistar; Thrombin; Thrombomodulin; Tretinoin

Acute promyelocytic leukemia (APL) is a type of acute leukemia showing unique clinical, morphological and cytogenetic features. A skin infiltration by APL cells is an extremely rare occasion, but there have been several case reports of leukemia cutis in APL, in which all-trans retinoic acid (ATRA) may have induced the skin infiltration. However, no immunohistochemical analyses of the APL cells in the skin have been done to date. A 30-year-old woman with APL developed multiple reddish purple nodules on the extremities in her second complete remission. Histological findings revealed a dense infiltration of medium to large atypical cells, which were positive for myeloperoxidase, throughout the dermis. Despite the conventional chemotherapy and ATRA therapy she died from disseminated intravascular coagulation during her third relapse. Leukemic cells in the peripheral blood before the treatment with ATRA revealed CD3-/CD4-/CD5-/CD7-/CD8-/CD10-/CD13++/CD14-/CD19 -/ CD20-/CD33++/CD38++/CD41-/Ia-, but they expressed CD3-/CD4-/CD5-/CD7++/ CD8-/CD10-/CD13++/CD14-/CD19-/CD20-/CD33++ /CD38++/CD41+/Ia+ after the treatment. We suggest that the alternation of the surface molecules on the tumor cells is closely associated with the skin infiltration of APL cells.

Topics: ADP-ribosyl Cyclase; ADP-ribosyl Cyclase 1; Adult; Antigens, CD; Antigens, CD19; Antigens, CD20; Antigens, CD7; Antigens, Differentiation; Antigens, Differentiation, Myelomonocytic; Antineoplastic Agents; Cause of Death; CD13 Antigens; CD3 Complex; CD4 Antigens; CD5 Antigens; CD8 Antigens; Cell Adhesion Molecules; Disseminated Intravascular Coagulation; Fatal Outcome; Female; Histocompatibility Antigens Class II; Humans; Keratolytic Agents; Leukemia, Promyelocytic, Acute; Leukemic Infiltration; Lipopolysaccharide Receptors; Membrane Glycoproteins; N-Glycosyl Hydrolases; Neprilysin; Peroxidase; Platelet Glycoprotein GPIIb-IIIa Complex; Sialic Acid Binding Ig-like Lectin 3; Skin; Tretinoin

A case of acute renal failure, due to occlusion of renal vessels in a patient with acute promyelocytic leukemia (APL) treated with all-trans-retinoic acid (ATRA) and tranexamic acid has been described recently. We report a case of acute renal failure in an APL patient treated with ATRA alone. This case further supports the concern about thromboembolic complications associated with ATRA therapy in APL patients. The patients, a 43-year-old man, presented all the signs and symptoms of APL and was included in a treatment protocol with ATRA. After 10 days of treatment, he developed acute renal failure that was completely reversible after complete remission of APL was achieved and therapy discontinued. We conclude that ATRA is a valid therapeutic choice for patients with APL, although the procoagulant tendency is not completely corrected. Thrombotic events, however, could be avoided by using low-dose heparin.

Topics: Acute Kidney Injury; Adult; Anticoagulants; Antineoplastic Agents; Blood Coagulation Factors; Disseminated Intravascular Coagulation; Fibrinolysis; Hemorrhage; Heparin; Humans; Kidney Glomerulus; Leukemia, Promyelocytic, Acute; Male; Thrombosis; Tretinoin

Acute promyelocytic leukemia, a subset of acute myelogenous leukemia, is commonly associated with disseminated intravascular coagulation (DIC). All-trans retinoic acid is effective in the treatment of acute promyelocytic leukemia and may prevent an exacerbation of DIC. There is limited information, however, regarding the use of this agent in pregnancy.. A 29-year-old woman with acute promyelocytic leukemia and DIC at 24 weeks' gestation was treated successfully with all-trans retinoic acid during the pregnancy, delivering a viable, normal infant at 33 weeks.. This case illustrates the successful use of all-trans retinoic acid in pregnancy for the treatment of acute promyelocytic leukemia. With the combined, intensive efforts of the perinatal, neonatal, and hematology-oncology services, a favorable outcome was achieved.

Topics: Adult; Antineoplastic Agents; Bone Marrow Examination; Disseminated Intravascular Coagulation; Female; Humans; Labor, Induced; Leukemia, Promyelocytic, Acute; Pregnancy; Pregnancy Complications, Hematologic; Pregnancy Outcome; Pregnancy Trimester, Second; Remission Induction; Tretinoin

A 51 year-old male admitted with petechiae and headache. Acute promyelocytic leukemia (APL) with disseminated intravascular coagulation (DIC) was diagnosed. He received all-trans retinoic acid (ATRA) with enocitabine and daunomycin for induction chemotherapy, and supportive therapy for DIC. On 2nd day after admission, subacute subdural hematoma was confirmed with CT scan. He had anisocoria and disturbance of consciousness, and was treated with neurosurgical operation for his life saving on the 3rd day. Although DIC was continued at this time, the operation was done without problem. The recurrence of hematoma has not occurred after the operation. Furthermore, the findings of DIC disappeared by the day 6 following induction therapy. He achieved a complete remission including cytogenetic findings on 35th day after administration of ATRA and received 3 times of combination chemotherapy as consolidation therapy. It may be difficult to do neurosurgical treatment in the setting of DIC. However, we should consider whether the indications for surgery operation according to the condition of each patient.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Disseminated Intravascular Coagulation; Hematoma, Subdural; Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Tretinoin

Coagulation patterns of 19 newly-diagnosed acute promyelocytic leukemia (APL) patients with disseminated intravascular coagulation (DIC) at presentation were studied. Seventeen patients had hemorrhagic complications, of which four were fatal. Fatal hemorrhages were related with lower fibrinogen level and lower platelet count. DIC of the APL patients without infection was characterized by low fibrinogen and normal antithrombin III (ATIII) level. Thrombin-ATIII complex level was elevated in all patients examined. Patients with infection had higher fibrinogen levels than those without infection and some patients had reduced ATIII level. Ten remission inductions were tried with multidrug chemotherapy and seven with all-trans retinoic acid (ATRA). Complete remission was achieved in seven of ten inductions with chemotherapy and in all seven inductions with ATRA. Two patients treated with chemotherapy had fatal hemorrhage after starting therapy but none treated with ATRA.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Blood Coagulation; Disseminated Intravascular Coagulation; Female; Hemorrhage; Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Remission Induction; Sepsis; Tretinoin

We report a case of acute promyelocytic leukemia (APL) following ulcerative colitis (UC). A 23-year-old man was diagnosed as UC in January 1991 and had been treated with salazosulfapyridine and prednisolone with good effect. In September 1993, he developed bleeding tendency and a diagnosis of APL with disseminated intravascular coagulation was made based on the results of bone marrow aspiration and coagulation profile. Complete remission was achieved with All-trans retinoic acid together with combined chemotherapy. He died of sepsis during consolidation chemotherapy in December 1993. Autopsy revealed no recurrence of UC.

Topics: Adult; Anticoagulants; Colitis, Ulcerative; Disseminated Intravascular Coagulation; Fatal Outcome; Gastrointestinal Agents; Heparin; Humans; Keratolytic Agents; Leukemia, Promyelocytic, Acute; Male; Sulfasalazine; Tretinoin

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Cerebral Hemorrhage; Disseminated Intravascular Coagulation; Female; Hematoma; Humans; Leukemia, Promyelocytic, Acute; Recurrence; Remission Induction; Tretinoin

Acute promyelocytic leukemia is a unique subset of acute myelogenous leukemia, characterized by a neoplastic proliferation of promyelocytes and a prompt response to all-trans retinoic acid (tretinoin), which induces differentiation of immature leukemic promyelocytes into mature neutrophils. Because of the high incidence of disseminated intravascular coagulation (DIC) associated with acute promyelocytic leukemia and the danger of exacerbation of DIC with pregnancy, management of acute promyelocytic leukemia during pregnancy requires prompt and careful attention.. A 29-year-old woman in her third trimester was diagnosed with acute promyelocytic leukemia and DIC. The infant was delivered by cesarean and the mother was successfully treated with tretinoin, inducing the leukemic promyelocytes to differentiate into mature granulocytes and possibly reversing the DIC.. If the fetus can be delivered safely, tretinoin as a single agent is an option for the initial treatment of maternal acute promyelocytic leukemia because it does not suppress the bone marrow and may ameliorate DIC. Because of the danger of hyperleukocytosis, chemotherapy should be added initially if the white blood cell count is greater than 5000/microL. If the fetus cannot be delivered at a viable stage, conventional cytotoxic chemotherapy is the alternative option.

Topics: Adult; Disseminated Intravascular Coagulation; Female; Humans; Leukemia, Promyelocytic, Acute; Pregnancy; Pregnancy Complications, Hematologic; Pregnancy Complications, Neoplastic; Tretinoin

Treatment of acute promyelocytic leukemia (APL) patients with all-trans retinoic acid (ATRA) was associated with rapid improvement in hemostatic markers. We made serial analyses of various hemostatic parameters in seven newly diagnosed APL patients. In all patients at diagnosis, plasma fibrinogen/fibrin degradation product (fragment-E), cross-linked fibrin degradation product (D-dimer fragment), thrombin-antithrombin III complex and plasmin-alpha 2-plasmin inhibitor complex were elevated, indicating the presence of disseminated intravascular coagulation (DIC). Antithrombin III (ATIII) levels were normal in all patients except for the patient with congenital ATIII deficiency. In four patients subsequently treated with ATRA without anticoagulant therapy, these hemostatic markers returned to near-normal levels by day 7 of treatment, indicating that DIC was essentially resolved. By contrast, in three patients who received conventional chemotherapy with a continuous low-dose heparin, improvement of coagulopathy was slower than in patients treated with ATRA. These results suggest that ATRA therapy exerts the rapid improvement in abnormal hemostatic markers in APL patients without any anticoagulant therapies, by inducing differentiation of leukemic cells and, in turns no massive release of procoagulant or fibrinolytic substances from these cells.

Topics: Adult; Blood Coagulation Tests; Disseminated Intravascular Coagulation; Female; Fibrin Fibrinogen Degradation Products; Hemostasis; Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Tretinoin

The bleeding diathesis in patients with acute promyelocytic leukemia (APL) is generally attributed to disseminated intravascular coagulation (DIC), initiated by the release of procoagulant activity from leukemic cells. Primary fibrinogenolysis, mediated by the release of leukocyte proteases, may also contribute to this disorder. We analyzed coagulation parameters in 15 non-septic APL patients. Before treatment, there was evidence of thrombin activation with DIC: increased levels of circulating thrombin-antithrombin III complexes, prothrombin fragments 1 + 2 and D-Dimer complexes. This DIC syndrome was probably limited, since no prothrombin time decrease, no significant factor V consumption, and normal levels of coagulation inhibitors (antithrombin III and protein C) were observed in APL patients when compared to normal controls. In this context, marked hypofibrinogenemia suggested primary fibrinogenolysis as the predominant etiology. Despite normal or high tissue plasminogen activator (tPA) and plasminogen activator inhibitor (PAI-1) antigen levels, the plasma PAI-1 activity and the formation of tPA/PAI-1 complexes were lower in APL patients than in normal controls, suggesting a proteolytic degradation of PAI-1, not able to complex tPA. Two other fibrinolytic inhibitor molecules (alpha-2 plasmin inhibitor antigen and histidine-rich glycoprotein antigen) were also significantly reduced, as well as the two subunits of fibrin stability factor XIII, although only subunit A is known to be susceptible to thrombin action. Evidence of degraded forms of von Willebrand factor in the plasma suggested an extended proteolytic activity. Four patients treated with all-trans-retinoic acid (ATRA) as a single differentiating agent were studied serially. A dissociation between these two syndromes--DIC and fibrinogenolysis/proteolysis--was observed. The rapid correction of the lysis markers contrasted with a more prolonged persistence of the procoagulant activity. We observed persistently high elastase/alpha 1-proteinase inhibitor complex levels during ATRA therapy, despite progressive correction of all lysis markers. Thus, the release of elastase from promyelocytic leukemic cells is probably not the only determinant of the fibrinogenolytic/proteolytic syndrome. In summary, the present findings provide new arguments for the association of DIC and proteolysis syndromes in APL-associated coagulation disorders. Further prospective studies are needed in order to confirm the pers

Topics: Adolescent; Cell Differentiation; Child; Disseminated Intravascular Coagulation; Female; Fibrin; Fibrin Fibrinogen Degradation Products; Fibrinogen; Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Prospective Studies; Thrombin; Time Factors; Tretinoin

In this paper we report on a 74-year-old female patient who was suffering from acute promyelocytic leukemia (APL) and who, upon admission to our hospital on February 20, 1992, was also found to be stricken with disseminated intravascular coagulation (DIC). The DIC, however, was quickly arrested by administration of heparin and there was no exacerbation. Also, on admission her peripheral blood leukocyte count was 700/ul, but after oral administration of all-trans retinoic acid (ATRA) (45 mg/m/day) was begun on February 22, this count gradually increased and peaked at 35,200/ul on March 7. Some of these matured leukocytes revealed dysplastic features; some had Auer bodies. At this time cytogenetic analysis of bone marrow cells showed 46XX, t (15;17). The leukocyte count gradually decreased to 1,500/ul, and the dysplastic features disappeared. On March 21 her thrombocytes and reticulocytes began to increase, and she achieved complete remission when her abnormal karyotype disappeared on March 24. She suffered no severe complications such as infection or hemorrhage during treatment. We therefore suggest that ATRA is very effective for APL in elderly patients. It neither exacerbates DIC nor increases the risk of infection. In fact, when ATRA treatment is compared to the standard cytotoxic chemotherapy there is a reduced risk of infection.

Topics: Administration, Oral; Aged; Disseminated Intravascular Coagulation; Female; Heparin; Humans; Infusions, Intravenous; Leukemia, Promyelocytic, Acute; Remission Induction; Tretinoin

Acute promyelocytic leukemia (APL) is associated with a high incidence of disseminated intravascular coagulation (DIC) and early hemorrhagic death. The risk of early fatal hemorrhage is increased when high peripheral-blood blast count and severe DIC accompanied by visceral hemorrhage are present at diagnosis. Progressive cytolysis induced by daily increased doses of chemotherapy, or differentiation all-trans-retinoic acid (ATRA) therapy have been proposed for initial control of DIC, but both are dangerous in hyperleukocytic APL patients. We report our results obtained in three high-risk APL patients treated with a combination of conventional chemotherapy and ATRA. All patients had documented hyperleukocytic APL [M3 or M3-variant subtype, (15, 17) translocation] with DIC, and all had critical clinical course before treatment. Patient 1 presented with cerebral hemorrhage, patients 2 and 3 had acute respiratory failure probably due to pulmonary leukemic infiltration and pulmonary hemorrhage. In order to minimize the severity of DIC during chemotherapy-induced acute cytolysis, ATRA (45 mg/m2 per day) was started on the first or second day of chemotherapy and withdrawn when complete remission (CR) was achieved. Despite adverse clinical features, CR was obtained in these three high-risk patients. Patient 1 showed no increase of cerebral bleeding during therapy. Patients 2 and 3 required transient intensive care, with mechanical ventilation from day 4 to day 11 for one of them. Differentiating granular cells were present in peripheral blood of all patients from the day 5, 12 and 8 of cytotoxic therapy. For the three patients, the number of days with white blood cell count < 1 x 10(9)/l was only 2, 7 and 11 days respectively. These results suggest that differentiation therapy with ATRA may be useful even in hyperleukocytic APL patients, when ATRA is used in combination with chemotherapy. The mechanisms of this putative beneficial effect are discussed.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Disseminated Intravascular Coagulation; Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Remission Induction; Tretinoin

Twenty-four patients with acute promyelocytic leukemia (APL) were treated with all-trans retinoic acid (45 to 100 mg/m2/day). Of these, eight cases had been either nonresponsive or resistant to previous chemotherapy; the other 16 cases were previously untreated. All patients attained complete remission without developing bone marrow hypoplasia. Bone marrow suspension cultures were studied in 15 of the 24 patients. Fourteen of these patients had morphological maturation in response to the retinoic acid (1 mumol/L). Chloroacetate esterase and alpha-naphthyl acetate esterase staining as well as electronmicroscopic examination confirmed that retinoic acid-induced cells differentiated to granulocytes with increased functional maturation (as measured by nitroblue tetrazolium reduction, NBT). The single nonresponder to retinoic acid in vitro was resistant to treatment with retinoic acid but attained complete remission after addition of low-dose cytosine arabinoside (ara-C). During the course of therapy, none of the patients showed any abnormalities in the coagulation parameters we measured, suggesting an absence of any subclinical disseminated intravascular coagulation. The only side effects consisted of mild dryness of the lips and skin, with occasional headaches and digestive symptoms. Eight patients have relapsed after 2 to 5 months of complete remission. The others remain in complete remission at 1+ to 11+ months and are still being followed up. We conclude that all-trans retinoic acid is an effective inducer for attaining complete remission in APL.

Topics: Adolescent; Adult; Bone Marrow; Cell Differentiation; Cells, Cultured; Child; Child, Preschool; Disseminated Intravascular Coagulation; Female; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Time Factors; Tretinoin