tretinoin and Central-Nervous-System-Neoplasms

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

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

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) 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

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

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

Isotretinoin (13-cis-retinoic acid; 13-cRA) is a differentiation inducer used to treat minimal residual disease after myeloablative therapy for high-risk neuroblastoma. However, more than 40% of children develop recurrent disease during or after 13-cRA treatment. The plasma concentrations of 13-cRA in earlier studies were considered subtherapeutic while 4-oxo-13-cis-RA (4-oxo-13-cRA), a metabolite of 13-cRA considered by some investigators as inactive, were greater than threefold higher than 13-cRA. We sought to define the metabolic pathways of 13-cRA and investigated the anti-tumour activity of its major metabolite, 4-oxo-13-cRA.. Effects of 13-cRA and 4-oxo-13-cRA on human neuroblastoma cell lines were assessed by DIMSCAN and flow cytometry for cell proliferation, MYCN down-regulation by reverse transcription PCR and immunoblotting, and neurite outgrowth by confocal microscopy. 13-cRA metabolism was determined using tandem MS in human liver microsomes and in patient samples.. Six major metabolites of 13-cRA were identified in patient samples. Of these, 4-oxo-13-cRA was the most abundant, and 4-oxo-13-cRA glucuronide was also detected at a higher level in patients. CYP3A4 was shown to play a major role in catalysing 13-cRA to 4-oxo-13-cRA. In human neuroblastoma cell lines, 4-oxo-13-cRA and 13-cRA were equi-effective at inducing neurite outgrowth, inhibiting proliferation, decreasing MYCN mRNA and protein, and increasing the expression of retinoic acid receptor-β mRNA and protein levels.. We showed that 4-oxo-13-cRA is as active as 13-cRA against neuroblastoma cell lines. Plasma levels of both 13-cRA and 4-oxo-13-cRA should be evaluated in pharmacokinetic studies of isotretinoin in neuroblastoma.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Central Nervous System Neoplasms; Chromatography, High Pressure Liquid; Cytochrome P-450 CYP3A; Humans; Isotretinoin; Mice, Inbred BALB C; Microsomes; N-Myc Proto-Oncogene Protein; Neurites; Neuroblastoma; Nuclear Proteins; Oncogene Proteins; Receptors, Retinoic Acid; RNA, Messenger; Tandem Mass Spectrometry; 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

Topics: Adult; Antineoplastic Agents; Central Nervous System; Central Nervous System Neoplasms; Humans; Leukemia, Promyelocytic, Acute; Male; Neoplasm Recurrence, Local; Tretinoin

Topics: Central Nervous System; Central Nervous System Neoplasms; Humans; Leukemia, Promyelocytic, Acute; Recurrence; Tretinoin

Central nervous system (CNS) involvement in acute promyelocytic leukemia (APL) is rare and tends to be seen mostly following treatment with all-trans retinoic acid (ATRA), due to prolonged patient survival and poor penetration of the drug in the CNS. At least 10% of extramedullary relapses in APL involve the CNS, and associated factors include an increased age, the BCR isoform, the development of differentiation syndrome, a high white cell count at presentation and hemorrhage into the CNS during induction therapy. We present the case of a patient with high-risk APL, CD56+, CD2+ in whom a CNS relapse was diagnosed through the presence of a PML/RARα rearrangement on PCR of the cerebrospinal fluid (CSF).

Topics: Adult; Antineoplastic Agents; CD56 Antigen; Central Nervous System Neoplasms; Fatal Outcome; fms-Like Tyrosine Kinase 3; Humans; Leukemia, Promyelocytic, Acute; Male; Neoplasm Recurrence, Local; Oncogene Proteins, Fusion; Polymerase Chain Reaction; Tretinoin

Central nervous system (CNS) involvement is rarely observed in acute promyelocytic leukemia (APML). Most cases of CNS involvement occur at relapse rather than at presentation. Because of the extremely low incidence of CNS disease, diagnostic lumbar puncture is not routinely required and prophylactic intrathecal chemotherapy is not routinely administered. Here, we describe a teenage patient with newly diagnosed APML, chloromas, and symptomatic CNS involvement confirmed by MRI and cerebrospinal fluid (CSF) findings.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Central Nervous System Neoplasms; Combined Modality Therapy; Cytarabine; Daunorubicin; Female; Humans; Leukemia, Promyelocytic, Acute; Leukemic Infiltration; Mercaptopurine; Methotrexate; Oncogene Proteins, Fusion; Radiotherapy; Sarcoma, Myeloid; Tretinoin

Glioblastoma, which is the most malignant brain tumor, remains incurable and almost always causes death. As a new treatment strategy, the combination of all-trans retinoic acid (ATRA) and paclitaxel was explored for controlling the growth of glioblastoma U87MG xenografts.. Human glioblastoma U87MG xenografts were developed in athymic nude mice for treatments with ATRA, paclitaxel, and ATRA plus paclitaxel. The efficacy of treatments in controlling tumor growth was assessed by histologic examination, Western blot analysis, and immunofluorescent labelings.. Astrocytic differentiation in U87MG xenografts was associated with increased GFAP expression and decreased telomerase expression. The combination of ATRA and paclitaxel was found to cause more apoptosis than paclitaxel alone. Apoptosis occurred with down-regulation of MEK-2 and overexpression of p-ERK, p-JNK, and p-p38 MAPK. Down-regulation of both Akt and p-Akt also favored the apoptotic process. Combination therapy activated the receptor-mediated pathway of apoptosis with induction of TNF-alpha, activation of caspase-8, and cleavage of Bid to tBid. Combination therapy also induced the mitochondria-mediated pathway of apoptosis with an increase in the Bax:Bcl-2 ratio and mitochondrial release of cytochrome c and Smac/Diablo into the cytosol. In addition, combination therapy promoted phosphorylation of Bcl-2 for its inactivation and down-regulated NF-kappaB and BIRC proteins, indicating suppression of several cell survival factors. Western blot analysis demonstrated that activation of cysteine proteases such as calpain, caspase-12, caspase-9, and caspase-3 contributed to apoptosis. Immunofluorescent labelings confirmed overexpression of cysteine proteases in apoptosis.. Treatment of U87MG xenografts with a combination of ATRA and paclitaxel induced differentiation and also multiple molecular mechanisms for apoptosis.

Topics: Animals; Antineoplastic Agents; Apoptosis; bcl-2-Associated X Protein; Cell Differentiation; Cell Line, Tumor; Central Nervous System Neoplasms; Cysteine Endopeptidases; Glial Fibrillary Acidic Protein; Glioblastoma; Humans; Inhibitor of Apoptosis Proteins; Mice; Mice, Nude; Mitogen-Activated Protein Kinase Kinases; NF-kappa B; Paclitaxel; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-bcl-2; Telomerase; Tretinoin; Ubiquitin-Protein Ligases; Xenograft Model Antitumor Assays

In this report, we present images from a patient with acute promyelocytic leukemia who experienced several central nervous system relapses.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Cell Nucleus; Central Nervous System Neoplasms; Female; Humans; Idarubicin; Leukemia, Promyelocytic, Acute; Oncogene Proteins, Fusion; Recurrence; Remission Induction; RNA, Neoplasm; Tretinoin

Central nervous system (CNS) involvement is rare in acute promyelocytic leukemia (APL). The majority of CNS relapses occur in patients with hyperleukocytosis at presentation, and the optimal management of such patients is still controversial. We describe a 13-year-old boy with APL who developed an isolated CNS relapse after first-line treatment with all-trans retinoic acid and chemotherapy. A second remission was achieved with a regimen consisting of intrathecal chemotherapy, intravenous high-dose cytarabine, and oral 6-mercaptopurine. All-trans retinoic acid was avoided owing to severe complications during initial therapy. The patient remains in molecular remission at 9 months after autologous stem cell transplant. Prognostic factors of CNS relapse in children with APL are needed to define the indications for CNS prophylaxis in this group of patients.

Topics: Adolescent; Central Nervous System Neoplasms; Humans; Leukemia, Promyelocytic, Acute; Male; Recurrence; Tretinoin

Extramedullary involvement in the absence of bone marrow disease is rare in patients with acute promyelocytic leukemia (APL). We report two patients with APL who had central nervous system (CNS) relapse without evidence of cytologic and molecular disease of bone marrow after all-trans-retinoic acid (ATRA) treatment. Both of the patients were treated successfully with combination of intrathecal chemotherapy and radiotherapy with or without systemic chemotherapy. Although increasing number of cases with extramedullary involvement of APL after ATRA including therapy have been reported, further studies with a large series of patients are necessary to determine whether ATRA increases the risk of development of extramedullary involvement of disease in patients with APL.

Topics: Adult; Central Nervous System Neoplasms; Humans; Leukemia, Promyelocytic, Acute; Male; Recurrence; Remission Induction; Treatment Outcome; Tretinoin

We describe a patient with an acute promyelocytic leukemia (APL) previously treated with two courses of cytarabin, idarubicin and all-trans retinoic acid (ATRA), who presented a medullary and meningeal relapse after 8 months of complete remission. A diagnosis of central nervous system (CNS) involvement was based on the appearance of APL blasts in the cerebrospinal fluid (CSF); magnetic resonance (MR) imaging was negative. The neurological symptoms were not evident at the time of recognition of the medullary recurrence, but appeared a few days later, when the patient had already received a reinduction treatment. When the CSF was first examined, showing atypical promyelocytes, there was no excess of blasts on bone-marrow examination. The patient was treated with ATRA and intrathecal administrations of cytoxic drugs, achieving a complete long-lasting CNS remission. The appearance of mature myeloid cells in the CSF during this treatment suggested a possible differentiating effect of ATRA towards extramedullary relapse.

Topics: Cell Differentiation; Central Nervous System Neoplasms; Cerebrospinal Fluid; Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Myeloid Cells; Recurrence; Tretinoin

We report a patient with acute promyelocytic leukemia (APL) involving the central nervous system. A 55-year-old male was admitted to our hospital with dysarthria and incomplete right hemiplegia. A CT scan of the brain revealed a low density area in the left cerebrum. APL was diagnosed by bone marrow aspiration and chromosomal analysis. The patient received all-trans retinoic acid (ATRA) in combination with chemotherapy. Complete hematological remission (CR) was obtained, and the patient's neurological symptoms improved. However, a cytospin smear of the cerebrospinal fluid after CR showed immature myelocytes ("intermediate cells") that had possibly been derived from leukemic promyelocytes. Comprehensive intrathecal treatment as well as cranial irradiation, caused a further reduction in dysarthria and a complete disappearance of hemiplegia with no atypical cells in the cerebrospinal fluid. The patient has undergone maintenance chemotherapy as an out-patient.

Topics: Brain Neoplasms; Cell Differentiation; Central Nervous System Neoplasms; Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Tretinoin

A 22-year-old woman with fever and bleeding tendency was given a diagnosis of acute promyelocytic leukemia (APL) on the basis of laboratory findings including a WBC count of 106 x 10(3)/microliter (90% blasts) and a platelet count of 1.6 x 10(4)/microliter. Induction therapy was started with all-trans retinoic acid (ATRA) and cytotoxic chemotherapy. After the patient achieved complete remission, ATRA was discontinued and consolidation chemotherapy was started. However, 4 months after onset, leukemic blasts were detected in cerebrospinal fluid. Temporal central nervous system remission was induced by intrathecal chemotherapy only. However, 2 months later, multiple focal mass lesions had developed in the brain. ATRA (45 mg/m2) was restarted together with multiple intrathecal injections of anticancer drugs, and a third remission was achieved. It is conceivable that the incorporation of ATRA in induction chemotherapy is related to the development of this rather rare complication of APL. The outcome in this case suggested orally administered ATRA may be effective in treating brain metastasis of APL.

Topics: Administration, Oral; Adult; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Central Nervous System Neoplasms; Cytarabine; Daunorubicin; Female; Humans; Injections, Spinal; Leukemia, Promyelocytic, Acute; Neoplasm Recurrence, Local; Remission Induction; Treatment Outcome; Tretinoin

Topics: Antineoplastic Agents; Central Nervous System Neoplasms; Female; Humans; Leukemia, Promyelocytic, Acute; Middle Aged; Recurrence; Remission Induction; Tretinoin

All-trans retinoic acid (ATRA) is currently recommended as standard treatment for acute promyelocytic leukaemia (APL). However, there has been increasing concern that ATRA is associated with unusual sites of relapse. We present three cases of APL previously treated with ATRA who ultimately relapsed within the central nervous system (CNS) and hypothesize that, by up-regulating intercellular adhesion molecules, ATRA may facilitate the passage of malignant promyelocytes across the blood-brain barrier.

Topics: Adult; Central Nervous System Neoplasms; Fatal Outcome; Female; Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Recurrence; Tretinoin