tretinoin and enocitabine

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

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

Due to advances in chemotherapy, differentiation therapy and bone marrow transplantation (BMT), adult acute myeloid leukemia (AML) has become a curable disease, and we are making further efforts to heighten the cure rate. The JALSG AML 89 study resulted in a 77% complete remission (CR) rate in 326 adults with AML, and a 38% 4.5-year disease-free survival (DFS) in CR cases. The JALSG AML92 study for APL with all-trans retinoic acid resulted in a 89% CR rate in 196 and 64% 4-year DFS in CR cases.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Cytarabine; Daunorubicin; Drug Resistance, Neoplasm; Humans; Infusions, Intravenous; Leukemia, Myeloid, Acute; Mercaptopurine; Middle Aged; Prednisolone; Tretinoin

We report herein the clinical results of a multicenter trial of the Japan Adult Leukemia Study Group for cases of newly diagnosed acute promyelocytic leukemia (APL) treated with all-trans retinoic acid and chemotherapy (JALSG AML-92 study). Of 196 evaluable patients, 173 (88%) achieved complete remission (CR). Multivariate analysis showed that no or minor purpura at diagnosis and age less than 30 years were favorable factors for achievement of CR. There was a significant difference in the 4-year event-free survival between the AML-92 study (54%) and both the AML-87 (32%) and AML-89 (32%) studies which consisted of intensive chemotherapy. Since prognosis in patients with APL largely depends on chemotherapy, it is important to consider more effective chemotherapy during induction and consolidation therapy.

Topics: Aclarubicin; Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Disease-Free Survival; Drug Administration Schedule; Female; Humans; Leukemia, Promyelocytic, Acute; Male; Mercaptopurine; Middle Aged; Mitoxantrone; Prognosis; Receptors, Retinoic Acid; Remission Induction; Retinoic Acid Receptor alpha; Tretinoin

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

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

An intermittent and cyclic regimen with All-Trans Retinoic Acid (ATRA) and intensive chemotherapy was conducted due to pharmacokinetic studies on ATRA for acute promyelocytic leukemia (APL) in children. We have treated 17 children with APL using ATRA for remission induction followed by an intermittent schedule of ATRA plus intensive chemotherapy (APL-ATRA protocol). There were 10 males and 7 females. The median age was 9.0 years old. The median baseline white blood cell count was 12.1 x 10(3)/microliter, hemoglobin 7.8 g/dl, platelet 4.5 x 10(4) microliters at diagnosis. Sixteen patients showed t(15; 17) translocation. RT-PCR analysis was available in 15 patients and showed PML/RAR alpha rearrangement in all patients. Overall, 13 or 17 newly diagnosed patients (88%) achieved complete remission and EFS was 67%. Compared to the control (same chemotherapy without ATRA regimen), remission induction and EFS were significantly increased. The toxicity of ATRA consisted of retinoic acid syndrome in 1 and pseudotumor cerebli in another. Other toxicities included headache, chelitis, gastrointestinal trouble and bone pain. These results suggest that intermittent and cyclic regimen with ATRA and intensive chemotherapy (APL-ATRA protocol) is highly effective for APL patients.

Topics: Aclarubicin; Administration, Oral; Adolescent; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Child; Cyclophosphamide; Cytarabine; Daunorubicin; Doxorubicin; Drug Administration Schedule; Female; Humans; Leukemia, Promyelocytic, Acute; Male; Mercaptopurine; Prednisolone; Tretinoin; Vincristine

We conducted a multicenter trial of treatment with all-trans retinoic acid (ATRA) for newly diagnosed acute promyelocytic leukemia (APL) in the AML-92 study and compared it with our previous study with standard intensive chemotherapy, the AML-89 study, in the view of complete remission (CR) rate, incidence of early death, and event-free survival (EFS). Patients were scheduled to receive oral ATRA 45 mg/m2 daily until CR. If patients had leukocyte counts above 3 x 10(9)/L at the start of therapy, they received daunorubicine (DNR) 40 mg/m2 for 3 days and behenoyl cytosine arabinoside (BHAC) 200 mg/m2 for 5 days in addition to ATRA. During the ATRA therapy, if patients showed myeloblast plus promyelocyte counts higher than 1 x 10(9)/L in the peripheral blood, they received additional DNR and BHAC in the same schedule, as well. A total of 110 patients were entered into the study. Median age was 43 years (range, 16 to 74). Twenty-eight (26%) of 109 patients (one died before the start of therapy) received ATRA alone. Ninety-seven patients (89%) achieved CR; 48 of 49 (98%) aged less than 40 years, 44 of 52 (84%) aged between 40 and 69, and 5 of 8 (63%) aged above 70 achieved CR, respectively; 25 of 28 (89%) with ATRA alone, 46 of 51 (90%) with ATRA plus initial chemotherapy and 26 of 30 (87%) with ATRA plus later chemotherapy attained CR, respectively. Nine (8%) patients died within 28 days after the start of therapy. In contrast, 44 of 62 patients (71%) attained CR, and 13 (21%) died within 28 days in the AML-89 study with the combination of DNR, BHAC, 6-mercaptopurine and prednisolone. Seven developed retinoic acid syndrome and one died of it in the present study. Other toxicities associated with this drug included cheilitis, desquamation, muscle pain, and hypertriglyceridemia. Predicted 23 months EFS for all ATRA-treated patients and disease-free survival (DFS) in the CR cases were 75% and 81%, respectively, in a median follow-up period of 21 months. Compared to the AML-89 study, there was a highly significant difference in remission rate (P = .004), EFS (P = .0007), and also early mortality rate (P = .02). Present results demonstrated that ATRA with or without chemotherapy gives a statistical improvement in CR rate and early mortality rate, as well as superior survival in newly diagnosed APL.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Cytarabine; Daunorubicin; Female; Humans; Immunologic Factors; Japan; Leukemia, Promyelocytic, Acute; Leukocytosis; Life Tables; Male; Mercaptopurine; Middle Aged; Prednisolone; Prospective Studies; Remission Induction; Syndrome; Treatment Outcome; Tretinoin

We describe a case of Adams-Stokes syncope due to complete atrioventricular block which occurred in a leukemic patient receiving all-trans retinoic acid (ATRA). Remission induction therapy was performed for a 46-year-old Japanese man with acute promyelocytic leukemia using ATRA (45 mg/m2), enocitabine (170 mg/m2, 5 days), and mitoxantrone (4 mg/m2, 3 days). On the 25th day of chemotherapy, syncope suddenly occurred. Electrocardiography revealed a complete atrioventricular block, and a temporary pacemaker was inserted on the following day. The block was persistent and the cardiac rhythm was dependent on the pacemaker. ATRA was discontinued on the 29th day because the arrhythmia was believed to be an adverse reaction to the ATRA regimen. The normal sinus rhythm was restored 15 days thereafter, and the patient eventually reached remission. He subsequently received 4 courses of consolidation therapy without any cardiovascular complications. Although ATRA sometimes induces arrhythmias, to the best of our knowledge this is the first report in the literature of such a critical ATRA-related arrhythmia.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Drug Administration Schedule; Heart Block; Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Mitoxantrone; Pacemaker, Artificial; Remission Induction; Tretinoin

We describe a patient with acute promyelocytic leukemia (APL) who developed pulmonary embolism (PE) and thrombotic thrombocytopenic purpura (TTP) during remission induction all-trans retinoic acid (ATRA) therapy. A 44-year-old man was diagnosed with APL and was treated with ATRA. On day 14, he developed PE, and on day 24, he developed TTP. Both PE and TTP occurred in association with leukocytosis due to ATRA administration. The PE responded to dexamethasone and TTP responded to plasma infusion. The PE and TTP remitted, and he achieved complete remission of APL. To our knowledge, there have been no reports of TTP occurring as a complication of ATRA therapy.

Topics: Adult; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Humans; Leukemia, Promyelocytic, Acute; Leukocytosis; Male; Pulmonary Embolism; Purpura, Thrombotic Thrombocytopenic; Remission Induction; Tretinoin

De novo acute myeloid leukemia (AML) with dysplastic features in erythroblasts, granulocytes and megakaryocytes, similar to those in myelodysplastic syndrome (MDS) has been described as AML with trilineage dysplasia (AML-TLD) since 1987. Several reports have suggested that AML-TLD is a subtype of de novo AML in adults and has a poor clinical outcome when treated by conventional chemotherapy. It is not certain whether allogeneic bone marrow transplantation (BMT) brings a favorable outcome for AML-TLD. To evaluate the therapeutic efficacy of allogeneic BMT for AML-TLD, we investigated the clinical data and outcomes of conventional chemotherapy and allogeneic BMT for 118 patients with de novo AML. These patients were registered consecutively for the Japan Adult Leukemia Study Group (JALSG) protocols at our institutes. We treated 28 AML-TLD patients and 90 AML-nonTLD patients with conventional chemotherapeutic protocols. AML-TLD patients did not have a significantly different complete remission (CR) rate (75.0% and 88.4% P = 0.1234), but had a significantly higher relapse rate than AML-nonTLD patients (94.1% and 49.3%, P= 0.0007). The outcome of chemotherapy for AML-TLD was significantly worse than that for AML-nonTLD. The overall survival (OS) and leukemia-free survival (LFS) at 6 years were 9.4% and 0% in AML-TLD group, and 51.9% (P= 0.0017) and 46.3% (P< 0.0001) in AML-nonTLD group, respectively. Meanwhile, among the patients who underwent allogeneic BMT, five of eight AML-TLD patients and eight of 14 AML-nonTLD patients were alive, and three and five patients survived more than 3 years, respectively. These results suggest that allogeneic BMT can improve the outcome for AML-TLD, which is poor when conventional chemotherapy is given alone. Allogeneic BMT before relapse may be the best therapeutic strategy for AML-TLD patients under 50 years of age if a donor is available.

Topics: Adolescent; Adult; Age Factors; Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Cell Lineage; Combined Modality Therapy; Cytarabine; Daunorubicin; Disease-Free Survival; Female; Humans; Japan; Leukemia, Myeloid; Life Tables; Male; Middle Aged; Neoplastic Stem Cells; Remission Induction; Retrospective Studies; Survival Analysis; Transplantation Conditioning; Transplantation, Homologous; Treatment Outcome; 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

A 54-year-old female was admitted to our hospital for gingival bleeding and was diagnosed as acute promyelocytic leukemia (APL). She received induction therapy according to the AML92 protocol of the Japan Adult Leukemia Study Group (JALSG) with all-trans retinoic acid (ATRA) plus chemotherapeutic agents. She achieved complete remission, but one year later had a relapse in her external auditory canal without leukemic cell in the bone marrow. Extramedullary disease is rare in APL. This case suggests the importance of careful observation for extramedullary relapse in patients who are treated with ATRA.

Topics: Agranulocytosis; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Combined Modality Therapy; Cytarabine; Daunorubicin; Ear Canal; Female; Granulocyte Colony-Stimulating Factor; Humans; Idarubicin; Leukemia, Promyelocytic, Acute; Mercaptopurine; Middle Aged; Mitoxantrone; Neoplasm Proteins; Oncogene Proteins, Fusion; Radiotherapy; Recurrence; Remission Induction; Salvage Therapy; Tretinoin; Vindesine

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

A 27-year-old woman visited Kanto Teishin Hospital complaining of fever and petechiae in September, 1992. Her fetus had suddenly died in the uterus two weeks before (in the sixth month of pregnancy). Total white blood cell (WBC) count was 3.2 x 10(3)/microliters with 80% promyelocytes. Bone marrow was hypercellular with 90% promyelocytes. Disseminated intravascular coagulation (DIC) was recognized. She was diagnosed as having acute promyelocytic leukemia (APL), and treatment with daily oral administration of all-trans retinoic acid (ATRA) (70 mg/body/day) was begun. On day 4, hemiplegia and aphasia appeared. Broad cerebral infarction was suspected from computed tomography. On day 9, the WBC count increased rapidly, standard chemotherapy was added and she achieved complete remission. ATRA is known to have stimulatory effects on the differentiation of APL cells, but some reports have described thromboembolic events during the administration of ATRA. In this case, ATRA might have affected coagulability resulting in cerebral infarction.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Cerebral Infarction; Cytarabine; Daunorubicin; Female; Humans; Leukemia, Promyelocytic, Acute; Tretinoin