mercaptopurine and Leukemia--Promyelocytic--Acute

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

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

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

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

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

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

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

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

Ph1-positive chronic myelocytic leukemia (CML) developing in a treated case of acute promyelocytic leukemia (APL) is reported. The patient was a 62-year-old male who was diagnosed as having APL in December 1978. He was treated with daunorubicin, Ara-C and 6MP and a complete remission was obtained 4 months later. But APL recurred in February 1981. He was treated with BHAC, aclarubicin, 6MP and prednisolone. He remained in continuous complete remission for 5 years, when all therapy was discontinued. After then, the leukocytes count continued to rise and a diagnosis of Ph1-positive CML was made in September 1986. His leukocytes count has been well controlled with the use of busulfan. The event in this case suggests a possibility of the Ph1-positive CML being a secondary disease related to prior long term chemotherapy.

Topics: Aclarubicin; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Promyelocytic, Acute; Male; Mercaptopurine; Methotrexate; Middle Aged; Prednisolone; Remission Induction

Purpose The Children's Oncology Group AAML0631 trial for newly diagnosed pediatric acute promyelocytic leukemia (APL) was a phase III historically controlled trial to determine the survival of patients receiving arsenic trioxide (ATO) consolidation and reduced doses of anthracyclines. Patients and Methods Patients age 2 to 21 years with de novo APL confirmed by PML-RARα polymerase chain reaction were stratified as standard risk (SR) or high risk (HR) on the basis of diagnostic WBC count. All patients received all-trans retinoic acid (ATRA) during induction, each consolidation course, and maintenance. All patients received two cycles of ATO therapy during consolidation 1, an additional two (SR) or three (HR) consolidation courses that included high-dose cytarabine and anthracycline, and maintenance therapy comprising ATRA, oral methotrexate, and mercaptopurine. Results One hundred one patients (66 SR and 35 HR) were evaluable for outcome. The 3-year overall survival was 94%, and event-free survival (EFS) was 91%. For SR and HR patients with APL, the overall survival was 98% versus 86% ( P = .003), and EFS was 95% versus 83% ( P = .03), respectively. The EFS for SR patients in AAML0631 was noninferior to that of patients in the AIDA 0493 historical control, which used a significantly higher anthracycline dose and did not include ATO consolidation. Relapse risk for patients in AAML0631 from end consolidation 1 (after ATO treatment) was only 4% at 3 years and did not differ significantly between SR and HR patients. Conclusion ATO consolidation cycles were well tolerated in pediatric patients with APL and allowed significant reduction in cumulative anthracycline doses while maintaining excellent survival and a low relapse risk for both SR and HR patients with APL.

Topics: Adolescent; Adult; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Child; Child, Preschool; Consolidation Chemotherapy; Cytarabine; Disease-Free Survival; Female; Historically Controlled Study; Humans; Leukemia, Promyelocytic, Acute; Male; Mercaptopurine; Methotrexate; Oxides; Young Adult

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

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

Initial therapy for patients with acute promyelocytic leukemia most often involves the combination of all-trans-retinoic acid with anthracycline-based chemotherapy. The role of non-anthracycline drugs in induction and consolidation is less well-established and varies widely between different cooperative group protocols.. In an attempt to minimize relapse and maximize survival for patients with newly diagnosed acute promyelocytic leukemia, the Australasian Leukaemia and Lymphoma Group utilized all-trans-retinoic acid and idarubicin as anti-leukemic therapy for both induction and consolidation. The protocol (known as APML3) was subsequently amended to incorporate maintenance with all-trans-retinoic acid, methotrexate and 6-mercaptopurine.. Eight (8%) of 101 patients died within 30 days, and 91 (90%) achieved complete remission. With a median estimated potential follow-up of 4.6 years, 4-year overall survival was 84%, and 71% of the patients remained in remission at 4 years. The cumulative incidence of all relapses was 28.1%, with 15 of the 25 relapses initially identified as an isolated molecular relapse. Both FLT3 mutations (internal tandem duplications and codon 835/836 kinase domain mutations) and increased white cell count at diagnosis were associated with inferior overall survival, but in multivariate analyses only FLT3 mutations remained significant (hazard ratio 6.647, P=0.005). Maintenance therapy was significantly associated with improved remission duration (hazard ratio 0.281, P<0.001) and disease-free survival (hazard ratio 0.290, P<0.001).. The combination of all-trans-retinoic acid and just two cycles of idarubicin followed by triple maintenance produced durable remissions in most patients, but patients with high-risk disease, especially those with FLT3 mutations, require additional agents or alternative treatment approaches. The significant reduction in relapse seen after the addition of maintenance to the protocol supports a role for maintenance in the context of relatively low chemotherapy exposure during consolidation. (actr.org.au identifier: ACTRN12607000410459).

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Consolidation Chemotherapy; Female; Follow-Up Studies; Humans; Idarubicin; Induction Chemotherapy; Leukemia, Promyelocytic, Acute; Male; Mercaptopurine; Middle Aged; Survival Rate; Tretinoin; Young Adult

To compare the difference in the long-term efficacy between all-trans retinoic acid (ATRA) combined Compound Huangdai Tablet and ATRA combined methotrexate (MTX) and 6-mercaptopurine (6MP) as the sequential maintenance treatment of acute promyelocytic leukemia (APL) patients.. Totally 83 APL patients in the molecular remission (PML/RARalpha negative) were randomly assigned to two groups, the treatment group (45 cases) and the control group (38 cases) after they were induced to the complete remission (CR) by ATRA combined chemotherapy, and treated by sequential chemotherapy as the consolidated treatment for 3 therapeutic courses. Those in the treatment group were sequentially treated with ATRA and Compound Huangdai Tablet as maintenance therapy, while those in the control group were treated with ATRA and MTX + 6MP as maintenance therapy. After a long-term follow-up (2003 -2011), the long-term therapeutic efficacy and adverse reactions were compared between the two therapeutic regimens.. The 5-year relapse-free survival (RFS) rate was 84.4% +/- 5.4% in the treatment group and 63.2% +/- 7.8% in the control group, showing statistical difference between the two groups (P < 0.05). The 5-year overall survival rate (OSR) was 86.7% +/- 5. 1% in the treatment group and 78.7% +/- 6.7% in the control group, showing no statistical difference between the two groups (P > 0.05). There was no statistical difference in the adverse reaction between the two groups (P > 0.05).. The application of ATRA and Compound Huangdai Tablet as maintenance therapy could elevate the long-term RFS rate of APL patients.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Drugs, Chinese Herbal; Female; Humans; Leukemia, Promyelocytic, Acute; Male; Mercaptopurine; Methotrexate; Middle Aged; Phytotherapy; Treatment Outcome; Tretinoin; Young Adult

Arsenic trioxide (As(2)O(3)) is a highly effective treatment for patients with relapsed acute promyelocytic leukemia (APL); its role as consolidation treatment for patients in first remission has not been defined. We randomized 481 patients (age ≥ 15 years) with untreated APL to either a standard induction regimen of tretinoin, cytarabine, and daunorubicin, followed by 2 courses of consolidation therapy with tretinoin plus daunorubicin, or to the same induction and consolidation regimen plus two 25-day courses of As(2)O(3) consolidation immediately after induction. After consolidation, patients were randomly assigned to one year of maintenance therapy with either tretinoin alone or in combination with methotrexate and mercaptopurine. Ninety percent of patients on each arm achieved remission and were eligible to receive their assigned consolidation therapy. Event-free survival, the primary end point, was significantly better for patients assigned to receive As(2)O(3) consolidation, 80% compared with 63% at 3 years (stratified log-rank test, P < .0001). Survival, a secondary end point, was better in the As(2)O(3) arm, 86% compared with 81% at 3 years (P = .059). Disease-free survival, a secondary end point, was significantly better in the As(2)O(3) arm, 90% compared with 70% at 3 years (P < .0001). The addition of As(2)O(3) consolidation to standard induction and consolidation therapy significantly improves event-free and disease-free survival in adults with newly diagnosed APL. This trial was registered at clinicaltrials.gov (NCT00003934).

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Cytarabine; Daunorubicin; Disease-Free Survival; Female; Humans; Leukemia, Promyelocytic, Acute; Male; Mercaptopurine; Methotrexate; Middle Aged; North America; Oxides; Survival Analysis; Treatment Outcome; Tretinoin; Young Adult

Seventy adults with acute promyelocytic leukemia were studied to clarify the significance of the level and kinetics of minimal residual disease (MRD) over their entire treatment course by realtime quantitative polymerase chain reaction. At a median follow-up of 44 months, nine relapses had occurred. The 5-year probabilities of relapse and disease-free survival were 17.3+/-5.4% and 81.5+/-5.4%, respectively. A MRD level of >10-3 after first consolidation was the most powerful predictor of relapse (85.7+/-13.2% versus 7.3+/-4.1%, p<0.001) and disease-free survival (14.3+/-13.2% versus 91.2%+/-4.3%, p<0.001). Prospective MRD monitoring may allow us to identify subgroups of patients at high risk of relapse earlier during treatment.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Disease Progression; Disease-Free Survival; Female; Humans; Idarubicin; Kinetics; Leukemia, Promyelocytic, Acute; Life Tables; Male; Mercaptopurine; Methotrexate; Middle Aged; Mitoxantrone; Neoplasm Proteins; Neoplasm, Residual; Oncogene Proteins, Fusion; Prognosis; Proportional Hazards Models; Prospective Studies; Remission Induction; Survival Analysis; Tretinoin

Shortly before the all-trans retinoic acid (ATRA) era, the GIMEMA cooperative group initiated a randomized study comparing idarubicin (IDA) alone with IDA plus arabinosylcytosine (Ara-C) as induction treatment in patients with newly diagnosed hypergranular acute promyelocytic leukemia (APL). Of the 257 patients evaluable for induction treatment, 131 were randomized to receive IDA alone (arm A) and 126 to receive IDA + Ara-C (arm B). Treatment in arm A consisted of 10 mg/m(2) IDA daily for 6 consecutive days, whereas in arm B it consisted of 12 mg/m(2) IDA daily for 4 days combined with 200 mg/m(2) Ara-C daily in continuous infusion for 7 days. Once in complete remission (CR), patients received 3 consolidation courses of standard chemotherapy, and those still in CR at the end of the consolidation were randomized to receive or not receive 1 mg/kg 6-mercaptopurine daily and intramuscular injections of 0.25 mg/kg methotrexate weekly for 2 years. Overall, 100 (76.3%) patients in arm A and 84 (66.6%) patients in arm B achieved CR (P = NS). Event-free survival (EFS) rates were 35% and 23% for patients in arm A and arm B, respectively (P =.0352). Multivariate analysis revealed that EFS was favorably influenced by induction treatment with IDA alone (P =.0352) and unfavorably influenced by white blood cell (WBC) counts greater than 3000/microL (P =.0001) and increasing age (P =.0251). These results indicate that anthracycline monochemotherapy with IDA favorably influences the EFS of patients with newly diagnosed hypergranular APL.

Topics: Adolescent; Adult; Age Factors; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Chemical and Drug Induced Liver Injury; Child; Cytarabine; Disease-Free Survival; Female; Follow-Up Studies; Hemorrhage; Humans; Idarubicin; Infections; Leukemia, Promyelocytic, Acute; Leukocyte Count; Male; Mercaptopurine; Methotrexate; Middle Aged; Remission Induction; Treatment Outcome; Vomiting

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

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

Early hemorrhagic death (within the first 10 d of treatment [EHD]) is reported as the main cause of death during induction therapy for acute promyelocytic leukemia (APL). In order to evaluate possible differences in the incidence of EHD during induction regimens based on all-trans retinoic acid (ATRA), we retrospectively analyzed a consecutive series of 86 APL patients, diagnosed and treated at our Institution from 1982. Forty-three patients received combination chemotherapy with anthracyclines and cytosine arabinoside (January 1982 to December 1991), while induction of the remaining 43 was based on ATRA alone or on a combination of ATRA and anthracyclines (January 1992 to October 1996). There were significantly less induction deaths in the ATRA group [9 (chemotherapy group-CT) vs. 2 (ATRA group-RA) overall and 8(CT) vs. 1(RA) of EHD; p = 0.01]. Hemostatic evaluations showed an earlier reduction of D-dimer in the ATRA group. No cases of morphological resistance were observed in the ATRA group after induction. In addition, the number of relapses occurring in the first 24 months from the achievement of complete remission (CR) was significantly lower in the ATRA group (15 vs. 7; p = 0.01), with a disease free survival at 2 yr of 67% vs. 31%. In conclusion, ATRA appears to be able to significantly reduce the incidence of EHD, increasing the number of possible long-term remissions.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Cytarabine; Daunorubicin; Hemorrhage; Humans; Leukemia, Promyelocytic, Acute; Mercaptopurine; Methotrexate; Remission Induction; Retrospective Studies; Tretinoin

All transretinoic acid (ATRA) followed by daunorubicin (DNR)-AraC chemotherapy (CT) has improved the outcome of acute promyelocytic leukemia (APL) by comparison to CT alone. In a randomized trial, (1) we compared 2 induction schedules (ATRA followed by CT [ATRA-->CT] and ATRA plus CT [ATRA+CT, with CT added on day 3 of ATRA treatment]) and (2) we assessed the role of maintenance treatment. Four hundred thirteen patients CT and ATRA+CT (initially randomized patients); patients with a WBC count greater than (high WBC count group, n = 163) and patients 66 to 75 years of age with a WBC count greater than 5,000/microL (elderly group, n = 42) were not initially randomized and received ATRA+CT from day 1 and ATRA -->CT, respectively. All patients achieving CR received 2 additional DNR-AraC courses (only 1 in patients 66 to 75 years of age) and were then randomized for maintenance between no treatment, intermittent ATRA (15 days every 3 months) for 2 years, continuous low-dose CT (6 mercaptopurine + methotrexate) for 2 years, or both, using a 2-by-2 factorial design. Overall, 381 (92%) of the patients achieved complete remission (CR), 31 (7%) suffered an early death, and only 1 patient had leukemic resistance. ATRA syndrome occurred in 64 patients (15%) and was fatal in 5 cases. The CR rate was similar in all induction treatment groups. Event-free survival (EFS) was significantly lower in the high WBC group (P =.0002) and close to significance in the elderly group (P =.086) as compared with initially randomized patients. Relapse at 2 years was estimated at 6% in the ATRA+CT group, versus 16% in the ATRA-->CT group (P =.04, relative risk [RR] =.41). EFS at 2 years was estimated at 84% in the ATRA+CT group, versus 77% in the ATRA-->CT group (P =.1, RR =.62). Two hundred eighty-nine patients were randomized for maintenance. The 2-year relapse rate was 11% in patients randomized to continuous maintenance CT and 27% in patients randomized to no CT (P =.0002) and 13% in patients randomized to intermittent ATRA and 25% in patients randomized to no ATRA (P =.02). An additive effect of continuous maintenance CT and intermittent ATRA was seen, and only 6 of the 74 patients who received both maintenance treatments had rel

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Drug Administration Schedule; Female; Humans; Infant; Leukemia, Promyelocytic, Acute; Male; Mercaptopurine; Methotrexate; Middle Aged; Remission Induction; Treatment Outcome; Tretinoin

To determine the effect of omission of cytarabine (ara-C) from treatment of newly diagnosed acute promyelocytic leukemia (APL), which allows administration of more anthracycline.. Induction consisted of all-trans retinoic acid (ATRA) 45 mg/m2 daily until complete remission (CR) and idarubicin 12 mg/m2 daily for 4 days beginning on day 5 of ATRA. Patients in CR received two courses of idarubicin 12 mg/m2 daily for 3 days and then, until 2 years post-CR date, alternated three cycles of mercaptopurine, vincristine, methotrexate, and prednisone (POMP) with one cycle of idarubicin 12 mg/m2 daily for 2 days. Results in the 43 patients treated (41 with t(15;17) on standard or Southern analysis) were compared with those in 57 historic newly diagnosed APL patients given ara-C with either doxorubicin, amsacrine (AMSA), or daunorubicin without ATRA, using logistic and Cox regression to assess effects of non-treatment-related covariates on patient outcomes.. The CR rate in the current group was 77% (95% confidence interval [CI], 62% to 88%) and was not significantly different from the historic rate. In contrast, disease-free survival (DFS) in CR is superior in the current group (probability at 1 year 0.87; 95% CI, 0.73 to 1.0). This has translated into superior overall DFS for the current group (P = .03 adjusting for the predictive covariates initial WBC and platelet count; 1-year DFS probability 0.67; 95% CI, 0.52 to 0.82; median follow-up 102 weeks). The current treatment appears better both in patients with and without t(15; 17) on standard cytogenetic analysis.. Given the difficulties inherent in comparing sequential studies and recognizing the multiple differences in treatment between current and historic groups, our results suggest that a large randomized trial incorporating use of ATRA should assess the utility of omitting ara-C from treatment of newly diagnosed APL, thus allowing delivery of more anthracycline.

Topics: Adolescent; Adult; Aged; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Female; Humans; Idarubicin; Leukemia, Promyelocytic, Acute; Logistic Models; Male; Mercaptopurine; Methotrexate; Middle Aged; Prednisone; Proportional Hazards Models; Remission Induction; Treatment Outcome; Tretinoin; Vincristine

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

The overall cure rate of adults with newly-diagnosed acute myelogenous leukemia (AML) treated with continuous infusion high-dose cytarabine (CIHDAC) is comparable to that with standard-dose ara-C plus anthracycline or amsacrine (AMSA). We tested whether the addition of AMSA to CIH-DAC improves the outcome of adults with untreated AML. 75 patients with untreated AML were treated with AMSA (75 mg/m2/day x 4) plus CIHDAC (1.5 g/m2/day x 4) for induction and, if in complete remission (CR), early and late intensification. Results were compared to those in 129 patients treated on a previous study with CIHDAC alone. The principal comparison in both groups was between those 117 patients (AMSA/CIHDAC n = 52, CIHDAC n = 65) who met the initial eligibility criteria for the AMSA/CIHDAC study (risk of early mortality < or = 1) and who were treated at a time when relatively few eligible patients were excluded (19% in the AMSA/CIHDAC group, 34% in the CIHDAC group). There was no difference between regimens in CR rate, remission duration, or survival in this cohort. When attention was turned to all 204 patients, outcome was superior with AMSA/CIHDAC very largely as a result of outcome in patients with APL. Aside from these patients, addition of amsacrine to CIHDAC did not appear to be productive.

Topics: Acute Disease; Adolescent; Adult; Age Factors; Aged; Aged, 80 and over; Amsacrine; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Female; Humans; Leukemia, Myeloid; Leukemia, Promyelocytic, Acute; Life Tables; Male; Mercaptopurine; Methotrexate; Middle Aged; Prednisone; Remission Induction; Survival Analysis; Treatment Outcome; 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

Initial results of ATRA in newly diagnosed APL showed that this drug was associated with a high complete remission (CR) rate but also (i) to a risk of hyperleukocytosis and of ATRA syndrome, (ii) to rapid relapse unless ATRA was followed by intensive chemotherapy. These findings prompted our group to design an approach combining ATRA and intensive chemotherapy in newly diagnosed APL, where chemotherapy could prevent relapses and also, in cases with increasing leukocyte counts, could prevent the ATRA syndrome. In a pilot study, this approach gave a high CR rate (96%) and (with now prolonged follow-up) a significant reduction in the incidence of relapse, as compared to a historical control treated with chemotherapy alone. The superiority of the combination of ATRA and chemotherapy over chemotherapy alone (especially for the incidence of relapse) was subsequently confirmed in a randomized European trial (APL 91 trial). We are now testing in a new European trial (APL 93 trial) whether chemotherapy should be administered with ATRA, or should follow ATRA during induction treatment, and whether maintenance therapy with intermittent ATRA, low-dose chemotherapy, or both can further reduce the risk of relapse.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Disease-Free Survival; Drug Administration Schedule; Europe; Humans; Leukemia, Promyelocytic, Acute; Leukocyte Count; Mercaptopurine; Methotrexate; Recurrence; Remission Induction; Treatment Outcome; Tretinoin

A large number of acute promyelocytic leukemia (APL) patients, treated with all-trans retinoic acid (ATRA) and chemotherapy, were studied. The results of the studies are as follows: (1) Among 65 patients investigated for the postremissional therapy, the 5-year survival probabilities were 0.20 +/- 0.13 (mean +/- SE) in the group treated with ATRA alone, 0.47 + 0.10 (mean +/- SE) in the group using chemotherapy alone and 0.42 +/- 0.09 (mean +/- SE) in the group treated with chemotherapy and ATRA. (2) The main severe adverse effects in the ATRA treatment include retinoic acid syndrome, renal failure, and thrombosis. These sequelae were observed more frequently in cases with persistent, marked elevation of white blood cell count without significant maturation of leukemic promyelocytes. (3) APL is not a homogeneous disease in that among 50 patients studied at the molecular level, although a PML-RARA fusion gene was detected in 45 cases, one had a variant translocation t(11;17) bearing fusion gene PLZF-RARA, one presented no obvious structural alteration of the PML gene while the RARA gene was rearranged, and three patients had no rearrangement of either PML or RARA genes. (4) Using RT/PCR to detect minimal residual disease, we found positive rates of 22%, 18.4%, and 11.5%, respectively, 12, 24, and 36 months after CR. This observation justifies the use of chemotherapy for at least 3 years after CR induced by ATRA. (5) It seems likely that the fusion gene PML-RARA plays an important role in APL leukemogenesis and in its response to the ATRA treatment.

Topics: Actuarial Analysis; Antineoplastic Combined Chemotherapy Protocols; Humans; Leukemia, Promyelocytic, Acute; Mercaptopurine; Methotrexate; Survival Analysis; Tretinoin

We entered 26 patients with newly diagnosed acute promyelocytic leukemia (APL) in a pilot study of all-transretinoic acid (ATRA) followed by intensive chemotherapy. Median age was 46 (range 25 to 63). No patient presented with leukocytes > 10 x 10(9)/L or had the microgranular APL variant. Cytogenetic analysis (25 patients) found a t(15;17) in 24 cases. Patients were scheduled to receive ATRA (45 mg/m2/d) until complete remission, followed by an intensive daunorubicin (DNR) + Ara C course ("4 + 7" course), then three "2 + 5" DNR + Ara C courses and maintenance chemotheapy. However, the "4 + 7" course was administered in emergency if hyperleukocytosis rapidly developed to prevent leukostasis. Twenty-five patients (96%) achieved CR, 14 with ATRA alone and 11 after the addition of the "4 + 7" course on day 2 to 30 of treatment, because leukocytes rapidly increased (9 cases), because of resistance to ATRA (1 case), and development of organomegaly (1 case). The remaining patient died on day 6, from CNS bleeding. Apart from hyperleukocytosis, side effects were usually moderate. In the 11 patients who could be studied in vitro, a very good correlation was found between in vivo and vitro differentiation and proliferation of APL blasts with ATRA. Three patients were allografted after the "4 + 7" course. Four patients did not receive this course but received the subsequent "2 + 5" courses and maintenance. The remaining patients followed the scheduled protocol. Three patients relapsed after 8, 11, and 15 months (including one allografted patient). Two patients died in CR, after 6 and 17 months. The other 20 patients remained in CR after 18+ to 34+ months (median 21). Actuarial disease free interval (DFI) and event free survival (EFS) were 87% and 77%, respectively, after 18 months. These results were compared to those obtained in our previous APL 84 trial with chemotherapy alone in newly diagnosed APL (after excluding patients included in this trial who presented with hyperleukocytosis). In APL 84 trial, the CR rate was 76%, the actuarial DFI and EFS were 59% and 48% after 18 months, respectively. Differences with the pilot study of ATRA followed by chemotherapy were significant for DFI (P = .02), EFS (P = .006), but not for CR rate (P = .08). Although this is a historical comparison, these results suggest that ATRA followed by chemotherapy may prove superior to chemotherapy alone in newly diagnosed APL, by slightly increasing the CR rate, but perhaps more important

Topics: Actuarial Analysis; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Cytarabine; Daunorubicin; Female; Follow-Up Studies; Humans; Leukemia, Promyelocytic, Acute; Male; Mercaptopurine; Methotrexate; Middle Aged; Mitoguazone; Pilot Projects; Time Factors; Treatment Outcome; Tretinoin

We report a rare case of hypercalcemia and acute pancreatitis in a subject with acute promyelocytic leukemia (APL) and pulmonary tuberculosis, during all-trans-retinoic acid (ATRA) treatment. Both associated complications were potentially due to several causes. A careful monitoring and exclusion of all causative factors must be addressed. Further research is necessary to improve our understanding of risk factors for these complications in patients with (APL). Studying these patterns may help us to improve outcomes for all children and young adults with hematologic malignancies.

Topics: Acute Disease; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Causality; Febrile Neutropenia; Humans; Hypercalcemia; Leukemia, Promyelocytic, Acute; Male; Mercaptopurine; Methotrexate; Middle Aged; Models, Biological; Pancreatitis; Pleural Effusion; Prednisone; Pulmonary Aspergillosis; Risk Factors; Tretinoin; Tuberculosis, Pulmonary; Vincristine

Individuals who are exposed to cytotoxic agents are at risk of developing therapyrelated myeloid neoplasms (t-MN). Cytogenetic findings of a neoplasm play an important role in stratifying patients into different risk groups and thus predict the response to treatment and overall survival.. A 59-year-old man was diagnosed with acute promyelocytic leukaemia. Following this, he underwent all-trans retinoic acid (ATRA) based chemotherapy and achieved remission. Four years later, the disease relapsed and he was given idarubicin, mitoxantrone and ATRA followed by maintenance chemotherapy (ATRA, mercaptopurine and methotrexate). He achieved a second remission for the next 11 years. During a follow-up later, his full blood picture showed leucocytosis, anaemia and leucoerythroblastic picture. Bone marrow examination showed hypercellular marrow with trilineage dysplasia, 3% blasts but no abnormal promyelocyte. Fluorescence in-situ hybridisation (FISH) study of the PML/RARA gene was negative. Karyotyping result revealed complex abnormalities and monosomal karyotype (MK). A diagnosis of therapy-related myelodysplastic syndrome/myeloproliferative neoplasm with unfavourable karyotypes and MK was made. The disease progressed rapidly and transformed into therapy-related acute myeloid leukaemia in less than four months, complicated with severe pneumonia. Despite aggressive treatment with antibiotics and chemotherapy, the patient succumbed to the illness two weeks after the diagnosis.. Diagnosis of t-MN should be suspected in patients with a history of receiving cytotoxic agents. Karyotyping analysis is crucial for risk stratification as MK in addition to complex aberrant karyotypes predicts unfavourable outcome. Further studies are required to address the optimal management for patients with t-MN.

Topics: Abnormal Karyotype; Antineoplastic Combined Chemotherapy Protocols; Humans; Idarubicin; In Situ Hybridization, Fluorescence; Karyotyping; Leukemia, Myeloid, Acute; Leukemia, Promyelocytic, Acute; Male; Mercaptopurine; Methotrexate; Middle Aged; Mitoxantrone; Neoplasm Recurrence, Local; Neoplasms, Second Primary; Tretinoin

All-trans retinoic acid (ATRA) has made acute promyelocytic leukemia (APL) a very curable disease also in patients aged >60 years; however, there are only few case reports in very elderly APL patients. To address this issue, we reviewed treatment results in 13 patients aged >70 years with newly diagnosed APL followed at our institution from January 1991 to December 2008. According to Sanz score, seven patients were at low risk, five at intermediate risk, and one at high risk. Induction therapy consisted of ATRA + idarubicin in nine patients (3/9 with reduced idarubicin dosage) and ATRA alone in four patients; in this latter group, however, 2/4 needed to add chemotherapy (CHT) due to hyperleukocytosis during ATRA treatment. All patients achieved both morphological and molecular complete remission (CR) after a median time of 51 [interquartile range (IR) 43-55] and 114 (IR 74-155) days, respectively. Infective complications were observed in 10/13 patients, APL differentiation syndrome in 3/13 patients. Twelve patients received consolidation therapy, followed by maintenance treatment in nine patients. Five patients relapsed after 7, 8, 11, 35, and 56 months. At present, seven patients are still alive, five died due to disease progression (four) or senectus while in CR (one), and one was lost to follow-up while in CR. The 5-year event-free survival was 56.1 % (95 % CI, 26.0-86.2); the 5-year overall survival (OS) was 64.5 % (95 % CI, 35.6-93.4). ATRA-based treatment of APL is safe and effective also in very elderly patients, with long-lasting disease-free OS.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Etoposide; Female; Follow-Up Studies; Humans; Idarubicin; Interferon-alpha; Leukemia, Promyelocytic, Acute; Male; Mercaptopurine; Mitoxantrone; Remission Induction; Survival Analysis; Time Factors; Treatment Outcome; Tretinoin

Topics: Anthracyclines; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Fever; Humans; Leukemia, Promyelocytic, Acute; Maintenance Chemotherapy; Male; Mercaptopurine; Methotrexate; Middle Aged; Recurrence; Tretinoin

The optimal maintenance therapy for patients with acute promyelocytic leukemia (APL) who achieved complete remission (CR) and complete consolidation chemotherapy is still controversial. Whether the use of arsenic trioxide (ATO) alone or along with all-trans retinoic acid (ATRA) improves overall survival (OS) or disease-free survival (DFS) is still debated.. A retrospective reivew was conducted of 20 patients diagnosed with APL according to the French - American - British system. After achieving CR and receiving consolidation chemotherapy, nine patients were given maintenance therapy for 1 year (ATRA 45 mg/m(2) /day p.o., mercaptopurine 60 mg/m(2) /day p.o. and ATO 0.15 mg/kg/day × 5 days/week for six cycles in five patients; ATRA 45 mg/m(2) /d p.o. alternating with ATO 0.15 mg/kg/day × 5 days/week in 1 patient; ATRA only in three patients).. In all patients the rates of CR, 3-year OS and 5-year OS were 75, 71 and 57%, respectively. For patients treated with ATO maintenance, the rates were 100% for both 5-year OS and 5-year DFS. Four of six patients on ATO maintenance had grade 1 or grade 2 adverse events. Excluding the two patients who died from intracerebral hemorrhage within 4 days after diagnosis, these rates were 85, 82 and 78%, respectively.. Upfront ATO maintenance therapy for one year is safe and appears to be effective, with the benefits restricted to patients with APL with t(15;17) translocation. Larger studies will be required to confirm this observation.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Disease-Free Survival; Humans; Leukemia, Promyelocytic, Acute; Maintenance Chemotherapy; Male; Mercaptopurine; Middle Aged; Oxides; Retrospective Studies; Tretinoin

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Erythropoietin; Female; Hemoglobins; Humans; Jehovah's Witnesses; Leukemia, Promyelocytic, Acute; Male; Mercaptopurine; Methotrexate; Middle Aged; Remission Induction; Treatment Outcome; Tretinoin

There are very limited data reported about the role of cytarabine (Ara-C) in childhood acute promyelocytic leukemia (APL). We review the clinical course and treatment outcome of APL and explore the role of standard-dose Ara-C for children.. Between January 1999 and December 2008, 36 children (<14 y) with newly diagnosed APL were included.. The overall complete remission rate was 97.2% (35/36). Two patients were lost to follow-up after induction. Two groups of patients were identified according to different consolidation chemotherapy regimens. Seventeen patients were given polychemotherapy in combination with standard-dose Ara-C (group I), 16 patients were given daunorubicin alone (group II). Although the 5-year estimate of disease-free survival between groups I and II had no statistically significant difference (P = 0.614), there was a 12% higher disease-free survival rate for group I.. Standard-dose Ara-C might play some role in the consolidation treatment of children suffering from APL.

Topics: Adolescent; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Cytarabine; Daunorubicin; Disease-Free Survival; Female; Humans; Infant; Kaplan-Meier Estimate; Leukemia, Promyelocytic, Acute; Male; Mercaptopurine; Methotrexate; Treatment Outcome; Tretinoin

Topics: Adult; Aminoglycosides; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Benzoates; Bone Marrow; Bone Neoplasms; Combined Modality Therapy; Doxorubicin; Drug Resistance, Neoplasm; Gemtuzumab; Hematopoietic Stem Cell Transplantation; Humans; Idarubicin; Leukemia, Promyelocytic, Acute; Leukemic Infiltration; Male; Mercaptopurine; Methotrexate; Oxides; Radionuclide Imaging; Remission Induction; Salvage Therapy; Sarcoma, Myeloid; Soft Tissue Neoplasms; Tetrahydronaphthalenes; Tretinoin

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Cells; Enterocolitis, Pseudomembranous; Humans; Idarubicin; Leukemia, Promyelocytic, Acute; Male; Mercaptopurine; Methotrexate; Necrosis; Recovery of Function; Remission Induction; Tretinoin; Vancomycin

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

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Bone Marrow Neoplasms; Brain Neoplasms; Chromosomes, Human, Pair 15; Chromosomes, Human, Pair 17; Cranial Irradiation; Cytarabine; Drug Administration Schedule; Female; fms-Like Tyrosine Kinase 3; Hematopoietic Stem Cell Transplantation; Humans; Idarubicin; Leukemia, Promyelocytic, Acute; Magnetic Resonance Imaging; Mercaptopurine; Methotrexate; Mutation; Nuclear Proteins; Oxides; Promyelocytic Leukemia Protein; Receptors, Retinoic Acid; Recurrence; Remission Induction; Retinoic Acid Receptor alpha; Reverse Transcriptase Polymerase Chain Reaction; Transcription Factors; Translocation, Genetic; Transplantation, Autologous; Treatment Outcome; Tretinoin; Tumor Suppressor Proteins

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Colonic Neoplasms; Colonic Polyps; Cytarabine; Daunorubicin; Doxorubicin; Female; Humans; Idarubicin; Indoles; Kidney Neoplasms; Leukemia, Promyelocytic, Acute; Lung Neoplasms; Male; Mercaptopurine; Methotrexate; Middle Aged; Neoplasms, Second Primary; Pyrroles; Remission Induction; Sunitinib; Time Factors; Tretinoin

To observe the effects of Tanshinone II A (Tan II A) on acute promyelocytic leukemia (APL) characterized by resistance to all-trans retinoic acid (ATRA) and arsenic trioxide (ATO).. A 21-year-old male patient with relapsed APL, who previously received the maintenance therapy with ATRA,ATO, 6-Mercaptopurine (6-MP) and Methotrexate (MTX) for 1 year, was given Tan II A 80 mg intravenously once a day, and the changes of hematological parameters and side effects of Tan II A were observed.. The patient reached morphologically complete remission after using Tan II A intravenously for 54 days. During Tan II A treatment, obvious side effect was not observed.. Tan II A treatment may be effective in relapsed APL cases with ATRA and ATO resistance.

Topics: Abietanes; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Humans; Leukemia, Promyelocytic, Acute; Male; Mercaptopurine; Methotrexate; Neoplasm Recurrence, Local; Oxides; Tretinoin; Young Adult

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Down Syndrome; Esophageal Stenosis; Esophagectomy; Humans; Leukemia, Promyelocytic, Acute; Male; Mercaptopurine; Methotrexate; Tretinoin

Although European conventional maintenance therapy for acute promyelocytic leukemia consisting of all-trans retinoic acid, 6-mercaptopurine, and methotrexate has been adopted in some trials, the adverse events of this therapy have not been described well. We describe adverse events of this therapy in detail and we find that the tolerance of maintenance therapy may depend on the race. Our results indicate that the race and dose intensity should be considered in addition to the number of consolidation courses and PML/RARA mRNA status in configuring the optimal regimen of maintenance therapy, because tolerability may depend much on the races and dose intensity.

Topics: Adult; Aged; Antineoplastic Agents; Drug Tolerance; Female; Humans; Leukemia, Promyelocytic, Acute; Male; Mercaptopurine; Methotrexate; Middle Aged; Racial Groups; Tretinoin

While the disease-free survival of acute promyelocytic leukemia (APML) now approaches 75%, some children continue to experience relapses, and questions remain as to the optimal management of these patients. We describe two young children who experienced combined relapses in the bone marrow and extramedullary locations following hematopoietic stem cell transplantation (HSCT). An induction regimen, consisting of all-trans retinoic acid (ATRA), methotrexate, and 6-mercaptopurine (6MP), successfully and safely achieved hematologic remission in one patient and molecular remission in the other. These cases demonstrate that there is a role for ATRA plus differentiating chemotherapy other than arsenic trioxide in the treatment of relapsed APML.

Topics: Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Child, Preschool; Female; Humans; Infant; Leukemia, Promyelocytic, Acute; Mercaptopurine; Methotrexate; Recurrence; Remission Induction; Tretinoin

Despite recent advances in the treatment of acute promyelocytic leukemia (APL), early mortality and relapses still occur. With the view to evaluate the role of FLT3 mutation in APL, 54 patients (median age 28 years, range11-57 years, male to female ratio 1.2:1, median TLC 8.4 x 10(9)/l, range 1-170 x 10(9)/l) were studied by reverse transcriptase-PCR. Forty-two patients (77%) achieved first remission (CR1). Ten (18.5%) of the 54 patients had internal tandem duplication of exons 11 and 12 of the FLT3 gene. The median TLC count was significantly higher in FLT3 positive cases (Median TLC 55.0 x 10(9)/l) as compared to FLT3 negative cases (Median TLC 6.8 x 10(9)/l) (p = 0.001). Induction CR was much lower (40%) in FLT3/ITD positive cases as compared to 86% of FLT3/ITD negative cases (p = 0.005). Early deaths too were significantly associated with FLT3/ITD positive cases (50 vs. 16% p = 0.033). The difference in the occurrence of bcr1 and bcr3 isoforms was not statistically significant between the two groups. The data suggest that the presence of FLT3/ITD in APL patients confers a poor prognosis.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Daunorubicin; Female; fms-Like Tyrosine Kinase 3; Follow-Up Studies; Gene Duplication; Humans; India; Leukemia, Promyelocytic, Acute; Leukocyte Count; Male; Mercaptopurine; Methotrexate; Middle Aged; Neoplasm Proteins; Oncogene Proteins, Fusion; Prognosis; Remission Induction; Tandem Repeat Sequences; Treatment Outcome; Tretinoin

Rare cases of acute promyelocytic leukemia (APL) are associated with a t(11;17) translocation and a PLZF-RARalpha fusion transcript. Because of molecular specificities of the fusion protein, ATRA efficiency is often reduced in these cases. We present herein the case of an 83-year old patient which has been successfully treated by ATRA and Daunorubicin. The described quantitative RT-PCR method allowed successful monitoring and confirmation of the molecular response.

Topics: Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Bone Marrow; Chromosomes, Human, Pair 15; Chromosomes, Human, Pair 17; Computer Systems; Daunorubicin; Humans; Leukemia, Promyelocytic, Acute; Mercaptopurine; Methotrexate; Neoplasm Proteins; Oncogene Proteins, Fusion; Remission Induction; Reverse Transcriptase Polymerase Chain Reaction; Translocation, Genetic; Tretinoin

To analyze the simultaneous combination of all-trans retinoic acid (ATRA) and anthracycline monochemotherapy for children with acute promyelocytic leukemia (APL).. Since November 1996, 66 children (younger than 18 years) with genetically proven APL received induction therapy with ATRA and idarubicin. Consolidation therapy consisted of three courses of anthracycline monochemotherapy. After November 1999, patients with intermediate and high risk of relapse received consolidation therapy with ATRA and slightly reinforced doses of idarubicin. Maintenance therapy consisted of ATRA and low-dose mercaptopurine and methotrexate.. Thirty-nine girls (59%) and 27 boys (41%) were included in this study. The WBC count at presentation was more than 10 x 10(9)/L in 26 patients (39%). Sixty-one children (92%) achieved complete remission (CR). Early deaths from hemorrhage and retinoic acid syndrome occurred in three patients and two patients, respectively. Toxicity was manageable during consolidation and maintenance therapy. No deaths in CR, clinical cardiomyotoxicity, or secondary malignancy occurred. Two patients had molecular persistence at the end of consolidation. Three clinical relapses and two molecular relapses were also observed. Apart from one molecular relapse, all these events occurred among children with hyperleukocytosis. The 5-year cumulative incidence of relapse was 17%, whereas disease-free and overall survival rates were 82% and 87%, respectively.. A high incidence of hyperleukocytosis in children with APL was confirmed. Besides low toxicity and a high degree of compliance, a risk-adapted therapy combining ATRA and anthracycline monochemotherapy showed an antileukemic efficacy comparable to those previously reported with other chemotherapy combinations in children.

Topics: Adolescent; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Female; Humans; Idarubicin; Incidence; Leukemia, Promyelocytic, Acute; Male; Mercaptopurine; Methotrexate; Neoplasm Recurrence, Local; Prognosis; Remission Induction; Risk Factors; Survival Rate; Tretinoin

Arsenic trioxide (As2O3) therapy at a daily dose of 0.15 mg/kg was given to a 60-yr-old Japanese male with refractory acute promyelocytic leukemia. White blood cell (WBC) of 6.6 x 10(3)/microl increased to 134 x 10(3)/microl following the administration of As2O3. Daily hydroxyurea (HU), and 6-mercaptopurine (6-MP) were added on days 7 and 19, respectively. Both HU and 6-MP were discontinued on day 28, when WBC declined to 54.0 x 10(3)/microl. He developed unexplained fever and profound cytopenia requiring multiple blood products transfusions. Bone marrow examination on day 42 revealed massive necrosis. Pharmacokinetics confirmed a mean maximum plasma arsenic concentration (Cpmax) and a half-life time (t1/2) of 6.9 microm and 3.2 h, respectively, in the therapeutic range. This is the first case of bone marrow necrosis after standard-dose As2O3 therapy.

Topics: Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Bone Marrow; Bone Marrow Diseases; Fever; Humans; Hydroxyurea; Leukemia, Promyelocytic, Acute; Male; Mercaptopurine; Middle Aged; Necrosis; Oxides; Pancytopenia; Remission Induction

The drug interaction between mercaptopurine and warfarin is documented, but case reports of the existence or magnitude of this interaction are rare. An increased warfarin dosage was required for a patient receiving 12-week cycles of mercaptopurine for acute promyelocytic leukemia. At the start of mercaptopurine therapy, an upward titration of 25% beyond the warfarin maintenance dosage was required to achieve a therapeutic international normalized ratio. When a cycle of mercaptopurine was completed, a sharp reduction in warfarin dosage was required. The mechanism behind this interaction is unclear. Mercaptopurine may inhibit gastrointestinal absorption of warfarin, or it may induce hepatic enzymes that metabolize the anticoagulant. With dramatic changes in warfarin or anticoagulant requirements, practitioners should be aware of potential thromboembolic sequelae or bleeding complications when these agents are prescribed concomitantly. Frequent monitoring and careful dosage titration are warranted during concomitant administration.

Topics: Aged; Aged, 80 and over; Anticoagulants; Antimetabolites, Antineoplastic; Drug Interactions; Drug Monitoring; Drug Therapy, Combination; Humans; Leukemia, Promyelocytic, Acute; Male; Mercaptopurine; Warfarin

Topics: Adult; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Leukemia, Myeloid, Acute; Leukemia, Promyelocytic, Acute; Mercaptopurine; Methotrexate; Myelodysplastic Syndromes; Neoplasms, Second Primary; Prednisone; Remission Induction; Tretinoin; Vincristine

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Histocytochemistry; Humans; Leukemia, Myeloid; Leukemia, Promyelocytic, Acute; Male; Mercaptopurine; Methotrexate; Testicular Neoplasms; Tretinoin

The combination of all-trans retinoic acid (ATRA) with chemotherapy has improved the outcome of acute promyelocytic leukaemia (APL). Effective induction as well as maintenance therapy for APL can be achieved using this combination of anti-leukaemic agents.. Twenty-four consecutive patients with newly-diagnosed APL were treated with ATRA daily together with either daunorubicin or idarubicin. Therapy with ATRA was continued until complete remission (CR) was achieved; thereafter, patients were treated with 2 cycles of an anthracycline-based consolidation chemotherapy (either daunorubicin or idarubicin). Maintenance therapy was achieved using 5 alternating cycles of low-dose methotrexate (MTX) plus 6-mercaptopurine (6MP) followed by ATRA alone.. Twenty-three out of 24 patients (96%) completed induction therapy and achieved haematological CR (HCR) as well as molecular remission (MR); however, 1 patient (5%) died from retinoic acid syndrome. Twenty-one out of 23 evaluable patients (91%) completed consolidation chemotherapy, and 2 patients (10%) died, 1 from neutropenic sepsis and the other from relapse following non-compliance to therapy. All 21 surviving patients in the present study received maintenance chemotherapy and are still in HCR and MR at a median follow-up of 23 months. The estimated actuarial 2-year overall survival (OS) and event-free survival (EFS) rates were both 84% +/- 9%.. The combination of ATRA with an anthracycline is an effective remission-induction therapy for newly-diagnosed APL. Maintenance therapy using alternating cycles of MTX plus 6MP followed by ATRA alone is effective in maintaining CR and MR as well as prolonging the survival of patients with APL.

Topics: Adolescent; Adult; Aged; Antibiotics, Antineoplastic; Antimetabolites, Antineoplastic; Daunorubicin; Female; Humans; Idarubicin; Leukemia, Promyelocytic, Acute; Male; Mercaptopurine; Methotrexate; Middle Aged; Tretinoin

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Drug Administration Schedule; Female; Humans; Leukemia, Promyelocytic, Acute; Mercaptopurine; Methotrexate; Remission Induction; Tretinoin

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Hydroxyurea; Idarubicin; Leukemia, Promyelocytic, Acute; Mercaptopurine; Methotrexate; Mitoxantrone; Primary Myelofibrosis; Remission Induction

Topics: Adult; Aged; Amsacrine; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Body Mass Index; Cytarabine; Daunorubicin; Female; Heart; Heart Failure; Humans; Leukemia, Promyelocytic, Acute; Male; Mercaptopurine; Obesity; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Remission Induction; Tretinoin

We describe a patient with acute promyelocytic leukemia (APL) who was successfully induced into remission with all-trans retinoic acid (ATRA) and idarubicin, but developed myelodysplastic syndrome (MDS) with monosomy 7 shortly after conclusion of maintenance therapy with idarubicin alternating with 6-mercaptopurine, vincristine, methotrexate and prednisone. Patients on combination regimens of ATRA or other retinoids and chemotherapy, which are being increasingly used in recent years, should be closely monitored for the development of potentially new complications including MDS.

Topics: Adult; Anemia, Refractory, with Excess of Blasts; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Idarubicin; Karyotyping; Leukemia, Promyelocytic, Acute; Mercaptopurine; Methotrexate; Prednisone; Remission Induction; Tretinoin; Vincristine

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

To characterize of the expression patterns of PML-RAR alpha fusion gene during differentiation therapy with ATRA.. A "neated" RT/PCR was established and subsequently used to study on 74 Acute Promyelocytic Leukemia (APL).. Two major isoforms (type S and L) were detected in leukemia cells from 44 novel patients with APL. 19 of 44 (43.2%) patients with type S isoforms were accompanied with poor prognosis. 15 cases were detected sequentially by the RT/PCR method for dynamic observation of MSD during postremission therapy with ATRA and chemotherapy alternatly. The positive rate was 46.7% in 6 months after CR, then the positive rate curve tended to down wards gradually from 33.5% (12 months after CR) to 26.7% (24 months after CR), 11.1% (36 months after CR), 8.3% on 48 months after CR. Other 30 cases of APL which are long-term survivals and received the same postremission program were detected by the RT/PCR method. The expression of the fusion gene reversed positivty in two cases on 56 and 60 months respectively, then both relapsed. One case was detected regularly once a year for 3 times. In another case, the fusion gene was detectable whoever was no any abnormal evidence in peripheral blood and bone marrow 26 cases were negative and had a long-term survival CCR of 47-114 months (medium 66).. The detection of RT/PCR PML-RAR alpha fusion gene plays an important role in clinical diagnosis, evaluation of prognosis and prediction of relapse in APL.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Child; Cloning, Molecular; Cytarabine; Female; Follow-Up Studies; Harringtonines; Humans; Leukemia, Promyelocytic, Acute; Male; Mercaptopurine; Middle Aged; Oncogene Proteins, Fusion; Tretinoin

All-trans retinoic acid (RA) induces complete remission in a high proportion of patients with acute promyelocytic leukemia (APL). Nevertheless, most of these patients develop RA resistance and relapse. The mechanisms of RA resistance by APL cells are still unclear. To understand the characteristics of human leukemia, human leukemic cell lines are useful tools for study. APL cells have a strikingly low proliferation potential in vitro; thus, only one APL cell line has been established. We developed a novel APL cell line (UF-1) from a patient clinically resistant to all-trans RA. Cell surface markers in the UF-1 cells were positive for CD7, CD13, CD33, and CD38. Cytogenetic analyses revealed additional abnormalities, 46XX, add(1)(q44), add(6)(q12), add(7)(q36), t(15;17) (q21;q21). Molecular analyses showed a PML/RAR alpha fusion transcript. Sequence analysis of the RAR alpha gene in RA-resistant HL-60 cells disclosed a point mutation in codon 411 (C to T substitution), whereas UF-1 cells showed the normal sequence. All-trans RA did not change morphological features of the cell, NBT reduction activity, or their expression of CD11b antigens as determined by FACS analysis except at 10(-6) mol/L. RA also did not alter the growth curve of the cells as determined by the MTT assay. These findings suggest that the UF-1 cell is the first permanent cell line with spontaneous RA-resistant APL cells. This RA-resistant APL cell line may be a useful model for molecular studies on the block of leukemic cell differentiation and as a means to investigate the mechanisms of RA resistance.

Topics: Adult; Antineoplastic Agents; Cell Differentiation; Cell Division; Chromosome Aberrations; Cytarabine; Daunorubicin; DNA Mutational Analysis; Drug Resistance, Neoplasm; Fatal Outcome; Female; HL-60 Cells; Humans; Immunophenotyping; Karyotyping; Leukemia, Promyelocytic, Acute; Mercaptopurine; Neoplasm Proteins; Oncogene Proteins, Fusion; Polymerase Chain Reaction; Prednisolone; Tretinoin; Tumor Cells, Cultured

We demonstrate two conventional chemotherapy-resistant cases of acute promyelocytic leukemia (APL) who were successfully treated with macrophage-colony stimulating factor (M-CSF). Case no 1 was a 40-year-old woman who was made diagnosis of APL on June, 1992, and treated repeatedly with a conventional chemotherapy, BHAC-DMP regimen, resulting in complete remission on October, 1992. After a couple of years, she had relapse with marked growth of APL cells in bone marrow. She was treated with BHAC-AMP and modified B-triple V but could not obtain remission. Case no 2 was a 36-year-old-man with APL who was treated with BHAC-DMP and BHAC-AMP and modified B-triple V therapy. These three conventional chemotherapy regimen were not effective for him. Eight million units of human native M-CSF was administered intravenously for 14 days after the last BHAC-AMP therapy in case no 1, and for 5 days after the last modified B-triple V therapy in case no 2. After the therapy, APL cells in peripheral blood or bone marrow of both patients disappeared completely and normal hemopoietic cells increased, obtaining in complete remission in both cases. These successful cases treated with M-CSF combining chemotherapy may suggest a new therapeutic strategy for APL in addition to all-trans retinoic acid.

Topics: Aclarubicin; Adult; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Drug Resistance; Female; Humans; Leukemia, Promyelocytic, Acute; Macrophage Colony-Stimulating Factor; Male; Mercaptopurine; Prednisolone; Remission Induction

We report a case of therapy-related acute myeloid leukemia (t-AML), M4 FAB subtype, with t(10;11)(p14;q21) chromosome abnormality developed in a patient treated for acute promyelocytic leukemia (APL) after 4 years of continuous complete remission (CCR). Two distinct forms of t-AML have been described: the classical type and the second type. Our case has many characteristics in common with the second type of t-AML such as: exposure to topoisomerase II active agents (idarubicin (IDA), mitoxantrone (MITOX), etoposide (VP16)), M4 FAB subtype, a latency period of 39 months and absence of a preleukemic phase. However, it differs in the chromosome 11 breakpoint (band q21 instead of q23) and absence of ALL-1 (Hrx, MLL, Htrx) gene involvement. This can represent the second observation of t-AML occurring after treatment for APL.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Chromosomes, Human, Pair 10; Chromosomes, Human, Pair 11; Chromosomes, Human, Pair 15; Chromosomes, Human, Pair 17; Cytarabine; Etoposide; Female; Humans; Idarubicin; Karyotyping; Leukemia, Myelomonocytic, Acute; Leukemia, Promyelocytic, Acute; Mercaptopurine; Methotrexate; Mitoxantrone; Neoplasms, Second Primary; Remission Induction; Thioguanine; Translocation, Genetic

Mucormycosis is a rare fungal infection that has been described mainly in oncologic and diabetic patients. We here report the cases of two leukaemic patients in whom pulmonary mucormycosis was diagnosed. Prompt diagnosis, therapy with amphotericin B and surgery when possible, are the cornerstones in the treatment of this fungal infection. Although infrequent, this infection must be suspected in oncohaematological patients with lung infiltrates.

Topics: Adult; Aged; Amphotericin B; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Fatal Outcome; Granulocyte Colony-Stimulating Factor; Humans; Immunologic Factors; Itraconazole; Leukemia, Promyelocytic, Acute; Lung Diseases, Fungal; Male; Mercaptopurine; Methotrexate; Mitoxantrone; Mucormycosis; Neutropenia; Opportunistic Infections; Precursor Cell Lymphoblastic Leukemia-Lymphoma

The thiopurines 6-thioguanine (6TG) and 6-mercaptopurine (6MP) are cytotoxic to proliferating cells by a mechanism involving incorporation into DNA via the purine salvage pathway, and resistance to these agents can be conferred by lack of the salvage pathway enzyme hypoxanthine-guanine phosphoribosyltransferase. However, human and murine hypoxanthine-guanine phosphoribosyltransferase-deficient leukemia cell lines have been shown to respond to 6TG by growth arrest and differentiation by a mechanism apparently not involving incorporation of 6TG into DNA. If so, leukemia cells resistant to 6MP should still respond to 6TG by growth arrest via an undescribed epigenetic mechanism. To test this, polyclonal 6MP-resistant variants were produced from three human leukemia cell lines, HL-60, U937, and CCRF-CEM. Treatment of both sensitive and resistant cells with 6TG induced growth arrest. The effect of 6TG in the 6MP-sensitive HL-60 and U937 cells was associated with significant loss of viability and DNA fragmentation. In contrast, the 6TG-treated 6MP-resistant cells exhibited a slower decline in viability and no DNA fragmentation. To identify the mechanism by which 6TG may induce growth arrest, tRNA was isolated from 6MP-resistant cells cultured for 48 h with 6TG. 6TG was found to be incorporated into tRNAs normally containing queuine in the anticodon wobble position. These studies may provide a basis for the development of new therapeutic regimens for the treatment of leukemia.

Topics: Apoptosis; Cell Differentiation; Cell Division; Drug Screening Assays, Antitumor; Humans; Hypoxanthine Phosphoribosyltransferase; Leukemia, Promyelocytic, Acute; Lymphoma, Large B-Cell, Diffuse; Mercaptopurine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; RNA, Transfer; Thioguanine; Tumor Cells, Cultured

50-year-old male was admitted to our hospital because of gingival bleeding and fever in August 1987. The leukocyte count was 13,300/microliters with 80.5% leukemic promyelocytes and bone marrow was hypercellular with 86.4% leukemic promyelocytes. A small number of mature neutrophils containing Auer rods were seen in bone marrow. On a diagnosis of acute promyelocytic leukemia and treated with induction chemotherapy consisting of behenoyl-arabinofuranosyl cytosine (BHAC), daunorubicin, 6-mercaptopurine (6-MP) and prednisolone (PSL) was reformed. After cytoreduction, leukemic cells reappeared in the peripheral blood, concomitant with mature neutrophils having Auer rods. Vitamin D3 was not effective as a differentiation inducing agent. Complete remission was obtained in November 1987 by the reinduction chemotherapy consisting of BHAC, aclarubicin, 6-MP and PSL. In this case, neutrophils with Auer rods might have been derived from the leukemic clone and differentiation of leukemic promyelocytes by intensive chemotherapy.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cell Differentiation; Cytarabine; Daunorubicin; Humans; Inclusion Bodies; Leukemia, Promyelocytic, Acute; Male; Mercaptopurine; Middle Aged; Neutrophils; Prednisolone; Remission Induction

Two patients with acute promyelocytic leukemia (APL) in 2nd and 3rd trimester of pregnancy are reported on. Case 1: 38-year-old female consulted our hospital because of bleeding tendency and pancytopenia in April, 1988. She was diagnosed as having APL with disseminated intravascular coagulopathy (DIC) and was found to be in the 14th week of gestation. Combined chemotherapy (BHAC-DMP) including the total dose (440 mg) of daunorubicin (DNR) resulted in intrauterine fetal death at 19 weeks of gestation. The fetus was severely anemic and the bone marrow was hypoplastic. Case 2: A 27-year-old female was diagnosed as having APL with DIC at 29 weeks of gestation. BHAC-DMP including 440 mg DNR achieved complete remission. At 35 weeks of gestation, she delivered a normal infant by Caesarean section. The child had normal hematological findings and showed normal growth. Both cases developed APL accompanied by DIC during pregnancy and were treated with a similar regimen including high dose of anthracyclines. Case 2 treated in the late period of gestation delivered a normal infant, while fetal death resulted in case 1, treated in the early period of gestation. We reviewed the literature regarding chemotherapy using anthracyclines during pregnancy.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Embryonic and Fetal Development; Female; Fetal Death; Humans; Leukemia, Promyelocytic, Acute; Mercaptopurine; Prednisolone; Pregnancy; Pregnancy Complications, Hematologic; Pregnancy Complications, Neoplastic

A variety of compounds inhibit the growth and induce differentiation of human promyelocytic leukemia (HL-60) cells. HL-60 subclones that lack the purine salvage enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT) can also be induced to differentiate with purine analogs. Mechanisms by which purine analogs induce differentiation offer unique possibilities for cancer chemotherapy. We have studied the effect of the purine analog 6-ethylmercaptopurine (e6MP) on the growth and induction of differentiation in both wild-type and HGPRT-deficient HL-60 cells. We have previously shown that e6MP inhibits cell growth in both wild-type and HGPRT-deficient HL-60 cells without activation through salvage pathways. In this report we evaluate the effect of e6MP on c-myc mRNA expression. c-Myc mRNA, which is amplified in HL-60 cells, has been shown to play a role in the induction of granulocytic differentiation in HL-60 cells. e6MP transiently down-regulates c-myc mRNA in wild-type cells but has no effect on c-myc mRNA expression in HGPRT-deficient HL-60 cells. Despite the differential effects of e6MP on c-myc mRNA, both wild-type and HGPRT-deficient HL-60 cells appear to engage in terminal differentiation. The morphological changes and nonspecific esterase activity induced by e6MP suggest differentiation down the monocytic pathway. However, early monocytic markers such as the rapid induction of c-fos and the stabilization of c-fms mRNA are not observed. In addition, e6MP inhibits TPA-induced monocytic/macrophage differentiation as characterized by stabilization of c-fms mRNA and cellular adherence.

Topics: Cell Differentiation; Gene Expression; Genes, fms; Genes, myc; Humans; Hypoxanthine Phosphoribosyltransferase; Leukemia, Promyelocytic, Acute; Mercaptopurine; RNA, Messenger; Tetradecanoylphorbol Acetate; Tumor Cells, Cultured

Co-incubation of human leukemia cell lines with naturally occurring nucleobases (hypoxanthine or adenine) significantly prevented the cytotoxic activity of 6-thiopurines. Extracellular hypoxanthine decreased the transport of 6-mercaptopurine into cells, but adenine had no significant effect. However, intracellular thioinosine monophosphate accumulation in the presence of 10 microM, 6-mercaptopurine was reduced to below 1% or 10% of that of the controls when 50 microM hypoxanthine or adenine was added, respectively. Finally, in adenine phosphoribosyl transferase deficient mutants, adenine provided no protective effect against 6-thiopurines, whereas hypoxanthine retained its modulating activity. These data suggest that the nucleobases compete with 6-thiopurines for the ribose-phosphate donor, 5'-phosphoribosyl-1-pyrophosphate, thus preventing the formation of active metabolites of 6-thiopurines.

Topics: 2-Aminopurine; Adenine; Adenine Phosphoribosyltransferase; Antineoplastic Agents; Biological Transport; Humans; Hypoxanthine; Hypoxanthine Phosphoribosyltransferase; Hypoxanthines; Inosine Monophosphate; Leukemia-Lymphoma, Adult T-Cell; Leukemia, Promyelocytic, Acute; Mercaptopurine; Thioguanine; Thionucleotides; Tumor Cells, Cultured

A variety of purine analogs inhibit the growth and induce the differentiation of human promyelocytic leukemia (HL-60) cells that lack the purine salvage enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT). Mechanisms by which purine analogs induce differentiation offer unique potential for cancer chemotherapy. The guanine analogs, 6-thioguanine and 8-azaguanine, induce granulocytic differentiation of HGPRT-deficient HL-60 promyelocytes. Although these compounds are useful as model purine analogs that induce differentiation in HGPRT-deficient HL-60 cells, they suffer the disadvantage that they are highly cytotoxic to wild-type cells. We studied the effect of the hypoxanthine analog 6-ethylmercaptopurine on wild-type and HGPRT-deficient HL-60 cells. 6-Ethylmercaptopurine inhibits growth and produces a specific terminal end-cell in both types of HL-60 cells. The mechanism appears to be independent of the normal modes of cytotoxic activation through HGPRT or adenine phosphoribosyltransferase (APRT), since no new peaks were seen in HPLC chromatograms of the nucleotide pools. Furthermore, hypoxanthine and adenine failed to prevent growth inhibition by 6-ethylmercaptopurine, and inhibition of IMP dehydrogenase and the consequential alteration of the guanine nucleotide pools does not appear to be involved. The mechanism differs from that of guanine analog-induced differentiation in HGPRT-deficient HL-60 cells.

Topics: Antimetabolites, Antineoplastic; Cell Transformation, Neoplastic; Depression, Chemical; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Hypoxanthine Phosphoribosyltransferase; Hypoxanthines; Leukemia, Promyelocytic, Acute; Mercaptopurine; Thioguanine; Tumor Cells, Cultured

A case of methicillin-resistant staphylococcal (MRSA) enterocolitis following combination chemotherapy for acute promyelocytic leukemia is presented. MRSA enterocolitis has characteristic clinical features of high fever, frequent vomiting and watery diarrhea, and its mortality rate is very high without a proper antibiotic therapy. When the patient with hematological malignancy has the above-mentioned clinical manifestations during antineoplastic chemotherapy, appropriate antibiotics for MRSA should be promptly begun before a bacteriological diagnosis.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Enterocolitis; Humans; Leukemia, Promyelocytic, Acute; Male; Mercaptopurine; Methicillin; Middle Aged; Penicillin Resistance; Prednisolone; Remission Induction; Staphylococcal Infections; Staphylococcus aureus

A 56-year-old man was admitted to the hospital in April, 1986, with the chief complaint of fatigue. The diagnosis of acute promyelocytic leukemia (APL) was made based on the proliferation of atypical promyelocytes in the bone marrow. No gingival swelling was found on admission. A complete remission was achieved by the BHAC-DMP therapy and maintained by the consolidation therapy and the intensification therapy. In July, 1987, he noticed a solitary gingival tumor around the left lower second molar. The biopsy showed the massive infiltration of leukemic cells, despite the hematological remission. Combination chemotherapy was not effective but the tumor disappeared by irradiation. A hematological relapse occurred in November, 1987, but the second complete remission was achieved by the AB-triple V therapy. He died because of the second hematological relapse in July, 1988. Along with the wide use of intensive chemotherapy for acute leukemia, tumor forming leukemia during the hematological remission, as seen in this case, would be increasing. Thus, we should not overlook any newly formed tumor in the treatment of leukemia.

Topics: Aclarubicin; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Etoposide; Gingival Neoplasms; Humans; Leukemia, Promyelocytic, Acute; Male; Mercaptopurine; Middle Aged; Prednisolone; Recurrence; Remission Induction; Vinblastine; Vincristine

A 24 year-old female was admitted because of hypermenorrhea and petechiae. The peripheral blood tests on admission were consistent with acute promyelocytic leukemia complicated with DIC. BHAC-DMP therapy was started along with platelet transfusions and heparin administration. On the day 9 of admission, on the contrary to the improvement of hematological data, the patient suffered from severe headache and nausea. The neurological examination revealed anisocoria. Right side chronic subdural hematoma was a diagnosis made by emergency CT scan and was treated with drainage of the hematoma. Post-operatively, the patient did well, and achieved complete remission on the day 43 of admission. Since intracranial hemorrhages due to DIC complicated with leukemia are often fatal, those patients are usually treated conservatively. However, as shown in this case report, some cases might have an indication for the neurosurgical operation. It is important to check conditions carefully whether the patient has an indication for the operation.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Cerebral Hemorrhage; Cytarabine; Daunorubicin; Disseminated Intravascular Coagulation; Drainage; Female; Hematoma, Subdural; Humans; Leukemia, Promyelocytic, Acute; Mercaptopurine; Prednisolone; Remission Induction

Topics: Afibrinogenemia; Blood Cell Count; Bone Marrow Examination; Drug Therapy; Factor V Deficiency; Fibrinogen; Humans; Hypoprothrombinemias; Leukemia; Leukemia, Myeloid; Leukemia, Promyelocytic, Acute; Mercaptopurine; Pathology; Statistics as Topic; Thrombocytopenia

Topics: Anemia; Anemia, Myelophthisic; Blood Cell Count; Blood Sedimentation; Bone Marrow Examination; Hemorrhage; Humans; Leukemia, Promyelocytic, Acute; Mercaptopurine; Neoplasms; Pathology; Prednisone