mitolactol and Leukemia--Myeloid--Acute

One thousand four hundred sixty patients with 2,590 patient-years of follow-up were treated on 15 protocols for metastatic breast cancer with dibromodulcitol (mitolactol; DBD)-containing regimens since 1976. Twenty-three patients developed myelodysplastic syndrome (MDS) and/or acute nonlymphocytic leukemia (ANLL). The overall risk of developing MDS or ANLL per person is 1.6%. In patients who had received more than 16,000 mg of DBD the risk per person is 6%, and in the high-dose subsets of patients who received no prior radiation or alkylator therapy, it is 7.9%. The risk per person increases to a maximum by 30 to 36 months (5.3%). The high risk was seen despite a study population of metastatic breast cancer patients with a median survival of 16 months. This analysis strongly suggests that DBD is one of the most potent of the reported leukemogenic-inducing agents. Further use of this drug in both the adjuvant and metastatic situation should be reconsidered.

Topics: Adult; Aged; Breast Neoplasms; Humans; Leukemia, Myeloid, Acute; Middle Aged; Mitolactol; Myelodysplastic Syndromes; Risk

Relapse is a major obstacle in the cure of acute myeloid leukemia (AML). The Pediatric Oncology Group AML Study 9421 tested 2 different strategies to improve event-free survival (EFS) and overall survival (OS). Patients were randomized to receive standard-dose DAT (daunorubicin, cytarabine, and thioguanine) or high-dose DAT during induction. To interfere with P-glycoprotein (P-gp)-dependent drug efflux, the second randomization tested the benefit of cyclosporine (CsA) added to consolidation chemotherapy. Of the 282 children randomly assigned to receive standard DAT induction, 248 (87.9%) achieved remission compared to 253 (91%) of the 278 receiving high-dose DAT (P = ns). Children with HLA-identical sibling donors who achieved a complete remission received an allogeneic bone marrow transplant as consolidation. For the 83 patients receiving a matched related donor bone marrow transplantation (BMT), the 3-year disease-free survival (DFS) is 67%. Of the 418 children who achieved remission and went on to consolidation with and without CsA, the DFS was 40.6% and 33.9%, respectively (P = .24). Overexpression of P-gp was infrequent (14%) in this pediatric population. In this study, intensifying induction with high-dose DAT and the addition of CsA to consolidation chemotherapy did not prolong the durations of remission or improve overall survival for children with AML.

Topics: Antineoplastic Combined Chemotherapy Protocols; ATP Binding Cassette Transporter, Subfamily B, Member 1; Child; Child, Preschool; Cyclosporine; Disease-Free Survival; Doxorubicin; Female; Humans; Immunosuppressive Agents; Infant; Karyotyping; Leukemia, Myeloid, Acute; Leukocyte Count; Male; Mitolactol; Remission Induction; Survival Analysis; Tamoxifen; Treatment Outcome

Seventy-two consecutive and previously untreated adults with acute non-lymphoblastic leukaemia (ANLL), having a median age of 36 years (range 12 to 71), were prospectively randomised to receive conventional doses of cytosine arabinoside and doxorubicin combined with either etoposide (CTR III) or 6-thioguanine (DAT). Morbidity was comparable between the two regimens and complete remission (CR) rates of 52% and 62% respectively (p greater than 0.50) were not influenced by age above or below 50 years, initial white cell count, French-American-British classification, or race. However, growth pattern in the GM: CFUc assay was found to identify a subgroup of patients who had a significantly higher CR rate. Similarly, the secretion of tissue plasminogen activator by leukaemic blasts in vitro uniformly predicted for primary drug resistance, whereas a CR rate of 68% was associated with production of the urokinase type or a mixture of both enzymes. Remission duration and survival did not differ between these two forms of chemotherapy, nor were they influenced by immunotherapy with C. parvum or the duration of maintenance therapy, whereas age below 50 and the species of plasminogen activator secreted were significant prognostic factors. It is concluded that etoposide can be substituted for 6-thioguanine in these cytosine arabinoside and doxorubicin-containing regimens and that for both combinations the most sensitive prognostic factor for CR and survival is the species of plasminogen activator secreted in vitro by the leukaemic blasts.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Child; Cytarabine; Doxorubicin; Etoposide; Female; Humans; Immunotherapy; Leukemia, Myeloid, Acute; Male; Middle Aged; Mitolactol; Prospective Studies; Randomized Controlled Trials as Topic; Remission Induction; Survival Rate; Tamoxifen

Topics: Breast Neoplasms; Female; Humans; Leukemia, Myeloid, Acute; Mitolactol; Myelodysplastic Syndromes

The safety of drugs in hepatic porphyrias has largely been established by clinical experience, which is very limited in the case of antineoplastic agents. We administered three cycles of polychemotherapy consisting of daunorubicin, cytarabine and 6-thioguanine, and modified supportive care to a 33-year-old Turkish woman suffering from acute myelogenous leukemia. The urinary excretion of total porphyrins, porphobilinogen, and aminolevulinic acid was continuously monitored. Excretion of these metabolites was permanently elevated, but the values were comparatively low during cytotoxic therapy while peak values were recorded at the onset of fever during bone marrow aplasia; yet there were no clinical signs of porphyritic attacks at that time. A few potentially unsafe drugs were tolerated without an increase in porphyrin excretion. Although the susceptibility to drugs is highly variable in patients with hepatic porphyrias, the treatment of malignancy in these patients seems justified as long as porphyrin excretion under therapy is not grossly elevated over baseline values and appropriately modified supportive care is administered.

Topics: Acute Disease; Adult; Aminolevulinic Acid; Antineoplastic Combined Chemotherapy Protocols; Chemical and Drug Induced Liver Injury; Doxorubicin; Female; Humans; Leukemia, Myeloid, Acute; Liver Diseases; Mitolactol; Porphobilinogen; Porphyrias; Porphyrins; Risk; Tamoxifen

Utilizing multivariate logistic regression statistical analysis, the authors evaluated prognostic features associated with achievement of complete remission (CR) and remission and survival duration in acute myelogenous leukemia (AML). These clinical variables were analyzed in 77 consecutive adult patients who underwent 108 courses of remission induction therapy with daunomycin, cytosine arabinoside, and 6-thioguanine (DAT) chemotherapy for newly diagnosed and first relapse of AML. Eight patients had developed leukemia in the setting of other malignant or immunologic diseases (therapy-linked AML) and 69 patients had not (primary AML). Sixty-three percent of patients with primary AML achieved CR with median remission and survival durations of 11 and 24 months, respectively. Significant unfavorable predictive features for achievement of CR were splenomegaly, and elevated leukocyte count or serum alkaline phosphatase levels. Patients who had leukocyte counts of less than or equal to 10,000/mm3 at diagnosis or less than or equal to 40,000/mm3 at the start of therapy, and those who received greater than 120 mg/m2 of daunomycin had significantly longer remissions and survival than those who did not. Fifty-seven percent of patients in first relapse also achieved CR; however, relative to first remissions, second remission durations were significantly shorter (median, 4.6 months). Sixty-two percent of patients with therapy-linked AML achieved CR, but remission durations (median, 2.8 months) were significantly shorter than first remissions of primary AML patients. These data identify clinical features associated with increased risk of failure to achieve CR and potential for short remission duration and survival. Alternative forms of therapy should be considered for such high-risk patients.

Topics: Adolescent; Adult; Aged; Alkaline Phosphatase; Antineoplastic Combined Chemotherapy Protocols; Doxorubicin; Female; Humans; Leukemia, Myeloid, Acute; Leukocyte Count; Male; Middle Aged; Mitolactol; Prognosis; Regression Analysis; Splenomegaly; Tamoxifen; Time Factors

Chromosomal karyotypes were determined with standard G-banding in 103 patients with acute myeloid leukaemia (AML). Abnormal clones were present in 52 (50.5%). Higher frequencies of abnormalities were observed in male than in female patients and in erythroleukaemia (EL) than in other subtypes of AML. Abnormalities were more frequent in myeloblastic (AMyL) than in myelomonocytic leukaemias (AMML) and mixtures of both normal and abnormal karyotypes were more common among elderly patients; these differences, though of marginal statistical significance, are consistent with previous reports. 9 of 10 cases with 5 or more aberrant chromosomes and 6 of 8 cases with unidentified marker chromosomes were either AMML or EL. Remission rates, median survivals and relative death rates were collated in 82 patients, in relation to the karyotype patterns NN (all normal), AN (mixed normal and abnormal) and AA (all abnormal). The differences between the groups did not reach statistical significance. Serial cytogenetic studies were performed in 10 patients. New karyotype changes emerged in only 1 of 6 relapses. 4 examples of t(8;21) and 2 of t(15;17) were found. 1 case of AMML showed trisomy 8 and double minute chromosomes. 1 case of EL showed 2 marker chromosomes with homogeneously staining regions.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Chromosome Aberrations; Chromosome Disorders; Doxorubicin; Drug Therapy, Combination; Female; Humans; Infant; Karyotyping; Leukemia, Erythroblastic, Acute; Leukemia, Myeloid, Acute; Male; Middle Aged; Mitolactol; Prognosis; Sex Factors; Tamoxifen