High‐dose cytosine arabinoside and amsacrine or mitoxantrone in relapsed and refractory acute myeloid leukaemia: a prospective randomized study
Philippe MartiatJ M GhilainAugustin FerrantChantal DoyenAndré DelannoyC ChatelainAndré BoslyJ. L. MichauxG. Sokal
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Abstract:
52 patients with refractory or relapsed acute myeloid leukaemia (AML) were randomly assigned to receive a combination of high‐dose cytosine arabinoside (HD Ara‐C), 3 g/m 2 /d and either mitoxantrone (MTX), 7 mg/m 2 /d (5 mg if older than 60 yr) or m‐amsacrine (AMSA), 120 mg/m 2 /d (90 mg if older than 60 yr) for 5 d. The overall response rate was 50% and did not differ significantly in the two groups (46% for AMSA and 56% for MTX, p = 0.415). The median survival was 11 months (8 months for AMSA and 12 months for MTX, p = 0.326) and the median duration of complete remission (CR) was 11 months for AMSA and 12 months for MTX (p = 0.643). In relapsed patients, the only significant predictive factor for obtaining a complete response was the length of first complete remission. Patients with a first CR shorter than 6 months had a CR rate of 36% while it was 65% if the first CR lasted more than 6 months (p = 0.03). Severe (WHO grade III‐IV) gastro‐intestinal toxicity was more frequent in the AMSA group (27% vs 4%, p = 0.021). Treatment‐related death occurred in 4 patients in the AMSA group and in 2 patients in the MTX group (p = 0.097). We conclude that neither of these two treatment modalities was shown to be superior in terms of CR rate and survival, with a better tolerance for MTX.Keywords:
Amsacrine
Mitoxantrone
Refractory (planetary science)
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69 patients (median age 53 years, 19-79 years old) with untreated acute non-lymphoblastic leukemia (ANLL) were randomized to receive either a regimen of amsacrine, cytarabine, thioguanine (AAT) or daunorubicin, cytarabine, thioguanine (DAT). AAT consisted of amsacrine 200 mg/m2/day x 5, thioguanine 100 mg/m2/12 h p.o. x 10; DAT was daunorubicin 50 mg/m2/day x 3, cytarabine 200 mg/m2/day x 5, thioguanine 100 mg/m2/12 h p.o. x 10. After one or two induction courses the patients subsequently received 2 consolidation courses. 17 patients were not assessable for response to therapy due to exitus during induction treatment. Complete remission could be obtained in 14/24 (58%) of DAT patients respectively. Patients less than 60 years of age achieved CR in 63% (AAT) vs 65% (DAT), whereas patients greater than or equal to 60 years obtained a CR in 50% (AAT) vs 13% (DAT). Toxicity appears not to be increased significantly with amsacrine. These data indicate that amsacrine could replace daunorubicin in remission induction regimens of ANLL containing cytosin arabinoside and thioguanine without decreasing the response rate.
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Based on promising preclinical data, a progressive series of evaluations of the use of high-dose mitoxantrone-based chemotherapy was initiated in acute leukaemia patients. A preliminary phase I study demonstrated that up to 80 mg/m2 of mitoxantrone in combination with cytarabine 3 g/m2 daily for 5 days could be given as induction therapy to leukaemic patients with acceptable toxicity. Pharmacokinetic data from these patients demonstrated that high concentrations of mitoxantrone were achievable in vivo to levels that were extremely cytotoxic in vitro. Subsequently, in a phase II study, 45 patients with untreated acute myelogenous leukaemia (AML) under the age of 60 received mitoxantrone 80 mg/m2 in combination with cytarabine 3 g/m2 daily for 5 days and etoposide 150 mg/m2 for 3 days. Following this induction, patients received five cycles of consolidation with cytarabine 3 g/m2 daily for 4 days with mitoxantrone 20 mg/m2 for 1 day on cycles 2 and 4, and etoposide 150 mg/m2 for 2 days with cytarabine on courses 1, 3 and 5. The patients in this study achieved a complete remission (CR) rate of 80% and a 3-year projected probability of survival of 40%. In a second AML study, 54 adults over the age of 60 with untreated AML were randomized to receive either high-dose or standard-dose mitoxantrone with cytarabine as a single induction regimen without consolidation. Patients receiving high-dose mitoxantrone did not experience increased morbidity or mortality compared with those given lower doses. Comparison of CR rates, disease-free and overall survival consistently favoured high-dose mitoxantrone, although the results did not achieve statistical significance. In patients with acute lymphocytic leukaemia (ALL), high-dose mitoxantrone with cytarabine was given as initial therapy in a phase II study involving 37 previously untreated adults. Results demonstrated that this dose-intensive regimen could produce a high CR rate (84%) with acceptable toxicity and compared favourably with experiences with vincristine/prednisone-based induction regimens. These studies demonstrate that high-dose mitoxantrone can be safely and effectively administered to patients with acute leukaemia and suggest that the incorporation of high doses of mitoxantrone into treatment regimens may lead to enhanced antileukaemic efficacy compared with standard doses. Phase III evaluations are planned.
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