We developed a high dose mitoxantrone-based induction regimen based on the steep dose-response curve for mitoxantrone. Currently we report long-term results of the treatment of patients with newly-diagnosed AML with a single high dose of mitoxantrone combined with once daily cytarabine. One-hundred sixty-five patients treated on four studies of high-dose mitoxantrone-based induction therapy are included.

Study 1: Phase II study, age <60.

Induction: mitoxantrone 80 mg/m2 x 1, ara-C 3 gm/m2/d x 5, VP-16 150 mg/m2/d qod x 3. Consolidation: 5 mos ara-C x 4d with mitoxantrone 20 mg/m2 months 3 + 5, and with VP-16 150 mg/m2 x 2 months 4 + 6.

Study 2: randomized study of high vs standard dose mitoxantrone with ara-C in pts ≥ 60 yrs. Pts did not receive consolidation. Only pts with high dose mitoxantrone are included here.

Study 3: Same as study 1 except pts received ATRA 45 mg/m2 x 3 doses. Pts < 60 received consolidation as in study 1. Pts ≥ 60 did not receive consolidation.

Study 4: Pts ≥ 60 yrs, same as study 2 + temozolomide postremission therapy. In each study, pts with prior antecedent hematologic disorder (AHD) or secondary AML were included. Median age: 59 (21–88); M/F: 91/80; cytogenetics(SWOG): good:13%, intermediate:50%, poor:26%, indeterminate:5%, IM:6%; Prior AHD: 32% of pts. The median follow up time is 65.9 months (95% CI: 55.7–86.2 months). The overall complete remission rate was 64%, with responses in 78% of patients less than 60 years of age and 52% of patients 60 years of age or older. The median duration of response is 21.2 months and 8.0 months, and overall survival is 15.4 months and 7.6 months, respectively. For a subset of patients who would be eligible for most US trials, the complete remission rate was 84% in younger patients and 60% in older patients. The median duration of response was 39.0 months and 8.2 months, and the median overall survival was 19.4 months and 7.6 months, respectively. Prospective analysis of secondary cytogenetic abnormalities showed such changes in 9 patients. Three of these were at the time of relapse, 3 had spontaneous resolution of these abnormalities, and 3 had MDS that evolved to AML. Two of the latter patients had Neurofibromatosis Type-1. Asymptomatic decreases in ejection fraction were common, however only 2 patients developed clinically significant cardiac dysfunction. The efficacy of these regimens compared favorably to results reported with standard “3+7” regimens. Use of a once-daily cytarabine regimen resulted in almost no neurotoxicity and allowed for administration of consolidation in the outpatient setting.

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