Idarubicin Dose Escalation During Consolidation Therapy for Adult Acute Myeloid Leukemia

Abstract

Higher doses of the anthracycline daunorubicin during induction therapy for acute myeloid leukemia (AML) have been shown to improve remission rates and survival. We hypothesized that improvements in outcomes in adult AML may be further achieved by increased anthracycline dose during consolidation therapy. Patients and MethodsPatients with AML in complete remission after induction therapy were randomly assigned to receive two cycles of consolidation therapy with cytarabine 100 mg/m 2 daily for 5 days, etoposide 75 mg/m 2 daily for 5 days, and idarubicin 9 mg/m 2 daily for either 2 or 3 days (standard and intensive arms, respectively). The primary end point was leukemia-free survival (LFS). ResultsTwo hundred ninety-three patients 16 to 60 years of age, excluding those with core binding factor AML and acute promyelocytic leukemia, were randomly assigned to treatment groups (146 to the standard arm and 147 to the intensive arm). Both groups were balanced for age, karyotypic risk, and FLT3-internal tandem duplication and NPM1 gene mutations. One hundred twenty patients in the standard arm (82%) and 95 patients in the intensive arm (65%) completed planned consolidation (P , .001). Durations of severe neutropenia and thrombocytopenia were prolonged in the intensive arm, but there were no differences in serious nonhematological toxicities. With a median follow-up of 5.3 years (range, 0.6 to 9.9 years), there was a statistically significant improvement in LFS in the intensive arm compared with the standard arm (3-year LFS, 47% [95% CI, 40% to 56%] v 35% [95% CI, 28% to 44%]; P = .045). At 5 years, the overall survival rate was 57% in the intensive arm and 47% in the standard arm (P = .092). There was no evidence of selective benefit of intensive consolidation within the cytogenetic or FLT3-internal tandem duplication and NPM1 gene mutation subgroups. ConclusionAn increased cumulative dose of idarubicin during consolidation therapy for adult AML resulted in improved LFS, without increased nonhematologic toxicity. J Clin Oncol 35:1678-1685. © 2017 by American Society of Clinical Oncology INTRODUCTIONAnthracyclines are one of the major classes of drugs active against acute myeloid leukemia (AML).1 Daunorubicin used at 45 mg/m 2 daily for 3 days is an integral component of the 7 + 3 regimen, which, with various modifications, has been the standard induction regimen for AML for more than three decades.2 Increased daunorubicin dosage from 45 to 50 mg/m 2 to 90 mg/m 2 daily for 3 days during induction therapy for AML has been shown in three studies to improve remission rates and survival in some patient subgroups, although another trial showed no benefit of 90 mg/m 2 compared with 60 mg/m 2 , with the caveat that the lower-dose arm received a median cumulative total of 330 mg/m 2 daunorubicin. [3][4][5][6][7] Another anthracycline widely used for AML induction is idarubicin. Several randomized trials have now been conducted comparing idarubicin 12 mg/m 2 daily for 3 days with daunorubicin 45 to 50 mg/m 2 in the same schedule, ...

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