Anthracycline dose intensification in acute myeloid leukemia

Abstract

Background: In young adults with acute myeloid leukemia (AML), intensification of the anthracycline dose during induction therapy has improved the rate of complete remission but not of overall survival. We evaluated the use of cytarabine plus either standard-dose or high-dose daunorubicin as induction therapy, followed by intensive consolidation therapy, in inducing complete remission to improve overall survival.

Methods: In this phase 3 randomized trial, we assigned 657 patients between the ages of 17 and 60 years who had untreated AML to receive three once-daily doses of daunorubicin at either the standard dose (45 mg per square meter of body-surface area) or a high dose (90 mg per square meter), combined with seven daily doses of cytarabine (100 mg per square meter) by continuous intravenous infusion. Patients who had a complete remission were offered either allogeneic hematopoietic stem-cell transplantation or high-dose cytarabine, with or without a single dose of the monoclonal antibody gemtuzumab ozogamicin, followed by autologous stem-cell transplantation. The primary end point was overall survival.

Results: In the intention-to-treat analysis, high-dose daunorubicin, as compared with a standard dose of the drug, resulted in a higher rate of complete remission (70.6% vs. 57.3%, P<0.001) and improved overall survival (median, 23.7 vs. 15.7 months; P=0.003). The rates of serious adverse events were similar in the two groups. Median follow-up was 25.2 months.

Conclusions: In young adults with AML, intensifying induction therapy with a high daily dose of daunorubicin improved the rate of complete remission and the duration of overall survival, as compared with the standard dose. (ClinicalTrials.gov number, NCT00049517.)

Conflict of interest statement

No other potential conflict of interest relevant to this article was reported.

2009 Massachusetts Medical Society

Figures

Figure 1. Hazard Ratios for Death, According to Subgroup

All hazard ratios are for patients who received a 90-mg dose of daunorubicin (high-dose group), as compared with those who received a 45-mg dose (standard-dose group). A univariate Cox proportional-hazards model was used to estimate hazard ratios and the significance of the comparison for overall survival. The horizontal lines represent 95% confidence intervals for the ratios. The box size is proportional to the inverse of the standard error of the hazard-ratio estimates.

Figure 2. Kaplan–Meier Estimates of Overall Survival

Data from the intention-to-treat analysis are shown for survival of all patients (Panel A), those with a favorable or an intermediate cytogenetic profile (Panel B), and those with an unfavorable cytogenetic profile (Panel C).

Figure 3. Kaplan–Meier Estimates of Overall Survival, According to Mutation Status

Data are shown for the overall survival of patients with the FLT3-ITD mutation (Panel A), those without the FLT3-ITD mutation (Panel B), those with the MLL-PTD mutation (Panel C), and those without the MLL-PTD mutation (Panel D). Also shown are survival curves for patients who received high-dose daunorubicin (90 mg per square meter of body-surface area per day), according to the presence or absence of the FLT3-ITD genotype (Panel E). ITD denotes internal tandem duplication, and PTD partial tandem duplication.