Benefit of high-dose daunorubicin in AML induction extends across cytogenetic and molecular groups

Abstract

The initial report of the Eastern Cooperative Oncology Group-American College of Radiology Imaging Network Cancer Research Group trial E1900 (#NCT00049517) showed that induction therapy with high-dose (HD) daunorubicin (90 mg/m2) improved overall survival in adults <60 years old with acute myeloid leukemia (AML); however, at initial analysis, the benefit was restricted to younger patients (<50 years) and patients without unfavorable cytogenetics or a FLT3-ITD mutation. Here, we update the results of E1900 after longer follow-up (median, 80.1 months among survivors), focusing on the benefit of HD daunorubicin on common genetic subgroups. Compared with standard-dose daunorubicin (45 mg/m2), HD daunorubicin is associated with a hazard ratio (HR) for death of 0.74 (P 5 .001). Younger patients (<50 years) benefited from HD daunorubicin (HR, 0.66; P 5 .002), as did patients with favorable and intermediate cytogenetics (HR, 0.51; P 5 .03 andHR, 0.68;P5.01, respectively). Patients with unfavorable cytogenetics wereshownto benefit from HD daunorubicin on multivariable analysis (adjusted HR, 0.66; P 5 .04). Patients with FLT3-ITD (24%), DNMT3A (24%), and NPM1 (26%) mutant AML all benefited from HDdaunorubicin (HR, 0.61, P5.009; HR, 0.62, P5.02; and HR, 0.50, P5.002; respectively).HD benefit was seen in the subgroup of older patients (50-60 years) with the FLT3-ITD or NPM1 mutation. Additionally, the presence of an NPM1 mutation confers a favorable prognosis only for patients receiving anthracycline dose intensification during induction.