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/m(2)) 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 aFLT3-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/m(2)), HD daunorubicin is associated with a hazard ratio (HR) for death of 0.74 (P= .001). Younger patients (<50 years) benefited from HD daunorubicin (HR, 0.66;P= .002), as did patients with favorable and intermediate cytogenetics (HR, 0.51;P= .03 and HR, 0.68;P= .01, respectively). Patients with unfavorable cytogenetics were shown to benefit from HD daunorubicin on multivariable analysis (adjusted HR, 0.66;P= .04). Patients with FLT3-ITD (24%),DNMT3A(24%), and NPM1(26%) mutant AML all benefited from HD daunorubicin (HR, 0.61,P= .009; HR, 0.62,P= .02; and HR, 0.50,P= .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.

Figure 1

Kaplan-Meier curves of FLT3-ITD, DNMT3A, and NPM1 mutant AML, by treatment assignment. Data for overall survival from the intention-to-treat analysis are shown for patients with (A) FLT3-ITD, (B) DNMT3A, and (C) NPM1 mutant AML according to assignment to SD daunorubicin (45 mg/m² per day) or HD daunorubicin (90 mg/m² per day).

Figure 2

HD daunorubicin is necessary for benefit of the NPM1 mutation. Data for overall survival from the intention-to-treat analysis are shown for patients with NPM1 mutant and NPM1 wild-type AML by receipt of HD daunorubicin or SD daunorubicin.