Higher-Dose Daunorubicin Is Effective in Patients with AML Who Harbor FLT3-ITD Mutations

Conference Correspondent - EHA 2016

The NCRI AML17 trial compared 2 doses of daunorubicin, 90 mg/m2 (DA90) and 60 mg/m2(DA60), in the first course of chemotherapy for patients with acute myeloid leukemia (AML). Preliminary findings showed no efficacy benefit for the 90-mg/m2 dose of daunorubicin and a higher rate of early mortality. The goal of this study was to learn if induction with high-dose daunorubicin improves overall survival (OS) in any cytogenetic or genetic subgroup of patients with AML between the ages of 18 and 60 years.1 Between September 2011 and October 2013, 1206 patients were randomized 1:1 to DA90 or DA60 (days 1, 3, and 5) in course 1, then daunorubicin at a dose of 50 mg/m2 (days 1, 3, and 5) in course 2. Ara-C was dosed at 100 mg/m2 on days 1 to 10 (course 1) and days 1 to 8 (course 2). Patients’ median age was 53 years (range, 16-72 years); 54% were male; 84% had de novo AML, 10% secondary, and 6% high-risk myelodysplastic syndromes. Ten percent of patients had favorable cytogenetics, 72% intermediate, and 18% adverse. Overall, 60-day mortality remained higher with DA90 (10% vs 5%; P = 0.002) and 3-year OS did not differ, suggesting that DA90 is not associated with an OS benefit. However, analysis stratified by FLT3-ITD showed significant heterogeneity. In ITD wild-type patients, OS outcomes were not affected (51% vs 49%; P = 0.3). However, in ITD-mutant patients, an OS benefit was observed (54% vs 34%; P = 0.03). Sixty-day mortality was not different (7% vs 6%; P = 0.8). These results indicate a potential role for DA90 in patients with FLT3-ITD mutations. In theory, DA90 could complement use of FLT3 inhibitors in these patients, but this decision would require early knowledge of mutation status. Delivery of the escalated daunorubicin dose could also be considered in the second induction course.  
  1. Russell N, et al. EHA 2016. Abstract S808.