A randomized comparison of daunorubicin 90 mg/m2 vs 60 mg/m2 in AML induction: results from the UK NCRI AML17 trial in 1206 patients

Abstract

Modifying induction therapy in acute myeloid leukemia (AML) may improve the remission rate and reduce the risk of relapse, thereby improving survival. Escalation of the daunorubicin dose to 90 mg/m(2) has shown benefit for some patient subgroups when compared with a dose of 45 mg/m(2), and has been recommended as a standard of care. However, 60 mg/m(2) is widely used and has never been directly compared with 90 mg/m(2). As part of the UK National Cancer Research Institute (NCRI) AML17 trial, 1206 adults with untreated AML or high-risk myelodysplastic syndrome, mostly younger than 60 years of age, were randomized to a first-induction course of chemotherapy, which delivered either 90 mg/m(2) or 60 mg/m(2) on days 1, 3, and 5 combined with cytosine arabinoside. All patients then received a second course that included daunorubicin 50 mg/m(2) on days 1, 3, and 5. There was no overall difference in complete remission rate (73% vs 75%; odds ratio, 1.07 [0.83-1.39]; P = .6) or in any recognized subgroup. The 60-day mortality was increased in the 90 mg/m(2) arm (10% vs 5% (hazard ratio [HR] 1.98 [1.30-3.02]; P = .001), which resulted in no difference in overall 2-year survival (59% vs 60%; HR, 1.16 [0.95-1.43]; P = .15). In an exploratory subgroup analysis, there was no subgroup that showed significant benefit, although there was a significant interaction by FLT3 ITD mutation. This trial is registered at http://www.isrctn.com as #ISRCTN55675535.

Figure 1

Trial design of AML17. Patients allocated either CEP-701 or everolimus post–course 1 carried this molecule forward into subsequent courses. *After closure of the CEP-701 randomization, patients were guided by risk score to either poor risk or not poor risk options. **After closure of the everolimus randomization, patients in this group received daunorubicin (DA) 50 mg alone. ***After closure of the D clofarabine arm, patients were recommended to receive FLAG-Ida (which was also the case if renal criteria were not met).

Figure 2

CONSORT diagram for AML17 daunorubicin dose randomization.

Figure 3

Nonhematologic toxicity after courses 1 and 2. (A) Course 1: toxicity according to NCI CTCAE v.3.0. (B) Course 2.

Figure 4

Outcomes after daunorubicin dose randomization. (A) Overall survival (OS); (B) cumulative incidence of relapse; (C) OS—favorable cytogenetics; (D) OS—intermediate cytogenetics; (E) OS—adverse cytogenetics; (F) survival censored at transplant.