Midostaurin plus Intensive Chemotherapy for Younger and Older Patients with AML and FLT3Internal Tandem Duplications

We conducted a single-arm phase-II trial (AMLSG 16-10) to evaluate midostaurin with intensive chemotherapy followed by allogeneic hematopoietic-cell transplantation (HCT) and a one-year midostaurin maintenance therapy in adult patients with acute myeloid leukemia (AML) and FLT3internal tandem duplication (ITD). Patients 18-70 years of age with newly diagnosed FLT3-ITD-positive AML were eligible. Primary and key secondary endpoints were event-free (EFS) and overall survival (OS). Results were compared to a historical cohort of 415 patients treated on 5 prior AMLSG trials; statistical analysis was performed using a double-robust adjustment with propensity score weighting and covariate adjustment. Results were also compared to patients (18-59yrs) treated on the placebo arm of the CALGB 10603/RATIFY trial. The trial accrued 440 patients (18-60yrs, n=312; 61-70yrs, n=128). In multivariate analysis, EFS was significantly in favor of patients treated within the AMLSG 16-10 trial compared to the AMLSG control (HR 0.55; P<0.001); both in younger (HR 0.59; P<0.001) and older patients (HR 0.42; P<0.001). Multivariate analysis also showed a significant beneficial effect on OS compared to the AMLSG control (HR 0.57; P<0.001) as well as to the CALGB 10603/RATIFY trial (HR 0.71; p=0.005). The treatment effect of midostaurin remained significant in sensitivity analysis including allogeneic HCT as a time-dependent covariate. Addition of midostaurin to chemotherapy was safe in younger and older patients. In comparison to historical controls, the addition of midostaurin to intensive therapy led to a significant improvement in outcome in younger and older patients with AML and FLT3-ITD. The AMLSG 16-10 trial is registered at clinicaltrialsregistry.eu(Eudra-CT number 2011-003168-63) and clinicaltrials.gov(NCT01477606).