Safety and efficacy of combining midostaurin and gemtuzumab ozogamicin with induction chemotherapy in FLT3-mutated AML.

Despite the use of FMS-like tyrosine kinase 3 (FLT3) inhibitors, outcomes for patients with FLT3-mutated (FLT3mut) acute myeloid leukemia (AML) remain suboptimal because of high rates of relapse. We evaluated the safety and efficacy of the combination of daunorubicin, cytarabine (DA), gemtuzumab ozogamicin (GO), and midostaurin (DAGO+m) for younger patients with newly diagnosed FLT3mut AML in the UK National Cancer Research Institute AML19 trial. A total of 195 patients were randomized to receive DA with either 1 or 2 doses of GO (DAGO1 and DAGO2). Overall, 77 had an FLT3 mutation and received midostaurin for 2 weeks after each chemotherapy course and then as maintenance for 1 year unless they received a transplant. A total of 39 patients received DAGO1+m and 38 DAGO2+m. Their median age was 51 years (range, 20-74), and 16 (20%) were aged >60 years. The overall response rate was 91%. Day 60 mortality was 0%, with no increase in toxicity compared with patients treated contemporaneously with DAGO1 and DAGO2 without midostaurin. Two-year overall survival was 77%. Two-year event-free survival and cumulative incidence of relapse were 62% and 31%, respectively. Measurable residual disease (MRD) clearance was enhanced compared with patients with FLT3mut AML treated with DAGO without midostaurin. Overall, 81% of evaluable patients were NPM1 MRD negative in the peripheral blood after course 2 (76% with DAGO1+m, and 86% with DAGO2+m), 79% were MRD negative in the bone marrow by FLT3-ITD next-generation sequencing, and all patients had FLT3-MRD levels <0.01%. DAGO+m appears safe and effective. DAGO2+m will now be evaluated in a randomized study. This trial was registered at www.isrctn.com as #ISRCTN78449203.