Midostaurin plus daunorubicin or idarubicin for young and elderly adults with FLT3-mutated AML: a Phase 3b trial.

The pivotal RATIFY study demonstrated midostaurin (50 mg b.i.d.) with standard chemotherapy significantly reducing mortality in adult patients (<60 years) with newly diagnosed (ND) FLT3mut acute myeloid leukemia (AML). Considering that AML often present in older patients who show poor response to chemotherapy, this open-label, multicenter Phase 3b trial was designed to further assess safety and efficacy of midostaurin plus chemotherapy in induction, consolidation, and maintenance monotherapy in young (60 years) and older (>60 years) patients with FLT3mut ND-AML. Compared with RATIFY, this study extended midostaurin treatment from 14 days to 21 days, substituted anthracyclines (idarubicin or daunorubicin), and introduced variation in standard combination chemotherapy dosing ("7+3" or "5+2" in more fragile patients). Total 301 patients (47.2% >60 years, 82.7% with FLT3-ITDmut) of median age 59 years entered induction phase. Overall, 295 patients (98.0%) had at least 1 adverse event (AE), including 254 patients (84.4%) with grade ≥3 AE. The grade ≥3 serious AEs occurred in 134 patients. No difference was seen in AE frequency between age groups, but grade ≥3AE frequency was higher in older patients. Overall, complete remission (CR) rate including incomplete hematological recovery (CR+CRi) (80.7% [95%CI: 75.74, 84.98]) was comparable between age groups (≤60 years [83.5%]; >60 to ≤70 years [82.5%]; little less in patients >70 years [64.1%]) and the type of anthracycline used in induction. CR+CRi rate was lower in males (76.4%) than females (84.4%). Overall, safety and efficacy of midostaurin remains consistent with previous findings, regardless of age, gender, or induction regimen. The trial is registered at clinicaltrials.gov: NCT03379727.