AML-256 A Phase 1 Study of Gilteritinib in Combination With Induction and Consolidation Chemotherapy in Patients With Newly Diagnosed Acute Myeloid Leukemia: Final Study Results

Context: Gilteritinib, an oral FLT3 inhibitor, demonstrated antileukemic responses in patients with FLT3^mut+ relapsed/refractory AML. Objective: Present final data from a phase 1 study of once-daily gilteritinib plus intensive chemotherapy in newly diagnosed (ND) AML. Design: This 4-part, open-label study (NCT02236013) assessed gilteritinib dose/schedule and effects of alternative anthracycline treatment. Intervention: Gilteritinib plus 7+3 induction with idarubicin or daunorubicin, plus ≤3 cycles of high-dose cytarabine and gilteritinib consolidation, and 2 years of single-agent gilteritinib maintenance treatment post consolidation or transplant. Patients: Adults with ND AML; FLT3 mutation not required for enrollment (known core binding factor fusions excluded). Main Outcome Measures: Safety, tolerability, PK, antileukemic effects. Results: Eighty patients were allocated to gilteritinib (safety analysis set, n=78 [age 23–77 y]; FLT3^mut+, n=44 [FLT3-ITD, n=33]). Median follow-up was 37.7 months. On-study HSCT was performed in 27/80 (33.8%) patients (FLT3^mut+, 26/44 [59.1%]). Dose-limiting toxicities occurred in 15/78 (19.2%) patients (200-mg/d cohort: neutropenia, n=1; neutropenic colitis, n=1). Maximum tolerated dose was 120 mg/d. Across the study, AEs led to gilteritinib discontinuation in 24.4% of patients. At end-of-treatment, composite complete remission (CRc: complete remission [CR] + CR with incomplete hematologic recovery [CRi] + CR with incomplete platelet recovery [CRp]), CR, CRi, and CRp rates were 79.7%, 54.4%, 21.5%, and 3.8%, respectively, in the overall population and 90.9%, 70.5%, 13.6%, and 6.8% among FLT3^mut+ patients. In the overall (n=79) and FLT3^mut+ populations (n=44), 60-day mortality rates were 1.3% and 0%, respectively, and median (95% CI) disease-free survival was 15.1 (9.5, 31.9) and 15.1 (4.9, 31.9) months. In the overall (n=69) and FLT3^mut+ populations (n=41) receiving ≥80 mg/d, median (95% CI) OS was 38.6 (21.7, NE) and 45.9 (30.8, NE) months, respectively, and the estimated 3-year OS rate was 56.0% and 60.1%. Anthracycline choice did not substantially impact CRc rate or toxicity. In patients who achieved CRc with gilteritinib ≥120 mg/d, mutational clearance of FLT3-ITD (summed FLT3 ITD:wildtype signal ratio ≤10–4) after consolidation was 84.6% (11/13). Conclusions: Gilteritinib plus induction and consolidation chemotherapy was well tolerated and resulted in CR, FLT3-ITD clearance, and long-term survival in patients with ND FLT3^mut+ AML, supporting ongoing randomized trials testing this approach against current standards.