Background
Phase 3 RCT (n=371), AML with FLT3 (ITD, or TKD D835/I836) mutations refractory to 1-2 cycles of anthracycline-based induction or in hematologic relapse after CR. Randomized 2:1 to gilteritinib vs salvage chemotherapy.
Interventions and follow up
Arm A: Gilteritinib 120 mg/day PO, 28-day cycles
Arm B: Salvage chemotherapy (investigator choice): MEC; FLAG-IDA; low-dose cytarabine; or azacitidine
Primary endpoint: OS
Median follow-up: 17.8 mo
Arm B: Salvage chemotherapy (investigator choice): MEC; FLAG-IDA; low-dose cytarabine; or azacitidine
Primary endpoint: OS
Median follow-up: 17.8 mo
Results
mOS: 9.3 vs 5.6 mo (A vs B); HR 0.64, 95%CI 0.49-0.83, P<.001
1-yr OS: 37.1% vs 16.7%
mEFS: 2.8 vs 0.7 mo, HR 0.79, 95%CI 0.58-1.09
CR/CRi: 34.0% vs 15.3%
CR: 21.1% vs 10.5%
Transfusion independence: achieved in a higher proportion on gilteritinib than chemotherapy.
1-yr OS: 37.1% vs 16.7%
mEFS: 2.8 vs 0.7 mo, HR 0.79, 95%CI 0.58-1.09
CR/CRi: 34.0% vs 15.3%
CR: 21.1% vs 10.5%
Transfusion independence: achieved in a higher proportion on gilteritinib than chemotherapy.
Adverse events
Hematologic/cytopenias (grade ≥3): Febrile neutropenia 45.9% vs 36.7%; anemia 40.7% vs 30.3%; thrombocytopenia 22.8% vs 16.5%.
Hepatic: Elevated ALT 13.8% vs 4.6%; elevated AST 36% vs 2%.
Other: Differentiation syndrome ~3% on gilteritinib; QT prolongation, PRES, and pancreatitis reported in FDA labeling. Discontinuation for AEs lower with gilteritinib than chemotherapy.
Hepatic: Elevated ALT 13.8% vs 4.6%; elevated AST 36% vs 2%.
Other: Differentiation syndrome ~3% on gilteritinib; QT prolongation, PRES, and pancreatitis reported in FDA labeling. Discontinuation for AEs lower with gilteritinib than chemotherapy.
Conclusions
Gilteritinib provided a significant OS benefit over salvage chemotherapy in relapsed/refractory FLT3-mutated AML, with higher remission rates and favorable tolerability.
Key Limitations
Open-label; heterogeneous control regimens of varying intensity. Subsequent allogeneic HCT permitted, confounding survival interpretation. Restricted to FLT3-mutated disease; resistance mechanisms (e.g., RAS/MAPK) limit durability.
Clinical Context
FDA (2018) and EMA-approved for relapsed/refractory FLT3-mutated AML. ELN/ASCO frameworks recommend gilteritinib as preferred therapy in this setting; responders should be considered for allogeneic HCT, with post-transplant gilteritinib maintenance under study.
FDA labeling
FDA labeling
References