FLT3 inhibitors in acute myeloid leukemia: A network meta-analysis of phase III trials.

Abstract

e18505 Background: FLT3 inhibitors improve outcomes in FLT3-mutated acute myeloid leukemia (AML); however, no head-to-head phase III comparisons exist among available agents. Updated randomized data from RATIFY (midostaurin), QUANTUM-First (quizartinib), and ADMIRAL (gilteritinib) enable indirect comparative effectiveness assessment of FLT3-directed therapy across treatment settings. Methods: A frequentist network meta-analysis was performed using phase III randomized trials enrolling FLT3-mutated AML patients. Reported hazard ratios (HRs) for overall survival (OS) and event-free survival (EFS) were extracted. Random-effects network models estimated treatment effects versus chemotherapy and ranking probabilities (P-scores). The evidence network was anchored through shared chemotherapy control arms. Frontline survival comparisons included RATIFY and QUANTUM-First; ADMIRAL was analyzed separately due to relapse/refractory (R/R) population differences. Results: Across five comparisons (~1,600 patients), midostaurin (HR 0.78; 95% CI 0.63–0.96) and quizartinib (HR 0.78; 95% CI 0.62–0.98) each significantly reduced mortality versus placebo in frontline AML. Indirect comparison demonstrated no detectable difference between the two agents (HR 1.00; 95% CI 0.73–1.36). Ranking analysis assigned near-identical P-scores to midostaurin and quizartinib (0.74 vs 0.74), supporting equivalent likelihood of benefit in the frontline setting. In the R/R population, gilteritinib significantly improved survival compared with salvage chemotherapy (HR 0.64; 95% CI 0.49–0.83). Conclusions: Midostaurin and quizartinib demonstrate equivalent survival probability in frontline FLT3-mutated AML based on current randomized evidence, challenging assumptions of superiority among FLT3 inhibitors. Gilteritinib remains an effective salvage option in relapsed disease but reflects a distinct treatment setting rather than comparative frontline potency. Interpretation is limited by cross-trial differences in age eligibility, FLT3 subtype inclusion, chemotherapy backbones, and trial era, which may affect transitivity assumptions in this network meta-analysis. This frequentist network meta-analysis incorporates mature survival updates from RATIFY and QUANTUM-First and demonstrates near-identical ranking probabilities (P-scores 0.74 vs 0.74), supporting equivalent frontline survival benefit of midostaurin and quizartinib. Future head-to-head trials incorporating MRD response and transplant-adjusted outcomes are warranted to refine sequencing strategies for FLT3-directed therapy.