Efficacy of second-generation FLT3 inhibitors in FLT3-mutated AML: A meta-analysis of randomized controlled trials

Background: Second-generation FLT3 inhibitors have demonstrated clinical efficacy in FLT3-mutated acute myeloid leukemia (AML), although results across randomized trials remain inconsistent. This meta-analysis aimed to evaluate the efficacy of second-generation FLT3 inhibitors in patients with FLT3-mutated AML. Methods: We systematically searched databases including PubMed, Web of Science, and the Cochrane Library (from inception to August 2025) to identify randomized controlled trials (RCTs) evaluating second-generation FLT3 inhibitors for treating FLT3-mutated AML. The primary endpoints were overall survival (OS) and progression-free survival (PFS). A random-effects model was used to calculate pooled hazard ratios (HRs) and their 95% confidence intervals (95% CIs). The study protocol was registered in PROSPERO (CRD420251132477). Results: This meta-analysis included eight RCTs involving 2,231 patients. The second-generation FLT3 inhibitors evaluated were gilteritinib and quizartinib, and control treatments included placebo or active non-FLT3-inhibitor regimens. Patients treated with second-generation FLT3 inhibitors exhibited significant improvements in both OS (HR: 0.72, 95% CI: 0.62-0.84; P<0.001) and PFS (HR: 0.73, 95% CI: 0.63-0.86; P<0.001). Subgroup analysis revealed that gilteritinib showed improvements in both OS (HR: 0.71, P=0.001) and PFS (HR: 0.71, P<0.001), and quizartinib significantly improved OS (HR: 0.72, P=0.013) with no significant difference in PFS (HR: 0.75, P=0.142). Among patients with newly diagnosed AML, second-generation FLT3 inhibitors did not significantly improve PFS (HR: 0.73, P=0.127) but significantly improved OS (HR: 0.80, P=0.037). Among patients with relapsed/refractory AML, significant benefits were observed in both OS (HR: 0.67, P<0.001) and PFS (HR: 0.74, P=0.04). Benefits were observed across both placebo-controlled and active-comparator trials. Conclusion: Second-generation FLT3 inhibitors significantly improve survival outcomes in FLT3-mutated AML, particularly for gilteritinib and in relapsed/refractory disease. Further studies are needed to clarify mutation subtype-specific and dose-specific effects.