Real-world outcomes of triplet therapy with hypomethylating agent, venetoclax, and FLT3 inhibitor versus doublet therapy in FLT3-mutated acute myeloid leukemia.

e18532 Background: FLT3-mutated acute myeloid leukemia (AML) is associated with inferior outcomes, particularly among older or medically unfit patients treated with hypomethylating agent (HMA)-based regimens. While HMA plus venetoclax has become a standard backbone, the real-world benefits and safety of adding an FLT3 inhibitor beyond clinical trials remain incompletely defined. We evaluated short- and intermediate-term outcomes of triplet therapy compared with doublet therapy in a large real-world cohort. Methods: Using the TriNetX global research network (111 healthcare organizations), we identified adults (≥18 years) with FLT3-mutated AML treated between January 2017 and January 2025. Patients received either triplet therapy (HMA + venetoclax + FLT3 inhibitor [gilteritinib, midostaurin, sorafenib, or quizartinib]) or doublet therapy (HMA + venetoclax). Propensity score matching (1:1) was performed using >20 baseline variables, yielding 459 patients per cohort. Outcomes included all-cause mortality, tumor lysis syndrome (TLS), acute kidney injury (AKI), and sepsis at 90 days and 1 year. Survival was assessed using Kaplan–Meier analysis and Cox proportional hazards models. Results: After propensity matching, 459 patients in the triplet cohort and 459 patients in the doublet cohort were included in the 90-day and 1-year mortality analysis. At 90 days, mortality occurred in 26.1% of patients treated with triplet therapy versus 28.8% with doublet therapy, HR 0.87; 95% CI 0.68-1.11; p = 0.27. Mortality at 1 year occurred in 50.8% of triplet-treated patients compared with 57.3% of doublet-treated patients. In the Kaplan-Meier analysis, the median overall survival was 293 days in the triplet cohort versus 228 days in the doublet cohort. Triplet therapy was associated with a statistically significant reduction in mortality on Cox proportional hazards modeling (HR 0.81; 95% CI 0.67-0.96; log-rank p = 0.017). No significant differences were observed in rates of TLS, AKI, or sepsis between groups at 90-days or at 1 year. TLS occurred in 7.7% of triplet-treated patients versus 9.2% of doublet-treated patients (HR 0.77; 95% CI 0.46-1.29; p = 0.32). AKI occurred in 28.5% versus 26.0%, respectively (HR 1.05; 95% CI 0.76-1.47; p = 0.77), while sepsis occurred in 26.2% versus 23.9% (HR 1.03; 95% CI 0.75-1.41; p = 0.38). Conclusions: In this large real-world analysis of FLT3-mutated AML, triplet therapy incorporating a FLT3 inhibitor was associated with a significant improvement in 1-year overall survival compared with HMA plus venetoclax alone, without an apparent increase in toxicity. These findings support the real-world feasibility and potential benefit of FLT3 inhibitor-based triplet regimens and complement emerging prospective data, particularly in older or unfit populations underrepresented in clinical trials.