Clinical and genetic characteristics predict outcomes of acute myeloid leukemia patients with FLT3 mutations receiving venetoclax-based therapy

Background: Acute myeloid leukemia (AML) is a heterogeneous disease, and its heterogeneity is associated with treatment response. Despite the demonstrated success of venetoclax (VEN)-based therapy for AML, the effect of FLT3 mutations on the efficacy of the therapy is poorly understood. We aimed to compare the efficacy of VEN-based therapy between FLT3-mutated (FLT3(mut)) and FLT3 wild-type (FLT3(wt)) patients and identify the predictors of efficacy in FLT3(mut) patients. Methods: A total of 266 AML patients (127 newly diagnosed [ND] and 139 refractory/relapsed [R/R]) receiving VEN-based regimens were enrolled in this study. A retrospective analysis was performed, and the treatment responses and overall survival (OS) of FLT3(mut) and FLT3(wt) patients were compared. Logistic regression and Cox proportional hazards model were applied to examine the clinical and genetic predictors of outcomes. Results: With a median of two cycles of VEN-based therapy, for the ND AML cohort, the FLT3(mut) group had a comparable composite complete remission (CRc) rate with the FLT3(wt) group (79.3% vs. 61.2%, p = 0.072). For the R/R AML cohort, the FLT3(mut) group exhibited a lower CRc rate than the FLT3(wt) group. With a median follow-up of 8.6 months (95% confidence interval [CI], 8.0-10), the median OS observed in the FLT3(mut) and FLT3(wt) groups for both cohorts were close (14.0 vs. 19.9 months, p = 0.356; 10.0 vs. 11.9 months, p = 0.680). For the ND AML cohort, in FLT3(mut) patients, MRD-positive and RNA-splicing mutation predicted inferior survival (hazard ratio [HR], 10.3; 95% CI: 2.0-53.8; p = 0.006; HR 11.3; 95% CI: 1.2-109.3; p = 0.036, respectively). For the R/R AML cohort, in FLT3(mut) patients, adverse ELN risk was associated with an inferior response (odds ratio [OR], 0.2; 95% CI: 0.1-0.8; p = 0.025), whereas NPM1 co-mutation was associated with a superior response (57.1%; OR, 6.7; 95% CI: 1.5-30.1; p = 0.014). CR/CRi predicted a better survival (HR 0.2; 95% CI: 0.1-0.8; p = 0.029), while DNMT3A mutation predicted an inferior survival (HR, 4.6; 95% CI: 1.4-14.9; p = 0.011). Conclusions: FLT3 mutations may influence response to VEN-based therapy in R/R AML patients but not in ND AML patients. Furthermore, clinical and genetic characteristics could predict outcomes of FLT3(mut) patients receiving VEN-based therapy.