Chen, Xin

Abstract Introduction Venetoclax combined with hypomethylating agents (VEN/HMA) is an approved frontline induction therapy for older or unfit patients with acute myeloid leukemia (AML). However, data comparing its efficacy and safety to intensive chemotherapy (IC) in intermediate-risk AML—characterized by molecular and cytogenetic heterogeneity—remain limited. Methods This multicenter, real-world retrospective study analyzed newly diagnosed intermediate-risk AML patients who received either VEN/HMA or IC. We evaluated composite complete remission (CRc) rates, transfusion and infection rates, long-term outcomes including overall survival (OS) and progression-free survival (PFS), and performed subgroup analyses to identify mutation-specific predictors of treatment response. Multivariable Cox regression was used to identify independent prognostic factors. Results A total of 229 intermediate-risk AML patients were included. VEN/HMA achieved a comparable CRc rate to IC (75.3% vs. 63.4%) with lower transfusion needs and fewer infections. Patients harboring FLT3-ITD, DNMT3A, or TET2 mutations showed greater benefit from VEN/HMA, while KIT-mutated patients responded more favorably to IC. Among patients who did not undergo allo-HSCT, VEN/HMA significantly improved 3-year OS (P = 0.001) and PFS (P = 0.008). No significant OS or PFS difference was observed in the allo-HSCT subgroup. In MRD-negative patients without transplant, those treated with VEN/HMA had superior OS compared to IC. Multivariable analysis identified VEN/HMA (HR = 0.613, P = 0.038) and allo-HSCT (HR = 0.11, P = 0.001) as independent predictors of better survival. Conclusions VEN/HMA is a safe and effective induction strategy for intermediate-risk AML, particularly in patients with BCL-2 inhibitor–sensitive mutations (FLT3-ITD, DNMT3A, TET2). These findings support a genotype-guided treatment approach in AML, complementing current risk stratification frameworks and informing individualized induction therapy decisions.