Venetoclax-based regimens are non-inferior to chemotherapy in core binding factor AML, including AML1-ETO

Abstract Background Core binding factor acute myeloid leukemia (CBF-AML) is a favorable-risk molecular subtype defined by the presence of either AML1-ETO (RUNX1::RUNX1T1) or CBFβ-MYH11 (CBFB::MYH11) fusion transcripts. While standard “7+3” induction chemotherapy remains the first-line treatment, venetoclax (VEN) combined with hypomethylating agents (HMAs) or cytotoxic agents has emerged as a promising alternative, particularly for unfit patients. However, recent small-cohort studies have reported suboptimal composite remission rates (CR/CRi <40–65%) with VEN-based regimens in AML1-ETO–positive patients, raising concerns regarding its efficacy in this subgroup. Comprehensive real-world comparisons across fusion subtypes and treatment regimens are lacking. Methods We retrospectively analyzed 203 patients diagnosed with CBF-AML at West China Hospital between 2019 and 2025, all harboring either AML1-ETO (n=115) or CBFβ-MYH11 (n=88) fusion genes. Patients were grouped by induction regimen: standard intensive chemotherapy (CHEM; n=123) or VEN-based therapy (VEN; n=80), including VEN+HMA or VEN+chemotherapy. Efficacy outcomes included composite complete remission (CR/CRi), partial remission (PR), and non-response (NR). Overall survival (OS) was estimated using the Kaplan–Meier method and compared via the log-rank test. The majority were newly diagnosed AML cases; only 19 patients (9.4%) were relapsed or refractory at VEN initiation. Results In the overall CBF-AML cohort, the CR/CRi rate was 82.3% in the VEN group and 71.0% in the CHEM group (p=0.187).Among AML1-ETO–positive patients, VEN resulted in a CR/CRi rate of 75.0% vs 66.2% with CHEM (p=0.406).Among CBFβ-MYH11–positive patients, CR/CRi rates were 89.1% with VEN vs 84.1% with CHEM (p=0.728). No significant differences in OS were observed between VEN and CHEM in the overall cohort (p=0.45), AML1-ETO subgroup (p=0.42), or CBFβ-MYH11 subgroup (p=0.61). Notably, several AML1-ETO patients who failed chemotherapy achieved remission after switching to VEN, highlighting its potential utility as a salvage regimen. Conclusion This real-world study demonstrates that VEN-based regimens achieve comparable remission and survival outcomes to standard chemotherapy in patients with molecularly defined CBF-AML. Importantly, even in the AML1-ETO subgroup-previously considered less responsive to VEN-favorable outcomes were observed, including in relapsed/refractory settings. These findings support VEN as a viable alternative or salvage option in CBF-AML and warrant further validation through prospective randomized trials.