Exploring Efficacy and Predictors of Response to Venetoclax and Hypomethylating Agents in Newly Diagnosed Acute Myeloid Leukemia: A Real‐World Study

This retrospective study aimed to identify molecular predictors of treatment response and survival in 207 newly diagnosed acute myeloid leukemia (AML) patients treated with Venetoclax combined with hypomethylating agents (VEN-HMAs). After one treatment course, the composite complete remission (CR/CRi) rate was 69.6% (144/207), with 70.5% (93/132) of responders achieving minimal residual disease (MRD) negativity. According to the 2017 ELN risk stratification, the CR/CRi rates in the favorable-, intermediate-, and high-risk groups were 77.2%, 64.0%, and 66.6%, respectively. For treatment response, RUNX1-RUNX1T1, FLT3-ITD, and TP53 mutations independently predicted unfavorable to VEN-HMAs therapy. Multivariable analysis identified NRAS and PTPN11 mutations as independent adverse prognostic factors for overall survival, while achievement of CR/CRi after the first treatment course and receiving hematopoietic stem cell transplantation (HSCT) were favorable predictors. Based on molecular status, patients were stratified into three prognostic groups. The median OS was 9.5 months in the TP53-mutant (low-benefit) group and 21 months in the medium-benefit group (TP53 wild-type with FLT3-ITD or K/NRAS mutations). The high-benefit group (wild-type TP53, no FLT3-ITD, and wild-type K/NRAS) had a significantly superior OS (not reached) compared to the others (p < 0.001), while OS between the medium- and low-benefit groups was comparable (p = 0.096). VEN-HMAs therapy is associated with high response rates in this real-world cohort, though treatment response varies substantially by molecular profile. A comprehensive understanding of these influencing factors and the development of refined risk stratification systems require further investigation.