Selective efficacy of venetoclax in unfit patients with acute myeloid leukemia with myelodysplasia-related gene mutations under low-intensity therapy.

According to the 2022 International Consensus Classification (ICC) guidelines, nine myelodysplasia-related (MDS-related) gene mutations are classified as adverse-risk markers in acute myeloid leukemia (AML) under intensive therapy (INT). Although venetoclax (VEN) has demonstrated clinical benefit in subsets of AML with MDS-related gene mutations (AML-MR), its efficacy across all nine mutations remains unclear. In this retrospective study involving 453 AML-MR patients, the overall composite complete remission (CRc) rate was 62.6% (275/439). Among fit patients receiving INT, 57.7% (86/149) achieved CRc after a single cycle of induction therapy (IND1), while 62.7% (79/126) of unfit patients receiving low-intensity therapy (LIT) achieved CRc after IND1. VEN significantly improved CRc rates in unfit patients treated with LIT (45.9% vs. 30.0%, P = 0.002), but not in fit patients receiving INT (61.1% vs. 45.0%, P = 0.052). In both groups, CRc after IND1 was strongly associated with improved overall survival (OS). Subgroup analysis showed that hematopoietic stem cell transplantation (HSCT) significantly prolonged OS and relapse-free survival (RFS) in patients without favorable-risk cytogenetics (P = 0.002 for OS, P < 0.001 for RFS), but conferred no survival benefit in those with favorable-risk cytogenetics (P = 0.119 for OS, P = 0.437 for RFS). These findings support the use of VEN to enhance early remission and survival outcomes in unfit AML-MR patients and suggest that HSCT should be considered primarily in those lacking favorable-risk cytogenetics.