This study compares the outcomes of venetoclax (VEN) in combination with hypomethylating agents (HMA) versus HMA-based therapy in treatment-naive TP53-mutated acute myeloid leukemia (AML). TP53 mutations are associated with poor prognosis and resistance to traditional therapies. The study analyzed data from 381 patients with TP53m AML, of which 154 were eligible for analysis (50 HMA and 104 HMA + VEN). Key findings include: - Higher complete remission rates (35% vs. 18%) and a longer median duration of response (15.6 months vs. 7.93 months) in the HMA + VEN group. - A higher proportion of patients in the HMA + VEN group progressed to allogeneic stem cell transplants (allo-HCT) (13% vs. 4%). - No significant differences in overall survival (OS) or event-free survival (EFS) between the two groups. - Multivariate analysis showed that achieving complete remission (CR/cri) and undergoing allo-HCT were favorable for OS, but complex cytogenetics were associated with shorter OS. The study highlights the need for more effective treatment strategies, particularly in TP53m AML, and suggests that immunotherapeutics and approaches targeting mutant TP53 protein may offer promise. However, the retrospective design and selection bias are limitations.This study compares the outcomes of venetoclax (VEN) in combination with hypomethylating agents (HMA) versus HMA-based therapy in treatment-naive TP53-mutated acute myeloid leukemia (AML). TP53 mutations are associated with poor prognosis and resistance to traditional therapies. The study analyzed data from 381 patients with TP53m AML, of which 154 were eligible for analysis (50 HMA and 104 HMA + VEN). Key findings include: - Higher complete remission rates (35% vs. 18%) and a longer median duration of response (15.6 months vs. 7.93 months) in the HMA + VEN group. - A higher proportion of patients in the HMA + VEN group progressed to allogeneic stem cell transplants (allo-HCT) (13% vs. 4%). - No significant differences in overall survival (OS) or event-free survival (EFS) between the two groups. - Multivariate analysis showed that achieving complete remission (CR/cri) and undergoing allo-HCT were favorable for OS, but complex cytogenetics were associated with shorter OS. The study highlights the need for more effective treatment strategies, particularly in TP53m AML, and suggests that immunotherapeutics and approaches targeting mutant TP53 protein may offer promise. However, the retrospective design and selection bias are limitations.