Simple SummaryTP53mutations are adverse-risk genetic aberrations in acute myeloid leukemia (AML). The optimal treatment approach in patients withTP53-mutated (TP53MUT) AML remains unclear. We aimed to evaluate the prognostic implications of different frontline treatment strategies and transplantation for patients withTP53MUTAML. Patients treated with intensive induction or azacitidine-venetoclax induction had no significant improvement in survival compared to patients treated with other HMA regimens despite having higher complete remission rates. Transplantation was not significantly associated with improved outcomes in time-dependent or landmark analysis, however, transplanted patients with lowerTP53MUTvariant allele frequency (VAF) at the time of diagnosis had superior outcomes compared to transplanted patients with higherTP53VAF. Current therapeutic strategies remain ineffective forTP53MUTAML patients, which highlights the urgent need for new treatment strategies for this high-risk population.AbstractTP53mutations are associated with extremely poor outcomes in acute myeloid leukemia (AML). The outcomes of patients withTP53-mutated (TP53MUT) AML after different frontline treatment modalities are not well established. Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative procedure for AML; however, long-term outcomes among patients withTP53MUTAML after allo-HCT are dismal, and the benefit of allo-HCT remains controversial. We sought to evaluate the outcomes of patients withTP53MUTAML after treatment with different frontline induction therapies and allo-HCT. A total of 113 patients withTP53MUTAML were retrospectively evaluated. Patients withTP53MUTAML who received intensive or azacitidine-venetoclax induction had higher complete remission rates compared to patients treated with other hypomethylating-agent-based induction regimens. However, OS and EFS were not significantly different among the induction regimen groups. Allo-HCT was associated with improved OS and EFS among patients withTP53MUTAML; however, allo-HCT was not significantly associated with improved OS or EFS in time-dependent or landmark analysis. While the outcomes of all patients were generally poor irrespective of therapeutic strategy, transplanted patients with lowerTP53MUTvariant allele frequency (VAF) at the time of diagnosis had superior outcomes compared to transplanted patients with higherTP53VAF. Our study provides further evidence that the current standards of care for AML confer limited therapeutic benefit to patients withTP53mutations.