TP53-mutated AML and treatment outcomes in the era of hypomethylating agent/venetoclax therapy

Abstract Background TP53 mutations, present in 5–15% of acute myeloid leukemia (AML) cases, confer poor prognosis and may involve 17p deletions, point mutations, or both. While induction therapy with a hypomethylating agent (HMA) and venetoclax is widely used, outcomes in TP53-mutated AML remain poor. TP53 allelic status, commonly classified as single- or double-hit using variant allele frequency (VAF) and cytogenetic criteria, may help refine prognostication. This review of TP53-mutated AML assesses the influence of TP53 allelic status on outcomes in the era of HMA/venetoclax therapy. Methods We queried the electronic medical record system of Northwell Health for patients with newly diagnosed AML between 2019 and 2024 and selected cases with TP53 point mutations as identified by next generation sequencing (NGS) with a VAF ≥2%, cytogenetic changes involving 17p as assessed by fluorescence in-situ hybridization (FISH) and karyotyping, or both. Survival outcomes were measured by Kaplan-Meier analysis with log-rank testing. TP53 allelic status was classified as single-hit or double-hit using the criteria described by Grob et al., 2022 who demonstrated their ability to predict outcomes. A case was considered to be double-hit if it met any of the following criteria: 2 or more distinct TP53 point mutations regardless of VAF, a TP53 point mutation with a 17p cytogenetic change, or a TP53 point mutation with a VAF 55%. Induction therapy was considered intensive if it contained an anthracycline and cytarabine back bone (7+3 or IDA-FLAG). Results 957 cases of AML were identified. 104 (10.9%) met criteria for TP53-mutated disease, with a median age of 72 (range 32-92) years. AML categories were de novo in 60.6% (n= 63), secondary from prior myeloid neoplasm in 18.3% (n= 19), and therapy-related in 21.2% (n= 22). The incidence rates of single- and double-hit cases did not differ significantly across AML categories (χ2= 2.54). 91 cases had classifiable hit status: 27.5% (n= 25) were found to be single-hit at diagnosis, 72.5% (n= 66) were double-hit. Complex karyotypes were present in 81.7% of cases overall and were more common in double-hit cases (92.4%, n= 61) than in single-hit cases (64.0%, n= 16). Of the 78 patients who received any form of induction therapy, 24.4% received intensive therapy and 60.3% received HMA/venetoclax. Intensive treatment was administered to 24.0% of single-hit vs. 19.7% of double-hit cases. HMA/venetoclax was given to 55.0% of single-hit vs. 54.5% of double-hit cases. 5 single-hit cases and 7 double-hit cases underwent allogeneic stem cell transplantation. The median OS (mOS) for the TP53-mutated cohort was 5.9 months (95% CI, 4.8–7.9 months). There was no significant OS difference by induction regimen (intensive vs. HMA/venetoclax: 5.8 vs. 6.9 months; p=0.898), however within the population that received intensive induction, those with single-hit status had significantly longer mOS compared to double-hit (18.2 vs. 3.0 months; p=0.0084). In contrast, no survival difference by hit status was observed in patients treated with HMA/venetoclax (7.4 vs. 6.9 months; p=0.964). Discussion While no overall survival difference was observed between single- and double-hit TP53-mutated AML patients, subgroup analysis revealed significantly improved survival among single-hit patients receiving intensive chemotherapy. This difference was not seen with HMA/venetoclax induction suggesting that TP53 allelic status may inform selection of induction therapy. Prior studies in TP53-mutated AML reporting no difference in survival based on induction type may have been confounded by the higher prevalence of biallelic status. Comprehensive TP53 hit status should be routinely reported to further clarify its prognostic and predictive relevance.