Prognostic and therapeutic impacts of mutant TP53 variant allelic frequency in newly diagnosed acute myeloid leukemia

TP53 mutations are associated with poor outcomes in acute myeloid leukemia (AML). The prognostic impact of mutant TP53 (TP53^mut) variant allelic frequency (VAF) is not well established, nor is how this information might guide optimal frontline therapy. We retrospectively analyzed 202 patients with newly diagnosed TP53-mutated AML who underwent first-line therapy with either a cytarabine- or hypomethylating agent (HMA)-based regimen. By multivariate analysis, TP53^mut VAF.40% was independently associated with a significantly higher cumulative incidence of relapse (P 5.003) and worse relapse-free survival (P 5.001) and overall survival (OS; P 5.003). The impact of TP53^mut VAF on clinical outcomes was driven by patients treated with a cytarabine-based regimen (median OS, 4.7 vs 7.3 months for VAF.40% vs #40%; P 5.006), whereas VAF did not significantly affect OS in patients treated with HMA. The addition of venetoclax to HMA did not significantly affect OS compared with HMA without venetoclax, both in the entire TP53-mutated population and in patients stratified by TP53^mut VAF. Among patients with TP53^mut VAF #40%, OS was superior in those treated with higher-dose cytarabine, whereas OS was similarly poor for patients with TP53^mut VAF.40% regardless of therapy. The best long-term outcomes were observed in those with 1 TP53 mutation with VAF #40% who received a frontline cytarabine-based regimen (2-year OS, 38% vs 6% for all others; P,.001). In summary, TP53^mut VAF provides important prognostic information that may be considered when selecting frontline therapy for patients with newly diagnosed TP53-mutated AML.