<i>TP53</i> variant allele frequency as a driver of survival in <i>TP53</i> -mutated acute myeloid leukemia.

Abstract

e18508 Background: TP53 -mutated AML represents a challenging subtype with only 10-15% of patients achieving long-term survival. Determinants that best predict disease behavior remain incompletely defined. Methods: We conducted a retrospective cohort study of adults with TP53- mutated AML treated at the University of Kentucky from 2016-2025. TP53 alterations were characterized by number of mutations, allelic status, mutation type, hotspot status, and maximum variant allele frequency (VAF). TP53 maximum VAF was assessed as both continuous and categorical variables. Primary endpoints were CR/CRi (per ELN), RFS, and OS. Survival was analyzed using Kaplan-Meier, and associations were tested using Cox models. Results: Sixty-five patients with TP53 -mutated AML were identified, with median age of 64 years. 69% were male, 28% had prior MDS, and 23% had therapy-related AML. Complex karyotype was present in 89%, most commonly involving 5q (83%), 7q (68%), and 17p (63%). Co-occurring pathogenic mutations were uncommon: 52% lacking additional pathogenic variants, while 15% had IDH1/2 and 11% had DNMT3A mutations. TP53 alterations were predominantly multi-hit (81%), with 72% of patients harboring a single mutation, while 25% had two or more. Mutations types included missense-only (77%), hotspot missense (24%), and truncating variants (15%). Induction therapy was HMA/venetoclax in 45% and intensive chemotherapy for 31%. Among treated patients, the overall CR/CRi rate was 37%. Median OS of the entire sample was 6.0 months. HMA/venetoclax was associated with a significantly higher likelihood of achieving CR/CRi compared with intensive induction chemotherapy (63% vs. 11%, p=0.002), although RFS did not differ among responders. Achievement of CR/CRi was similar between those with TP53 VAF &lt;40% and ≥40% (42% vs. 33%, p=0.7) Factors independently associated with inferior OS included deletion 5q (HR 2.57, p=0.038), TP53 VAF ≥40% (HR 2.71, p=0.002), and increasing age (HR 1.38 per 10 years, p=0.016). Median OS for TP53 VAF &lt;40% was 12.8 months and 4.5 months for TP53 VAF ≥40%. After adjusting for age and allogeneic HSCT in multivariable analysis, TP53 VAF ≥40% remained independently associated with inferior OS (HR 2.50, p=0.006). Continuous modeling of TP53 VAF showed a dose-dependent relationship with OS. In contrast, type of TP53 mutation (truncating, splice-site, missense-only, or hotspot), allelic status, and number of TP53 mutations were not associated with response, RFS, or OS. Conclusions: These findings highlight substantial biological heterogeneity within TP53 -mutated AML. TP53 allelic burden, rather than mutation class, represents a strong prognostic indicator. &lt;40% (n 28) ≥40% (n 34) p-value Age (months) 66 (63-69) 63 (58 - 73) 0.3 Prior MDS % 36 21 0.3 tAML % 29 21 0.6 TP53 % Multihit 73 88 0.12 Muts - 1, ≥2 75, 25 74, 26 Truncating 15 15 Splice 11 6 Missense Only 75 79 Hotspot 30 18 Induction % &gt;0.9 HMA/Ven 46 44 Intensive 32 30