# Low-VAF TP53-Mutated AML Displays Distinct Biological Features in a Single-Center Cohort

## TL;DR

This study finds that TP53-mutated AML with low variant allele frequency has unique biological features and may be a distinct subgroup.

## Contribution

The study identifies distinct biological and molecular features of TP53-mutated AML with low variant allele frequency (VAF < 10%).

## Key findings

- Low-VAF TP53-mutated AML cases show fewer adverse cytogenetic abnormalities and a more adverse molecular profile.
- These cases have higher frequencies of ASXL1 and SRSF2 mutations and a distinct blast immunophenotype.
- TP53 hotspot mutations are more common in low-VAF cases, but survival outcomes are similarly poor.

## Abstract

Background: The International Consensus Classification (ICC) currently proposes an empirical variant allele frequency (VAF) threshold of 10% to define TP53-mutated acute myeloid leukemia (AML) and to distinguish oncogenic driver from concomitant mutations. However, the optimal cutoff remains uncertain, and the biological and clinical features of low-VAF cases have not been systematically characterized. Methods: In this single-center retrospective cohort study, we stratified TP53-mutated AML by a 10% VAF cutoff and compared clinical characteristics, cytogenetic and molecular profiles, and survival outcomes between groups. Results: The VAF < 10% group exhibited a distinctive profile: fewer adverse cytogenetic abnormalities [complex karyotype, −7, −5/del(5q)], a more adverse molecular profile (EVI1 overexpression, greater co-mutation burden, higher frequencies of ASXL1 and SRSF2 mutations), and a higher proportion of CD34+CD38− blast immunophenotype. TP53 hotspot mutations were also more common. Survival analyses showed poor prognosis in both groups, and the VAF < 10% group showed numerically longer survival without statistical significance, indicating no clear survival advantage for low VAF. Conclusions: These data support the clinical relevance of the ICC 10% threshold. TP53-mutated AML with VAF < 10% may represent a biologically distinct subgroup. Further multicenter studies with larger cohorts are needed to validate and refine the VAF threshold for prognostic evaluation and individualized management.