Overall survival in TP53-mutated AML and MDS

Area of Science:

• Hematology
• Oncology
• Genetics

Background:

• TP53 mutations are common in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), often indicating a poor prognosis.
• Updated 2022 International Consensus Classification (ICC) and World Health Organization (WHO) guidelines classify p53-mutated AML/MDS.
• The prognostic implications of TP53 mutations under these new guidelines, including co-mutations and their impact on overall survival (OS), require further investigation.

Purpose of the Study:

• To evaluate the prognostic significance of TP53 mutations in AML and MDS patients based on the 2022 ICC and WHO classification criteria.
• To identify key clinical and molecular predictors of overall survival (OS) in this patient cohort.

Main Methods:

• Retrospective chart review of 210 AML or MDS patients with TP53 mutations identified via next-generation sequencing (NGS) at Yale New Haven Hospital (2015-2023).
• Classification of patients according to the 2022 ICC and WHO guidelines.
• Kaplan-Meier curves, log-rank testing, and Cox proportional hazards models were used to analyze the association between clinical/molecular data and OS.

Main Results:

• Multi-hit TP53 mutations correlated with poorer OS in MDS (WHO: p=.02; ICC: p=.01) but not AML.
• The strongest predictors of OS were platelet count < 50K (HR: 2.01) and TP53 variant allele frequency (VAF) ≤ 40% (HR: 0.68).
• Blast count, complex karyotype, and specific TP53 mutation features did not show a significant association with OS.

Conclusions:

• In a cohort classified by 2022 ICC/WHO criteria, TP53 VAF and thrombocytopenia are significant predictors of OS in AML/MDS.
• These findings suggest that VAF and platelet count are more critical prognostic indicators than blast count or TP53 mutation characteristics.
• The results underscore the utility of the updated criteria in identifying patients with aggressive disease biology and poor prognosis.