Impact of TP53 mutations and their variant allele frequency in adults with newly diagnosed acute lymphoblastic leukemia Available to Purchase

• TP53 mutations are prevalent in Ph-negative B-cell ALL, increase in frequency with age, and often persist at remission.

• TP53 VAF ≥45% is associated with high relapse risk and poor survival in patients aged 60 years or older with Ph-negative B-cell ALL.

TP53 mutations are associated with unfavorable survival in many hematological malignancies. However, the impact of TP53 mutations and their variant allele frequency (VAF) in acute lymphoblastic leukemia (ALL) remain unclear. We retrospectively analyzed TP53 mutations and their VAF in newly diagnosed ALL. The overall incidence of TP53 mutations was 17.2%; TP53 mutations were more common in older patients (median age: 61 vs. 45 years, p<0.001) and in those with Ph-negative B-cell ALL (28% vs. 3% in others, p<0.001). The median TP53 VAF was 42% (range, 1-94). Patients ≥60 years with Ph-negative B-cell ALL and TP53 VAF ≥45% had poor outcomes, with 4-year event-free survival (EFS) and overall survival (OS) of 28%, driven primarily by increased relapse risk, even among patients treated with frontline inotuzumab ozogamicin (INO) and/or blinatumomab. Among patients <60 years who received frontline INO and/or blinatumomab, neither TP53 mutation nor VAF impacted EFS or OS. However, younger patients with TP53 VAF ≥45% had higher 4-year CIR (35%) than those with VAF <45% (8%) or wildtype (WT) TP53 and no high-risk features (4%). In multivariate analysis, TP53 VAF≥45% was independently associated with worse outcomes in patients ≥60 years, while neither TP53 status nor VAF predicted outcomes in younger patients. TP53 persistence at remission occurred in 44% of tested patients and was associated with increased ALL relapse risk. These results demonstrate that TP53 VAF is prognostic in older patients with Ph-negative B-cell ALL; high VAF may increase relapse risk but is not independently associated with survival in younger patients.