TP53 Mutations with Low Variant Allele Frequency Predict Short Survival in Chronic Lymphocytic Leukemia

Area of Science:

• Oncology
• Genetics
• Hematology

Background:

• TP53 mutations are linked to poor prognosis and treatment resistance in chronic lymphocytic leukemia (CLL).
• The clinical significance of low-variant allele frequency (VAF) TP53 mutations in CLL remains incompletely understood.

Purpose of the Study:

• To investigate the clinical impact of subclonal TP53 mutations (below 10-15% VAF) in chronic lymphocytic leukemia (CLL).
• To determine if low-VAF TP53 mutations affect patient survival and treatment outcomes.

Main Methods:

• Retrospective analysis of TP53 mutations using deep next-generation sequencing in training and validation cohorts.
• Evaluation of mutation variant allele frequency (VAF) above (high-VAF) and below (low-VAF) a 10.0% threshold.
• Confirmation of findings in a cohort of CLL patients treated with fludarabine-cyclophosphamide-rituximab (FCR) or similar regimens.

Main Results:

• TP53 mutations were detected in 97/684 patients (training) and 71/536 patients (validation).
• Patients with TP53 mutations had significantly shorter overall survival (OS) compared to TP53 wild-type patients, regardless of VAF.
• A prognostic model incorporating low-VAF TP53 mutations improved risk stratification compared to models considering only high-VAF mutations (c-indices 0.643 vs. 0.603, P < 0.0001).

Conclusions:

• TP53 mutations impact overall survival in CLL irrespective of their variant allele frequency.
• The findings suggest a revised definition of TP53 mutated CLL for clinical application.
• Incorporating low-VAF TP53 mutations enhances prognostic accuracy in CLL.