<i>TP53</i> Mutations with Low Variant Allele Frequency Predict Short Survival in Chronic Lymphocytic Leukemia.

Abstract

In chronic lymphocytic leukemia (CLL), <i>TP53</i> mutations are associated with reduced survival and resistance to standard chemoimmunotherapy (CIT). Nevertheless, the clinical impact of subclonal <i>TP53</i> mutations below 10% to 15% variant allele frequency (VAF) remains unclear. Using a training/validation approach, we retrospectively analyzed the clinical and biological features of <i>TP53</i> mutations above (high-VAF) or below (low-VAF) the previously reported 10.0% VAF threshold, as determined by deep next-generation sequencing. Clinical impact of low-VAF <i>TP53</i> mutations was also confirmed in a cohort (<i>n</i> = 251) of CLL treated with fludarabine-cyclophosphamide-rituximab (FCR) or FCR-like regimens from two UK trials. In the training cohort, 97 of 684 patients bore 152 <i>TP53</i> mutations, while in the validation cohort, 71 of 536 patients had 109 <i>TP53</i> mutations. In both cohorts, patients with the <i>TP53</i> mutation experienced significantly shorter overall survival (OS) than <i>TP53</i> wild-type patients, regardless of the <i>TP53</i> mutation VAF. By combining <i>TP53</i> mutation and 17p13.1 deletion (del17p) data in the total cohort (<i>n</i> = 1,220), 113 cases were <i>TP53</i> mutated only (73/113 with low-VAF mutations), 55 del17p/<i>TP53</i> mutated (3/55 with low-VAF mutations), 20 del17p only, and 1,032 (84.6%) <i>TP53</i> wild-type. A model including low-VAF cases outperformed the canonical model, which considered only high-VAF cases (c-indices 0.643 vs. 0.603, <i>P</i> < 0.0001), and improved the prognostic risk stratification of CLL International Prognostic Index. Clinical results were confirmed in CIT-treated cases (<i>n</i> = 552) from the retrospective cohort, and the UK trials cohort. <i>TP53</i> mutations affected OS regardless of VAF. This finding can be used to update the definition of <i>TP53</i> mutated CLL for clinical purposes.