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PURPOSE: In chronic lymphocytic leukemia (CLL), TP53 mutations are associated with reduced survival and resistance to standard chemo-immunotherapy (CIT). Nevertheless, the clinical impact of subclonal TP53 mutations below 10-15% variant allele frequency (VAF) remains unclear. EXPERIMENTAL DESIGN: Using a training/validation approach, we retrospectively analyzed the clinical and biological features of TP53 mutations above (high-VAF) or below (low-VAF) the previously reported 10.0% VAF threshold, as determined by deep next-generation-sequencing (NGS). Clinical impact of low-VAF TP53 mutations was also confirmed in a cohort (n=251) of CLL treated with FCR or FCR-like regimens from two UK trials. RESULTS: In the training cohort 97/684 patients bore 152 TP53 mutations while in the validation cohort 71/536 patients had 109 TP53 mutations. In both cohorts, TP53 mutated patients experienced significantly shorter overall survival (OS) than TP53 wild-type (wt) patients, irrespective of the TP53 mutation VAF. By combining TP53 mutation and 17p13.1 deletion (del17p) data in the total cohort (n=1,220), 113 cases were TP53 mutated only (73/113 with low-VAF mutations), 55 del17p/TP53 mutated (3/55 with low-VAF mutations), 20 del17p only, and 1,032 (84.6%) TP53wt. A model including low-VAF cases outperformed the canonical model, which considered only high-VAF cases (c-indices 0.643 vs. 0.603, P<0.0001), and improved the prognostic risk stratification of CLL-IPI. Clinical results were confirmed in CIT-treated cases (n=552) from the retrospective cohort, and the UK trials cohort. CONCLUSIONS: TP53 mutations impacted OS irrespective of VAF. This finding can be used to update the definition of TP53 mutated CLL for clinical purposes.

Original publication

DOI

10.1158/1078-0432.CCR-21-0701

Type

Journal article

Journal

Clin Cancer Res

Publication Date

20/07/2021