1. TP53 Mutations with Low Variant Allele Frequency Predict Short Survival in Chronic Lymphocytic Leukemia
- Author
-
Peter Hillmen, Davide Rossi, Riccardo Bomben, Filippo Vit, Michele Berton, Gabriele Pozzato, Anna Hockaday, Giovanni D'Arena, Jared A. Cohen, Pietro Bulian, Ilaria Cattarossi, Fortunato Morabito, Massimo Degan, Jacopo Olivieri, Gilberto Fronza, Chris Pepper, Francesco Di Raimondo, Anna Schuh, Annalisa Biagi, Jerry Polesel, Antonella Zucchetto, Francesca Rossi, Erika Tissino, Massimo Gentile, Giovanni Del Poeta, Valter Gattei, Francesco Zaja, Paola Nanni, Elena Vendramini, Eva Zaina, Annalisa Chiarenza, Federico Pozzo, Tamara Bittolo, Enrico Santinelli, Tiziana D'Agaro, Paola Varaschin, Alessandra Braida, Bomben, R., Rossi, F. M., Vit, F., Bittolo, T., D'Agaro, T., Zucchetto, A., Tissino, E., Pozzo, F., Vendramini, E., Degan, M., Zaina, E., Cattarossi, I., Varaschin, P., Nanni, P., Berton, M., Braida, A., Polesel, J., Cohen, J. A., Santinelli, E., Biagi, A., Gentile, M., Morabito, F., Fronza, G., Pozzato, G., D'Arena, G., Olivieri, J., Bulian, P., Pepper, C., Hockaday, A., Schuh, A., Hillmen, P., Rossi, D., Chiarenza, A., Zaja, F., Di Raimondo, F., Del Poeta, G., and Gattei, V.
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,endocrine system diseases ,business.industry ,Chronic lymphocytic leukemia ,Variant allele ,Tp53 mutation ,medicine.disease ,Training cohort ,Chemoimmunotherapy ,Internal medicine ,Cohort ,Overall survival ,Medicine ,Small TP53 Mutated sub-clones in CLL ,business ,neoplasms ,Short survival - Abstract
Purpose: In chronic lymphocytic leukemia (CLL), TP53 mutations are associated with reduced survival and resistance to standard chemoimmunotherapy (CIT). Nevertheless, the clinical impact of subclonal TP53 mutations below 10% to 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. Clinical impact of low-VAF TP53 mutations was also confirmed in a cohort (n = 251) of CLL treated with fludarabine-cyclophosphamide-rituximab (FCR) or FCR-like regimens from two UK trials. Results: In the training cohort, 97 of 684 patients bore 152 TP53 mutations, while in the validation cohort, 71 of 536 patients had 109 TP53 mutations. In both cohorts, patients with the TP53 mutation experienced significantly shorter overall survival (OS) than TP53 wild-type patients, regardless 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%) TP53 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, P < 0.0001), and improved the prognostic risk stratification of CLL International Prognostic Index. Clinical results were confirmed in CIT-treated cases (n = 552) from the retrospective cohort, and the UK trials cohort. Conclusions: TP53 mutations affected OS regardless of VAF. This finding can be used to update the definition of TP53 mutated CLL for clinical purposes.
- Published
- 2021