Tumor mutational load predicts time to first treatment in chronic lymphocytic leukemia (CLL) and monoclonal B-cell lymphocytosis beyond the CLL international prognostic index. American journal of hematology Kleinstern, G. n., O'Brien, D. R., Li, X. n., Tian, S. n., Kabat, B. F., Rabe, K. G., Norman, A. D., Yan, H. n., Vachon, C. M., Boddicker, N. J., Call, T. G., Parikh, S. A., Bruins, L. n., de Campos, C. B., Leis, J. F., Shanafelt, T. D., Ding, W. n., Cerhan, J. R., Kay, N. E., Slager, S. L., Braggio, E. n. 2020

Abstract

Next-generation sequencing identified ~60 genes recurrently mutated in chronic lymphocytic leukemia (CLL). We examined the additive prognostic value of the total number of recurrently mutated CLL genes [i.e., tumor mutational load (TML)] or the individually mutated genes beyond the CLL international prognostic index (CLL-IPI) in newly diagnosed CLL and high-count monoclonal B-cell lymphocytosis (HC MBL). We sequenced 59 genes among 557 individuals (112 HC MBL/445 CLL) in a multi-stage design, to estimate hazard ratios (HR) and 95% confidence intervals (CI) for time-to-first treatment (TTT), adjusted for CLL-IPI and sex. TML was associated with shorter TTT in the discovery and validation cohorts, with a combined estimate of continuous HR=1.27 (CI:1.17-1.39, P=2.6x10-8 ; c-statistic=0.76). When stratified by CLL-IPI, the association of TML with TTT was stronger and validated within low/intermediate risk (combined HR=1.54, CI:1.37-1.72, P=7.0x10-14 ). Overall, 80% of low/intermediate CLL-IPI cases with 2+ mutated genes progressed to require therapy within 5?years, compared to 24% among those without mutations. TML was also associated with shorter TTT in the HC MBL cohort (HR=1.53, CI:1.12-2.07, P=0.007; c-statistic=0.71). TML is a strong prognostic factor for TTT independent of CLL-IPI, especially among low/intermediate CLL-IPI risk and a better predictor than any single gene. Mutational screening at early stages may improve risk stratification and better predict TTT. This article is protected by copyright. All rights reserved.

View details for DOI 10.1002/ajh.25831

View details for PubMedID 32279347