The landscape and evolution of clonal hematopoiesis in chronic lymphocytic leukemia

Chronic lymphocytic leukemia (CLL) and clonal hematopoiesis (CH) both commonly occur in older individuals. To characterize CH in CLL, 620 patients were analyzed (CLL12 [ibrutinib vs placebo] and CLL14 [venetoclax-obinutuzumab (Ven-Obi) vs chlorambucil-obinutuzumab (Clb-Obi)]) using error-corrected next-generation sequencing with a variant allele frequency (VAF) threshold of 0.5%. Median follow-up was 76.1 months, and median age was 68 years. CH was detected in 58.2% of patients, most commonly affecting DNMT3A, TET2, TP53, and ASXL1. Longitudinal analysis in CLL14 revealed persistence of the majority of CH clones during follow-up, whereas in more than half of the patients, additional CH mutations were detected. BAX- and U2AF1-mutated CH emerged during Ven-Obi exposure, and PPM1D-mutated CH emerged during Clb-Obi exposure, highlighting treatment gene-specific selection. Clonal fitness analyses revealed accelerated CH clone expansion during therapy, followed by slower growth after treatment. In vitro, genetically modified CD34+ hematopoietic stem/progenitor cells harboring BAX mutations showed enhanced survival and decreased apoptosis. CH was associated with neutropenia, and all patients with Richter transformation (RT; n = 11) had CH. Whole-exome sequencing delineated the contribution of CH mutations in 2 of 4 investigated patients with RT. Large CH clone size (>10% VAF) was independently associated with shorter overall survival with placebo (P = .049) and shorter progression-free survival with Clb-Obi after adjusting for age, immunoglobulin heavy chain variable status, and del(17p). In contrast, CH had no prognostic impact in patients receiving targeted therapies. This study demonstrates the high prevalence of CH, highlights its differential impact across CLL therapies, and underscores its adverse influence on patient outcomes.