The Landscape and Evolution of Clonal Hematopoiesis in Chronic Lymphocytic Leukemia
- Author(s)
- Al-Sawaf, O; Locher, BN; Christen, F; Hablesreiter, R; Rajamani, A; Robrecht, S; Zhang, C; Fink, AM; Tausch, E; Schneider, C; Ritgen, M; Kreuzer, KA; Kopp, K; Mertz, ME; Fustero-Torre, C; Kleo, K; Seymour, JF; Blombery, P; Bullinger, L; Chyla, B; Jin, HY; Jiang, Y; Stilgenbauer, S; Hallek, MJ; Eichhorst, BF; Langerbeins, P; Fischer, K; Damm, F;
- Journal Title
- Blood
- Publication Type
- Online publication before print
- Abstract
- Chronic lymphocytic leukemia (CLL) and clonal hematopoiesis (CH) both commonly occur in elderly individuals. To characterize CH in CLL, 620 patients from two German CLL Study Group trials 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 VAF threshold of 0.5%. Median follow-up was 76.1 months, median age 68 years. CH was detected in 58.2%, most commonly affecting DNMT3A, TET2, TP53, and ASXL1. Longitudinal analysis in CLL14 revealed persistence of the vast majority of CH clones during follow-up, while in more than half of patients additional CH mutations were detected. BAX- and U2AF1-mutated CH emerged during Ven-Obi, and PPM1D-mutated CH during Clb-Obi exposure, highlighting treatment-gene-specific selection. Clonal fitness analyses revealed accelerated CH clone expansion during therapy, followed by slower growth post-treatment. In-vitro, genetically modified CD34+ hematopoietic stem/progenitor cells harboring BAX mutations showed enhanced survival and decreased apoptosis. CH was associated with neutropenia (p=0.031) and all patients with Richter transformation (RT; n=11) had CH (p=0.004). Whole-exome sequencing delineated the contribution of CH mutations in 2 out 4 investigated RT cases. Large CH clone size (>10% VAF) was independently associated with shorter OS with placebo (p=0.049), and shorter PFS with Clb-Obi (p=0.007) after adjusting for age, IGHV 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 various CLL therapies and underscores its adverse influence on patient outcomes.
- Department(s)
- Haematology; Pathology
- Publisher's Version
- https://doi.org/10.1182/blood.2025029905
- Open Access at Publisher's Site
https://doi.org/10.1182/blood.2025029905- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2026-01-20 12:06:10
Last Modified: 2026-01-20 12:06:31