The landscape and evolution of clonal hematopoiesis in chronic lymphocytic leukemia
Abstract
Abstract 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.
Article Details
Authors (28)
Othman Al-Sawaf
Benjamin N. Locher
3Department of Hematology, Oncology, and Cancer Immunology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
Friederike Christen
1Department of Hematology, Oncology, and Cancer Immunology, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin Institute of Health, Berlin, Germany
Raphael Hablesreiter
1Department of Hematology, Oncology, and Cancer Immunology, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin Institute of Health, Berlin, Germany
Anantharamanan Rajamani
1Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Faculty of Medicine and University Hospital of Cologne, Cologne, Germany
Sandra Robrecht
Department I of Internal Medicine, Center of Integrated Oncology Aachen Bonn Cologne Düsseldorf, University Hospital of Cologne, Cologne, Germany
Can Zhang
School of Integrated Circuits and Electronics, MIIT Key Laboratory for Low-Dimensional Quantum Structure and Devices
Anna Maria Fink
Department I of Internal Medicine, Center of Integrated Oncology Aachen Bonn Cologne Düsseldorf, University Hospital of Cologne, Cologne, Germany
Eugen Tausch
Division of CLL, Department of Internal Medicine III, Ulm University, Ulm, Germany
Christof Schneider
Division of CLL, Department of Internal Medicine III, Ulm University, Ulm, Germany
Matthias Ritgen
Universitaetsklinikum Schleswig-Holstein, Medizinische Klinik II, Kiel, Germany
Karl-Anton Kreuzer
Department I of Internal Medicine, Center of Integrated Oncology Aachen Bonn Cologne Düsseldorf, University Hospital of Cologne, Cologne, Germany
Klara Kopp
1Department of Hematology, Oncology, and Cancer Immunology, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin Institute of Health, Berlin, Germany
Marie-Elisa Mertz
3Department of Hematology, Oncology, and Cancer Immunology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
Coral Fustero-Torre
3Department of Hematology, Oncology, and Cancer Immunology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
Karsten Kleo
6Department of Pathology, Charité-Universitätsmedizin Berlin, Freie Universität Berlin Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
John Seymour
7Peter MacCallum Cancer Center, Melbourne, Australia
Piers Blombery
Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
Lars Bullinger
Brenda Chyla
Abbvie, North Chicago, Illinois, United States
Hyun Yong Jin
12Genentech, Inc, South San Francisco, CA
Yanwen Jiang
12Genentech, Inc, South San Francisco, CA
Stephan Stilgenbauer
Division of CLL, Department of Internal Medicine III, Ulm University, Ulm, Germany
Michael Hallek
Department I of Internal Medicine, Center of Integrated Oncology Aachen Bonn Cologne Düsseldorf, University Hospital of Cologne, Cologne, Germany
Barbara Eichhorst
Department I of Internal Medicine, Center of Integrated Oncology Aachen Bonn Cologne Düsseldorf, University Hospital of Cologne, Cologne, Germany
Petra Langerbeins
University Hospital, Cologne, Germany
Kirsten Fischer
Department I of Internal Medicine, Center of Integrated Oncology Aachen Bonn Cologne Düsseldorf, University Hospital of Cologne, Cologne, Germany
Frederik Damm
Charité–Universitätsmedizin Berlin, Berlin