Recent evidence suggests that the prognostic impact of gene mutations in patients with chronic lymphocytic leukemia (CLL) may differ depending on the immunoglobulin heavy variable (IGHV) gene somatic hypermutation (SHM) status. In this study, we assessed the impact of nine recurrently mutated genes (BIRC3, EGR2, MYD88, NFKBIE, NOTCH1, POT1, SF3B1, TP53, and XPO1) in pre-treatment samples from 4580 patients with CLL, using time-to-first-treatment (TTFT) as the primary end-point in relation to IGHV gene SHM status. Mutations were detected in 1588 (34.7%) patients at frequencies ranging from 2.3-9.8% with mutations in NOTCH1 being the most frequent. In both univariate and multivariate analyses, mutations in all genes except MYD88 were associated with a significantly shorter TTFT. In multivariate analysis of Binet stage A patients, performed separately for IGHV-mutated (M-CLL) and unmutated CLL (U-CLL), a different spectrum of gene alterations independently predicted short TTFT within the two subgroups. While SF3B1 and XPO1 mutations were independent prognostic variables in both U-CLL and M-CLL, TP53, BIRC3 and EGR2 aberrations were significant predictors only in U-CLL, and NOTCH1 and NFKBIE only in M-CLL. Our findings underscore the need for a compartmentalized approach to identify high-risk patients, particularly among M-CLL patients, with potential implications for stratified management.

All India Institute of Medical Sciences New Delhi India

Cancer Genomics School for Cancer Sciences Faculty of Medicine University of Southampton Southampton UK

Cancer Research Center CSIC University of Salamanca Salamanca Spain

Central European Institute of Technology Masaryk University Brno Czech Republic

Central Hospital of Southern Pest National Institute of Hematology and Infectious Diseases Budapest Hungary

Centre for Research and Technology Hellas Institute of Applied Biosciences Thessaloniki Greece

Centro de Investigación Biomédica en Red de Cáncer Madrid Spain

Clinical Epidemiology Division Department of Medicine Solna Karolinska Institutet Stockholm Sweden

Clinical Genetics Karolinska University Hospital Solna Sweden

Department of Hematology Hospital Universitari Vall d'Hebron Department of Medicine Universitat Autònoma de Barcelona Barcelona Spain

Department of Hematology INCLIVA Research Insitute University of Valencia Valencia Spain

Department of Hematology Oncology and Cancer Immunology Charité Universitätsmedizin Berlin Corporate Member of Freie Universität Berlin Humboldt Universität zu Berlin Berlin Germany

Department of Hematology Rigshospitalet Copenhagen University Hospital Copenhagen Denmark

Department of Hematology University Hospital of Salamanca Salamanca Spain

Department of Immunology Genetics and Pathology Uppsala University Uppsala Sweden

Department of Internal Medicine Hematology and Oncology University Hospital Brno Brno Czech Republic

Department of Mathematics University of Ioannina Ioannina Greece

Department of Molecular Medicine and Surgery Karolinska Institutet Stockholm Sweden

Department of Oncology and Haematology University Hospital and University of Zurich Zurich Switzerland

Division of Hematology Department of Translational Medicine Università del Piemonte Orientale Novara Italy

Division of Hematology Oncology Institute of Southern Switzerland Bellinzona Switzerland

Faculty of Medicine Masaryk University Brno Czech Republic

Haematology Department Beaumont Hospital Dublin Ireland

HCEMM SE Molecular Oncohematology Research Group Department of Pathology and Experimental Cancer Research Semmelweis University Budapest Hungary

Hematological Diseases Laboratory CIMA LAB Diagnostics University of Navarra Pamplona Spain

Hematology Department of Medical Sciences University of Ferrara Ferrara Italy

Hospital Clínic of Barcelona Barcelona Spain

Hospital Universitario 12 Octubre Madrid Spain

IdiSNA Navarra Institute for Health Research Pamplona Spain

Institut d'Investigacions Biomèdiques August Pi i Sunyer Barcelona Spain

Instituto de Investigación Biomédica Salamanca Spain

Laboratory of Experimental Hematology Institute of Oncology Research Bellinzona Switzerland

MLL Munich Leukemia Laboratory Munich Germany

Molecular Cytogenetics Laboratory Pathology Department Hospital del Mar and Translational Research on Hematological Neoplasms Group Hospital del Mar Research Institute Barcelona Spain

Molecular Pathology Department University Hospitals Dorset Bournemouth UK

Patrick G Johnston Centre for Cancer Research Queen's University Belfast Belfast UK

Service d'hématologie Biologique Hôpital Avicenne Assistance Publique des Hôpitaux de Paris Bobigny France

Sorbonne Université Service d'Hématologie Clinique Hôpital Pitié Salpêtrière APHP Paris France

Spanish National Cancer Research Madrid Spain

Università Vita Salute San Raffaele and IRCCS Ospedale San Raffaele Milano Italy

Universitat de Barcelona Barcelona Spain

Erratum v

Leukemia. 2023 Feb;37(2):504. doi: 10.1038/s41375-023-01813-3. PubMed

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