BACKGROUND: About 30% of cases of chronic lymphocytic leukaemia (CLL) carry quasi-identical B-cell receptor immunoglobulins and can be assigned to distinct stereotyped subsets. Although preliminary evidence suggests that B-cell receptor immunoglobulin stereotypy is relevant from a clinical viewpoint, this aspect has never been explored in a systematic manner or in a cohort of adequate size that would enable clinical conclusions to be drawn. METHODS: For this retrospective, multicentre study, we analysed 8593 patients with CLL for whom immunogenetic data were available. These patients were followed up in 15 academic institutions throughout Europe (in Czech Republic, Denmark, France, Greece, Italy, Netherlands, Sweden, and the UK) and the USA, and data were collected between June 1, 2012, and June 7, 2013. We retrospectively assessed the clinical implications of CLL B-cell receptor immunoglobulin stereotypy, with a particular focus on 14 major stereotyped subsets comprising cases expressing unmutated (U-CLL) or mutated (M-CLL) immunoglobulin heavy chain variable genes. The primary outcome of our analysis was time to first treatment, defined as the time between diagnosis and date of first treatment. FINDINGS: 2878 patients were assigned to a stereotyped subset, of which 1122 patients belonged to one of 14 major subsets. Stereotyped subsets showed significant differences in terms of age, sex, disease burden at diagnosis, CD38 expression, and cytogenetic aberrations of prognostic significance. Patients within a specific subset generally followed the same clinical course, whereas patients in different stereotyped subsets-despite having the same immunoglobulin heavy variable gene and displaying similar immunoglobulin mutational status-showed substantially different times to first treatment. By integrating B-cell receptor immunoglobulin stereotypy (for subsets 1, 2, and 4) into the well established Döhner cytogenetic prognostic model, we showed these, which collectively account for around 7% of all cases of CLL and represent both U-CLL and M-CLL, constituted separate clinical entities, ranging from very indolent (subset 4) to aggressive disease (subsets 1 and 2). INTERPRETATION: The molecular classification of chronic lymphocytic leukaemia based on B-cell receptor immunoglobulin stereotypy improves the Döhner hierarchical model and refines prognostication beyond immunoglobulin mutational status, with potential implications for clinical decision making, especially within prospective clinical trials. FUNDING: European Union; General Secretariat for Research and Technology of Greece; AIRC; Italian Ministry of Health; AIRC Regional Project with Fondazione CARIPARO and CARIVERONA; Regione Veneto on Chronic Lymphocytic Leukemia; Nordic Cancer Union; Swedish Cancer Society; Swedish Research Council; and National Cancer Institute (NIH).

1st Department of Propaedeutic Medicine University of Athens Athens Greece

Central European Institute of Technology Masaryk University and University Hospital Brno Brno Czech Republic

Central European Institute of Technology Masaryk University Brno Czech Republic

Department of Haemato Oncology Belfast City Hospital Belfast UK

Department of Haematology Royal Bournemouth Hospital Bournemouth UK

Department of Hematology Erasmus MC University Medical Center Rotterdam Rotterdam Netherlands

Department of Hematology Rigshospitalet Copenhagen Denmark

Department of Immunology Department of Medicine Mayo Clinic Rochester MN USA

Department of Immunology Erasmus MC University Medical Center Rotterdam Rotterdam Netherlands

Department of Immunology Genetics and Pathology Science for Life Laboratory Uppsala University Uppsala Sweden

Department of Immunology Genetics and Pathology Science for Life Laboratory Uppsala University Uppsala Sweden; Hematology Department and HCT Unit G Papanicolaou Hospital Thessaloniki Greece

Department of Immunology Genetics and Pathology Science for Life Laboratory Uppsala University Uppsala Sweden; Hematology Department and HCT Unit G Papanicolaou Hospital Thessaloniki Greece; Institute of Applied Biosciences CERTH Thessaloniki Greece

Department of Immunology Genetics and Pathology Science for Life Laboratory Uppsala University Uppsala Sweden; Institute of Applied Biosciences CERTH Thessaloniki Greece

Department of Informatics Aristotle University of Thessaloniki Thessaloniki Greece

Department of Medicine Hematology and Clinical Immunology Branch Padua University School of Medicine Italy; Venetian Institute of Molecular Medicine Padova Italy

Department of Medicine Solna Clinical Epidemiology Unit Karolinska Institutet Stockholm Sweden

Division of Hematology Department of Medicine Mayo Clinic Rochester MN USA

Hematology Department and HCT Unit G Papanicolaou Hospital Thessaloniki Greece

Hematology Department Nikea General Hospital Piraeus Greece

Hôpital Pitié Salpêtrière Service d'Hématologie Biologique Paris France

IMGT the International ImMunoGeneTics Information System University of Montpellier LIGM Institut de Génétique Humaine IGH Montpellier France

Institute of Applied Biosciences CERTH Thessaloniki Greece

Lund University and Hospital Department of Hematology Lund Stem Cell Center Lund Sweden

Molecular Pathology Unit and Haematology Department Niguarda Cancer Center Niguarda Ca' Granda Hospital Milan Italy

The Feinstein Institute for Medical Research North Shore Long Island Jewish Health System Manhasset NY USA

Università Vita Salute San Raffaele Milan Italy; Division of Molecular Oncology and Department of Onco Hematology IRCCS San Raffaele Scientific Institute Milan Italy

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