An unresolved issue in chronic lymphocytic leukemia (CLL) is whether IGHV3-21 gene usage, in general, or the expression of stereotyped B-cell receptor immunoglobulin defining subset #2 (IGHV3-21/IGLV3-21), in particular, determines outcome for IGHV3-21-utilizing cases. We reappraised this issue in 8593 CLL patients of whom 437 (5%) used the IGHV3-21 gene with 254/437 (58%) classified as subset #2. Within subset #2, immunoglobulin heavy variable (IGHV)-mutated cases predominated, whereas non-subset #2/IGHV3-21 was enriched for IGHV-unmutated cases (P = .002). Subset #2 exhibited significantly shorter time-to-first-treatment (TTFT) compared with non-subset #2/IGHV3-21 (22 vs 60 months, P = .001). No such difference was observed between non-subset #2/IGHV3-21 vs the remaining CLL with similar IGHV mutational status. In conclusion, IGHV3-21 CLL should not be axiomatically considered a homogeneous entity with adverse prognosis, given that only subset #2 emerges as uniformly aggressive, contrasting non-subset #2/IGVH3-21 patients whose prognosis depends on IGHV mutational status as the remaining CLL.

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 Haematology Royal Bournemouth Hospital Bournemouth United Kingdom;

Department of Hemato Oncology Belfast City Hospital Belfast United Kingdom;

Department of Hematology Erasmus Medical Center University Medical Center Rotterdam Rotterdam The Netherlands;

Department of Hematology Rigshospitalet Copenhagen Denmark;

Department of Immunology Erasmus Medical Center University Medical Center Rotterdam Rotterdam The 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; Institute of Applied Biosciences Centre for Research and Technology Hellas Thessaloniki Greece;

Department of Immunology Genetics and Pathology Science for Life Laboratory Uppsala University Uppsala Sweden; Institute of Applied Biosciences Centre for Research and Technology Hellas Thessaloniki Greece; Hematology Department and Hematopoietic Cell Transplantation Unit Georgios Papanicolaou Hospital Thessaloniki Greece;

Department of Immunology Mayo Clinic Rochester MN; and

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;

Hematology Department and Hematopoietic Cell Transplantation Unit Georgios Papanicolaou Hospital Thessaloniki Greece;

Hematology Department and University Pierre et Marie Curie Hopital Pitie Salpetriere Paris France;

Hematology Department Nikea General Hospital Piraeus Greece;

Hôpital Pitié Salpêtrière Service d'Hématologie Biologique Paris France;

ImMunoGeneTics Université de Montpellier Laboratoire d'Informatique Gaspard Monge Institut de Génétique Humaine Montpellier France;

Institute of Applied Biosciences Centre for Research and Technology Hellas 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;

Università Vita Salute San Raffaele Milan Italy; Division of Molecular Oncology and Department of Onco Hematology Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele Scientific Institute Milan Italy;

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