Chronic lymphocytic leukemia (CLL) patients with differential somatic hypermutation status of the immunoglobulin heavy variable genes, namely mutated or unmutated, display fundamental clinico-biological differences. Considering this, we assessed prognosis separately within mutated (M-CLL) and unmutated (U-CLL) CLL in 3015 patients, hypothesizing that the relative significance of relevant indicators may differ between these two categories. Within Binet A M-CLL patients, besides TP53 abnormalities, trisomy 12 and stereotyped subset #2 membership were equivalently associated with the shortest time-to-first-treatment and a treatment probability at five and ten years after diagnosis of 40% and 55%, respectively; the remaining cases exhibited 5-year and 10-year treatment probability of 12% and 25%, respectively. Within Binet A U-CLL patients, besides TP53 abnormalities, del(11q) and/or SF3B1 mutations were associated with the shortest time-to-first-treatment (5- and 10-year treatment probability: 78% and 98%, respectively); in the remaining cases, males had a significantly worse prognosis than females. In conclusion, the relative weight of indicators that can accurately risk stratify early-stage CLL patients differs depending on the somatic hypermutation status of the immunoglobulin heavy variable genes of each patient. This finding highlights the fact that compartmentalized approaches based on immunogenetic features are necessary to refine and tailor prognostication in CLL.

Cancer Genomics Academic Unit of Cancer Sciences Cancer Research UK Centre and Experimental Cancer Medicine Centre Faculty of Medicine University of Southampton UK

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

Department of Haematology Royal Bournemouth Hospital UK

Department of Hemato Oncology Belfast City Hospital UK

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

Department of Medicine Solna Clinical Epidemiology Unit Karolinska Institutet Stockholm Sweden

Department of Molecular Medicine and Surgery Karolinska Institutet Stockholm Sweden

Department of Pathology University of Barcelona Spain

Division of Experimental Oncology IRCCS Istituto Scientifico San Raffaele and Università Vita Salute San Raffaele Milan Italy

Division of Hematology Department of Translational Medicine Amedeo Avogadro University of Eastern Piedmont Novara Italy

Hematology Department and HCT Unit G Papanicolaou Hospital Thessaloniki Greece

Hematology Department Hospital Clinic Barcelona Spain

Hematology Department Nikea General Hospital Pireaus Greece

Hemopathology Unit Hospital Clinic Barcelona Spain

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

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

MLL Munich Leukemia Laboratory Munich Germany

Oncology Institute of Southern Switzerland Bellinzona Switzerland

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