Through the European Research Initiative on chronic lymphocytic leukemia (CLL) (ERIC), we screened 3490 patients with CLL for mutations within the NOTCH1 (n=3334), SF3B1 (n=2322), TP53 (n=2309), MYD88 (n=1080) and BIRC3 (n=919) genes, mainly at diagnosis (75%) and before treatment (>90%). BIRC3 mutations (2.5%) were associated with unmutated IGHV genes (U-CLL), del(11q) and trisomy 12, whereas MYD88 mutations (2.2%) were exclusively found among M-CLL. NOTCH1, SF3B1 and TP53 exhibited variable frequencies and were mostly enriched within clinically aggressive cases. Interestingly, as the timespan between diagnosis and mutational screening increased, so too did the incidence of SF3B1 mutations; no such increase was observed for NOTCH1 mutations. Regarding the clinical impact, NOTCH1 mutations, SF3B1 mutations and TP53 aberrations (deletion/mutation, TP53ab) correlated with shorter time-to-first-treatment (P<0.0001) in 889 treatment-naive Binet stage A cases. In multivariate analysis (n=774), SF3B1 mutations and TP53ab along with del(11q) and U-CLL, but not NOTCH1 mutations, retained independent significance. Importantly, TP53ab and SF3B1 mutations had an adverse impact even in U-CLL. In conclusion, we support the clinical relevance of novel recurrent mutations in CLL, highlighting the adverse impact of SF3B1 and TP53 mutations, even independent of IGHV mutational status, thus underscoring the need for urgent standardization/harmonization of the detection methods.

] Science for Life Laboratory Department of Immunology Genetics and Pathology Rudbeck Laboratory Uppsala University Uppsala Sweden [2] Hematology Department and HCT Unit G Papanicolaou Hospital Thessaloniki Greece

] Science for Life Laboratory Department of Immunology Genetics and Pathology Rudbeck Laboratory Uppsala University Uppsala Sweden [2] Hematology Department and HCT Unit G Papanicolaou Hospital Thessaloniki Greece [3] Institute of Applied Biosciences CERTH Thessaloniki Greece

] Science for Life Laboratory Department of Immunology Genetics and Pathology Rudbeck Laboratory Uppsala University Uppsala Sweden [2] Institute of Applied Biosciences CERTH Thessaloniki Greece

] Università Vita Salute San Raffaele Milan Italy [2] Division of Molecular Oncology and Department of Onco Hematology San Raffaele Scientific Institute Milan Italy

Cancer Sciences Faculty of Medicine University of Southampton Southampton UK

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

Department of Haematology Royal Bournemouth Hospital Bournemouth UK

Department of Internal Medicine 3 Ulm University Ulm Germany

Department of Medicine Solna Clinical Epidemiology Unit Karolinska Institutet Stockholm Sweden

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

Hematology Department and HCT Unit G Papanicolaou Hospital Thessaloniki Greece

Hematology Department Nikea General Hospital Pireaus Greece

Hematopathology Unit and Department of Hematology Hospital Clinic University of Barcelona Institut d'Investigacions Biomèdiques August Pi iSunyer Barcelona Spain

Institute of Applied Biosciences CERTH Thessaloniki Greece

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

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

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