BACKGROUND: Patients with chronic lymphocytic leukemia (CLL) have a higher risk of developing other malignancies (OMs) compared to the general population. However, the impact of CLL-related risk factors and CLL-directed treatment is still unclear and represents the focus of this work. METHODS: We conducted a retrospective international multicenter study to assess the incidence of OMs and detect potential risk factors in 19,705 patients with CLL, small lymphocytic lymphoma, or high-count CLL-like monoclonal B-cell lymphocytosis, diagnosed between 2000 and 2016. Data collection took place between October 2020 and March 2022. FINDINGS: In 129,254 years of follow-up after CLL diagnosis, 3513 OMs were diagnosed (27.2 OMs/1000 person-years). The most common hematological OMs were Richter transformation, myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Non-melanoma skin (NMSC) and prostate cancers were the most common solid tumors (STs).The only predictor for MDS and AML development was treatment with fludarabine and cyclophosphamide with/without rituximab (FC ± R) (OR = 3.7; 95% CI = 2.79-4.91; p < 0.001). STs were more frequent in males and patients with unmutated immunoglobulin heavy variable genes (OR = 1.77; 95% CI = 1.49-2.11; p < 0.001/OR = 1.89; 95% CI = 1.6-2.24; p < 0.001).CLL-directed treatment was associated with non-melanoma skin and prostate cancers (OR = 1.8; 95% CI = 1.36-2.41; p < 0.001/OR = 2.11; 95% CI = 1.12-3.97; p = 0.021). In contrast, breast cancers were more frequent in untreated patients (OR = 0.17; 95% CI = 0.08-0.33; p < 0.001).Patients with CLL and an OM had inferior overall survival (OS) than those without. AML and MDS conferred the worst OS (p < 0.001). INTERPRETATION: OMs in CLL impact on OS. Treatment for CLL increased the risk for AML/MDS, prostate cancer, and NMSC. FCR was associated with increased risk for AML/MDS. FUNDING: AbbVie, and EU/EFPIAInnovative Medicines Initiative Joint Undertaking HARMONY grant n° 116026.

1st Faculty of Medicine 1st Department of Medicine Hematology Charles University and General Hospital Prague Czech Republic

4th Department of Internal Medicine Haematology University Hospital and Faculty of Medicine Hradec Králové Czech Republic

Antalya Training and Research Hospital Antalya Turkey

Biological Haematology Department Dijon Bourgogne University Hospital Haematological Malignancies Registry LNC UMR 1231 Dijon 21000 France

Central European Institute of Technology Masaryk University Brno Czech Republic

Clinic for Hematology and Stem Cell Transplantation West German Cancer Center University Hospital Essen University of Duisburg Essen Essen Germany

Clinic for Hematology University Clinical Center of Serbia Belgrade Serbia

Clinical Haematology Belfast City Hospital Belfast United Kingdom

Consultative Hematology Department with a Day Hospital for Intensive High Dose Chemotherapy National Medical Research Center for Hematology Moscow Russia

Department and Clinic of Hematology Blood Neoplasms and Bone Marrow Transplantation Wroclaw Medical University Wroclaw Poland

Department of Clinical Hematology ICO Hospital Duran i Reynals IDIBELL Barcelona Spain

Department of Haematology Athens Medical Center Psychikon Branch Athens Greece

Department of Haematology Royal Bournemouth Hospital Bournemouth United Kingdom

Department of Haematology University Hospital of Salamanca Salamanca Spain

Department of Haematology University Hospital Vall d'Hebron Autonomous University Barcelona Spain

Department of Haematooncology University Hospital Ostrava Ostrava Czech Republic

Department of Hemato Oncology Institut Paoli Calmettes Marseille France

Department of Hematological Malignancies and Stem Cell Transplantation Research Institute of Marques de Valdecilla Santander Spain

Department of Hematology and Bone Marrow Transplantation Unit National and Kapodistrian University of Athens Laikon General Hospital Athens Greece

Department of Hematology and Cell Therapy Estaing University Hospital Clermont Ferrand France

Department of Hematology and Stem Cell Transplant Armed Forces Bone Marrow Transplant Center National Institute of Blood and Marrow Transplant Rawalpindi Pakistan

Department of Hematology Centre Hospitalier Le Mans Le Mans France

Department of Hematology Hospital del Mar Barcelona Spain

Department of Hematology Hospital Universitario de Burgos Burgos Spain

Department of Hematology Oncology and Chemotherapy S P Botkin's City Hospital Moscow Russia

Department of Hematology Shaare Zedek Medical Center Affiliated with the Hebrew University Medical School Jerusalem Israel

Department of Hematology Shamir Medical Center Zerifin Israel

Department of Hematology Tel Aviv Sourasky Medical Center and Sackler School of Medicine Tel Aviv University Tel Aviv Israel

Department of Hematology University Hospital Dubrava Zagreb Croatia

Department of Hematology University Hospital Marqués de Valdecilla Santander Spain

Department of Hematology University Hospital of Alexandroupolis Democritus University of Thrace Alexandroupolis Greece

Department of Internal Medicine Albert Schweitzer Hospital Dordrecht the Netherlands

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

Department of Internal Medicine Postgraduate Institute of Medical Education and Research Chandigarh India

Department of Mathematics University of Ioannina Ioannina Greece

Department of Medical Oncology and Hematology All India Institute of Medical Sciences Rishikesh India

Department of Medicine Pamela Youde Nethersole Eastern Hospital Chai Wan Hong Kong China

Department of Medicine School of Clinical Medicine The University of Hong Kong Hong Kong China

Department of Molecular Hematology National Medical Research Center for Hematology Moscow Russia

Dept Hematooncology and Bone Marrow Transplantation Medical University in Lublin Lublin Poland

Dept of Hematology Cancer Center Amsterdam Amsterdam University Medical Centers University of Amsterdam Amsterdam the Netherlands

Dipartimento di Diagnostica per Immagini Radioterapia Oncologica ed Ematologia Fondazione Policlinico Universitario Agostino Gemelli IRCCS Rome Italy

Division of Hematology A O U Città della Salute e della Scienza di Torino and Department of Molecular Biotechnology and Health Sciences University of Turin Turin Italy

Division of Hematology Department of Internal Medicine University Hospital Center Zagreb Zagreb Croatia

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

Division of Hematology Dokuz Eylul University Izmir Turkey

Division of Hematology University of Siena Siena Italy

Experimental Hematooncology Department Medical University of Lublin Lublin Poland

Faculty of Medicine and Dentistry Department of Hemato Oncology Palacký University and University Hospital Olomouc Olomouc Czech Republic

Faculty of Medicine Clinical Centre of Vojvodina University of Novi Sad Novi Sad Serbia

Faculty of Medicine Comprehensive Cancer Center Augsburg University of Augsburg Stenglinstrasse 2 Augsburg 86156 Germany

Faculty of Medicine Department of Haematology School of Health Sciences University of Ioannina Stavros Niarchos Avenue Ioannina 45110 Greece

Faculty of Medicine Department of Medicine Kuwait University Kuwait City Kuwait

Faculty of Medicine University of Belgrade Belgrade Serbia

Federal State Budgetary Educational Institution of Higher Education Academician 1 P Pavlov 1st St Petersburg State Medical University of the Ministry of Healthcare of Russian Federation St Petersburg Russia

Fujian Provincial Key Laboratory of Hematology Fujian Institute of Hematology Fujian Medical University Union Hospital Fuzhou 350001 China

Fundacion Jimenez Diaz University Hospital Health Research Institute IIS FJD Madrid Spain

Gazi University Medical Faculty Ankara Turkey

Haematology Department Hospital Universitario de La Princesa Madrid Spain

Haematology University of Athens Laikon General Hospital Athens Greece

Hematology and Clinical Immunology Unit Department of Medicine University of Padova Padova Italy

Hematology and Oncology Faculty of Medicine University of Augsburg Stenglinstrasse 2 Augsburg 86156 Germany

Hematology and Stem Cell Transplantation Unit Ospedale Oncologico A Businco ARNAS G Brotzu Cagliari Italy

Hematology Bnai Zion Medical Center Haifa Israel

Hematology Clinic ASUFC Udine Italy

Hematology Department and HCT Unit G Papanicolaou Hospital Thessaloniki Greece

Hematology Department Colentina Clinical Hospital Bucharest Romania

Hematology Department Hospital Universitario 12 de Octubre Madrid Spain

Hematology Department Infanta Leonor University Hospital Madrid Spain

Hematology Department Ramón y Cajal University Hospital Madrid Spain

Hematology Department St John's Cancer Center Lublin Poland

Hematology Department University Medical Center Groningen University of Groningen Groningen the Netherlands

Hematology Section Department of Medical Oncology National Center for Cancer Care and Research Doha Qatar

Hematology Unit 1st Dept of Internal Medicine AUTH AHEPA Hospital Thessaloniki Greece

Hematology Unit Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico of Milan Milan Italy

Hematopathology Laboratory Hamad Medical Corporation Doha Qatar

Hospital Costa del Sol Málaga Spain

Hospital de Clinicas Montevideo Uruguay

Hospital Italiano La Plata Buenos Aires Argentina

Hull York Medical School Hull United Kingdom

Institut Bergonié Bordeaux France

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

Institute of Hematology and Center for Hemato Oncology Research University of Perugia and Santa Maria della Misericordia Hospital Perugia Italy

Internal Medicine Department Universidade Federal do Espírito Santo Vila Velha ES Brazil

Laboratory of Molecular Biology National Cancer Institute National Institutes of Health Bethesda MD USA

Laboratory Oncology Unit Dr B R A IRCH All India Institute of Medical Sciences New Delhi India

Medical Faculty University Clinic of Hematology University Ss Cyril and Methodius Skopje North Macedonia

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

Oncology Center Mansoura University Mansoura Egypt

Pathology Faculty of Medicine University of Augsburg Stenglinstrasse 2 Augsburg 86156 Germany

Peter MacCallum Cancer Centre St Vincent's Hospital University of Melbourne Melbourne VIC 3000 Australia

Royal North Shore Hospital Sydney NSW Australia

Sackler Faculty of Medicine Tel Aviv University Tel Aviv Israel

Section of Hematology Department of Clinical and Experimental Medicine University of Pisa Pisa Italy

Service d'Hématologie Oncologie Centre Hospitalier de Versailles Le Chesnay France

Servicio de Hematología Consorcio Hospital General Universitario de Valencia Fundación de Investigación Hospital General Universitario de Valencia Valencia Spain

Sezione di Ematologia Dipartimento di Scienze Radiologiche ed Ematologiche Università Cattolica del Sacro Cuore Rome Italy

St Anna University Hospital Ferrara Italy

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

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Realizing precision medicine in chronic lymphocytic leukemia: Remaining challenges and potential opportunities