Central nervous system involvement (CNSi) of chronic lymphocytic leukemia (CLL) is a rare condition with no consensus on diagnostic criteria and limited evidence for management and outcome. Here, we report an international, multicenter, retrospective study conducted by the European Research Initiative on CLL. The study defined CNSi of CLL by the following: (1) detection of CLL cells in the cerebrospinal fluid or confirmation of CLL infiltration of the CNS based on a tissue biopsy, (2) clinical or radiographic evidence of neurologic disease, and (3) the absence of other explanations for the neurologic findings. A total of 48 patients from 26 centers in 15 countries met all 3 diagnostic criteria of CLL-CNSi. Median age at diagnosis of CNSi was 64 years. Most patients were males (73%), had Binet stage A at CLL diagnosis (61%), and had untreated CLL at the time of CNSi (63%). Motor impairment was the most common symptom (38%) followed by visual impairment (32%). Of 47 patients who received treatment for CNSi, half (51%) received targeted agents, most often a Bruton tyrosine kinase inhibitor (BTKi), and 34% received chemoimmunotherapy. Initial treatment was highly effective, leading to a reduction (83%) or complete resolution (71%) of neurologic symptoms and imaging findings in most patients. The estimated 5-year overall survival (OS) from the CNSi diagnosis was 77.1%. The 5-year time to next treatment or death was 94% for patients treated with BTKi compared with 64% for those treated with CIT. Treatment-sensitive disease, represented by attainment of CNS complete response after initial therapy, was associated with longer OS.

4th Department of Internal Medicine Hematology Faculty of Medicine in Hradec Králové University Hospital and Charles University Hradec Králové Czech Republic

Centre for Molecular Medicine Central European Institute of Technology Masaryk University Brno Czech Republic

Clinical Department of Hematology Cell Therapies and Internal Diseases Wroclaw Medical University Wroclaw Poland

Department of Clinical Haematology Peter MacCallum Cancer Centre and Royal Melbourne Hospital Melbourne VIC Australia

Department of Diagnostic Haematology Royal Melbourne Hospital Melbourne VIC Australia

Department of Hematology Copenhagen University Hospital Rigshospitalet Copenhagen Denmark

Department of Hematology Democritus University of Thrace Alexandroupolis Greece

Department of Hematology Gazi University Faculty of Medicine Ankara Turkey

Department of Hematology Hospital Clínico Universitario Valencia Spain

Department of Hematology Hospital del Mar Barcelona Spain

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

Department of Hematology Santa Chiara Hospital Azienda Provinciale per i Servizi Sanitari Trento Trento Italy

Department of Hematology Shamir Medical Center Zerifin Israel

Department of Hematooncology and Bone Marrow Transplantation Medical University in Lublin Lublin Poland

Department of Internal Medicine Hematology and Oncology and Institute of Medical Genetics and Genomics University Hospital Brno and Medical Faculty Masaryk University Brno Czech Republic

Department of Medical Biology The University of Melbourne Melbourne VIC Australia

Department of Medical Oncology Dana Farber Cancer Institute Boston MA

Department of Pathology Peter MacCallum Cancer Centre Melbourne VIC Australia

Department of Pharmacy Health and Nutritional Science University of Calabria Rende Italy

Division of Blood Cells and Blood Cancer Walter and Eliza Hall Institute Melbourne VIC Australia

Division of Hematology Department of Medicine University Hospital Dubrava Medical School University of Zagreb Zagreb Croatia

Division of Hematology Department of Translational Medicine Università del Piemonte Orientale Novara Italy

Fundaleu Buenos Aires Argentina

Gray Faculty of Medicine Tel Aviv University Tel Aviv Israel

Hematology Branch Danish Cancer Institute Copenhagen Denmark

Hematology Department Papanicolaou Hospital Thessaloniki Greece

Hematology Department Ramón y Cajal University Hospital Madrid Spain

Hematology Unit Department of Medicine University of Padua Padua Italy

Hematology Unit Department of Onco Hematology Azienda Ospedaliera of Cosenza Cosenza Italy

Hospital Universitario Puerta de Hierro Majadahonda Madrid Spain

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

Institute of Hematology Kaplan Medical Center Rehovot Israel

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

Ospedale San Raffaele Milan Italy

Sanatorio Británico de Rosario Santa Fe Argentina

Tel Aviv Sourasky Medical Center Tel Aviv Israel

Universidade Federal de Sao Paulo Sao Paulo Brazil

Università Vita Salute San Raffaele Milan Italy

University Medical Centre Ljubljana and Faculty of Medicine University of Ljubljana Ljubljana Slovenia

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