Patients with chronic lymphocytic leukemia (CLL) exhibit diverse clinical outcomes. An expanding array of genetic tests is now employed to facilitate the identification of patients with high-risk disease and inform treatment decisions. These tests encompass molecular cytogenetic analysis, focusing on recurrent chromosomal alterations, particularly del(17p). Additionally, sequencing is utilized to identify TP53 mutations and to determine the somatic hypermutation status of the immunoglobulin heavy variable gene. Concurrently, a swift advancement of targeted treatment has led to the implementation of novel strategies for patients with CLL, including kinase and BCL2 inhibitors. This review explores both current and emerging diagnostic tests aimed at identifying high-risk patients who should benefit from targeted therapies. We outline existing treatment paradigms, emphasizing the importance of matching the right treatment to the right patient beyond genetic stratification, considering the crucial balance between safety and efficacy. We also take into consideration the practical and logistical issues when choosing a management strategy for each individual patient. Furthermore, we delve into the mechanisms underlying therapy resistance and stress the relevance of monitoring measurable residual disease to guide treatment decisions. Finally, we underscore the necessity of aggregating real-world data, adopting a global perspective, and ensuring patient engagement. Taken together, we argue that precision medicine is not the mere application of precision diagnostics and accessibility of precision therapies in CLL but encompasses various aspects of the patient journey (e.g., lifestyle exposures and comorbidities) and their preferences toward achieving true personalized medicine for patients with CLL.

Cancer Institute University College London London UK

Central European Institute of Technology Masaryk University Brno Czech Republic

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

Clinical Genetics Karolinska University Hospital Stockholm Sweden

Department 1 of Internal Medicine and German CLL Study Group Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf University of Cologne Faculty of Medicine and University Hospital of Cologne Cologne Germany

Department of Hematology Cancer Center Amsterdam Amsterdam University Medical Centers University of Amsterdam Amsterdam The Netherlands

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 Molecular Medicine and Surgery Karolinska Institutet Stockholm Sweden

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

Francis Crick Institute London London UK

Haematological Malignancy Diagnostic Service Leeds Teaching Hospitals Trust Leeds UK

Medical School Università Vita Salute San Raffaele Milano Italy

Strategic Research Program on CLL IRCCS Ospedale San Raffaele Milano Italy

UMR INSERMU978 Paris 13 University Bobigny France

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