The integration of BTK and BCL2 inhibitors into the treatment of patients with chronic lymphocytic leukemia (CLL) represents a paradigm shift and has led to significant improvements in clinical outcomes, including prolonged survival and enhanced quality of life. However, despite the efficacy of these agents, resistance to targeted therapy remains a major challenge, ultimately resulting in treatment failure and disease progression for a significant proportion of patients. Related to this, diagnostic testing for genetic variants associated with resistance, such as mutations in BTK, PLCG2 and BCL2, may become an increasingly common part of clinical routine practice. Addressing the need for placing the current knowledge in context, here we summarize the evidence from clinical studies and examine the underlying biology of both genetic and non-genetic resistance. Furthermore, we outline methodological approaches for the detection of gene alterations associated with targeted therapy resistance, discuss how to interpret these findings and highlight interpretation challenges. Finally, we offer insights into the clinical relevance of identifying genetic resistance to inform personalized treatment strategies and improve patient outcomes.

Blood Cells and Blood Cancers Division Walter and Eliza Hall Institute of Medical Research Melbourne VIC Australia

Central European Institute of Technology Masaryk University Brno Czech Republic

Clinic of Hematology Oncology Institute of Southern Switzerland Bellinzona Switzerland

Clinical Genetics and Genomics Karolinska University Hospital Stockholm Sweden

Clinical Haematology Melbourne VIC Australia

Collaborative Centre for Genomics Cancer Medicine University of Melbourne Melbourne VIC Australia

Comprehensive Cancer Center Ulm Department of Internal Medicine 3 University Hospital Ulm Ulm Germany

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 Oncology Dana Farber Cancer Institute Boston MA USA

Department of Molecular Medicine and Surgery Karolinska Institutet Stockholm Sweden

Division of Hematology Department of Internal Medicine The Ohio State University Columbus OH USA

Division of Hematology Department of Translational Medicine University of Eastern Piedmont and Maggiore Charity Hospital Novara Italy

Faculty of Biomedical Sciences Università della Svizzera Italiana Lugano Switzerland

Faculty of Medicine Dentistry and Health Sciences The University of Melbourne Melbourne VIC Australia

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

Institute of Oncology Research Laboratory of Experimental Hematology Bellinzona Switzerland

NIH National Heart Lung Blood Institute Bethesda MD USA

Sir Peter MacCallum Department of Oncology University of Melbourne Melbourne VIC Australia

Strategic Research Program on CLL IRCCS Ospedale San Raffaele Milano Italy

Structural Biology Division Walter and Eliza Hall Institute of Medical Research Melbourne VIC Australia

Università Vita Salute San Raffaele Milano Italy

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