Resistance to targeted therapies in chronic lymphocytic leukemia: Current status and perspectives for clinical and diagnostic practice
Year: 2025
Type: review
Abstract: 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.
Source: Leukemia
Authors: Piers Blombery, Thomas Chatzikonstantinou, Marina Gerousi, Richard Rosenquist, Gianluca Gaidano, Sarka Pospisilova, Andrew W. Roberts, Richard W. Birkinshaw, Davide Rossi, Lydia Scarfo, John F. Seymour, Stephan Stilgenbauer, Adrian Wiestner, Jennifer A. Woyach, Jennifer R. Brown, Paolo Ghia, Kostas Stamatopoulos
Institutions: The Royal Melbourne Hospital, The University of Melbourne, Peter MacCallum Cancer Centre, Centre for Research and Technology Hellas, Karolinska University Hospital, Karolinska Institutet, Università degli Studi del Piemonte Orientale “Amedeo Avogadro”, Azienda Ospedaliero Universitaria Maggiore della Carita, Masaryk University, Central European Institute of Technology – Masaryk University, University Hospital Brno, Walter and Eliza Hall Institute of Medical Research, Institute of Oncology Research, Istituto Oncologico della Svizzera Italiana, Università della Svizzera italiana, Vita-Salute San Raffaele University, IRCCS Ospedale San Raffaele, University Hospital Ulm, National Heart, Lung, and Blood Institute, The Ohio State University, Dana-Farber Cancer Institute
Language: English
Subfield: Genetics (clinical)
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $5,190
OpenAlex ID: W4411576685