Resistance to targeted therapies in chronic lymphocytic leukemia: Current status and perspectives for clinical and diagnostic practice

Blombery, P; Chatzikonstantinou, T; Gerousi, M; Rosenquist, R; Gaidano, G; Pospisilova, S; Roberts, AW; Birkinshaw, RW; Rossi, D; Scarfo, L; Seymour, JF; Stilgenbauer, S; Wiestner, A; Woyach, JA; Brown, JR; Ghia, P; Stamatopoulos, K; ERIC, the European Research Initiative on CLL

Author(s): Blombery, P; Chatzikonstantinou, T; Gerousi, M; Rosenquist, R; Gaidano, G; Pospisilova, S; Roberts, AW; Birkinshaw, RW; Rossi, D; Scarfo, L; Seymour, JF; Stilgenbauer, S; Wiestner, A; Woyach, JA; Brown, JR; Ghia, P; Stamatopoulos, K; ERIC, the European Research Initiative on CLL;
Details: Publication Year 2025-09,Volume 39,Issue #9,Page 2049-2060
Journal Title: Leukemia
Publication 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.
Publisher: Springer Nature
Keywords: Humans; *Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy/diagnosis/genetics; *Drug Resistance, Neoplasm/genetics; *Molecular Targeted Therapy/methods; *Protein Kinase Inhibitors/therapeutic use; Mutation; Agammaglobulinaemia Tyrosine Kinase/genetics; *Antineoplastic Agents/therapeutic use
Department(s): Haematology
Publisher's Version: https://doi.org/10.1038/s41375-025-02662-y
Open Access at Publisher's Site: https://doi.org/10.1038/s41375-025-02662-y
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2025-07-22 03:30:55

Last Modified: 2025-08-28 05:52:24