Blombery Piers, Chatzikonstantinou Thomas, Gerousi Marina, Rosenquist Richard, Gaidano Gianluca, Pospisilova Sarka, Roberts Andrew W, Birkinshaw Richard W, Rossi Davide, Scarfo Lydia, Seymour John F, Stilgenbauer Stephan, Wiestner Adrian, Woyach Jennifer A, Brown Jennifer R, Ghia Paolo, Stamatopoulos Kostas
Clinical Haematology (Peter MacCallum Cancer Centre/Royal Melbourne Hospital), Melbourne, VIC, Australia.
Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia.
Leukemia. 2025 Jun 24. doi: 10.1038/s41375-025-02662-y.
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.
将布鲁顿酪氨酸激酶（BTK）和B细胞淋巴瘤-2（BCL2）抑制剂纳入慢性淋巴细胞白血病（CLL）患者的治疗代表了一种范式转变，并已使临床结局得到显著改善，包括延长生存期和提高生活质量。然而，尽管这些药物有效，但对靶向治疗的耐药性仍然是一个重大挑战，最终导致相当一部分患者治疗失败和疾病进展。与此相关的是，针对与耐药相关的基因变异（如BTK、磷脂酶Cγ2（PLCG2）和BCL2中的突变）的诊断检测可能会越来越成为临床常规实践的一部分。为满足将当前知识融会贯通的需求，我们在此总结临床研究证据，并审视遗传和非遗传耐药的潜在生物学机制。此外，我们概述了检测与靶向治疗耐药相关基因改变的方法，讨论如何解读这些发现并强调解读挑战。最后，我们深入探讨识别遗传耐药性对指导个性化治疗策略和改善患者结局的临床意义。
