Targeted therapies have transformed modern management of chronic lymphocytic leukaemia (CLL). Still, CLL remains an incurable disease, and key unresolved challenges include development of treatment resistance and intolerance. To address these challenges, it is necessary to define clinically actionable biomarkers that can predict individual treatment responses. Here, we aimed to map the treatment sensitivity and resistance landscapes of CLL cells from treatment-naïve and treatment-exposed patients to understand the evolution of treatment vulnerabilities. We performed ex vivo drug screens with 94 single agents and 87 drug combinations on CLL cells from treatment-naïve, ibrutinib-exposed or idelalisib-exposed patients. We found that overall drug sensitivity was reduced in cells from patients who had received treatment. Specifically, sensitivity to B-cell lymphoma 2 (Bcl-2) inhibitors was significantly reduced in both ibrutinib-exposed and idelalisib-exposed patient cells. Furthermore, combined Bruton's tyrosine kinase inhibitor (BTK)/Bcl-2 inhibition became less relevant in advanced disease, while dual mitogen-activated protein kinase kinase (MEK)/Bcl-2 inhibition was identified as an effective new treatment modality. Our findings provide valuable insights that may assist clinical decisions regarding treatment sequencing and treatment options for relapsed/refractory disease.
Keywords: BTK inhibitor; Bcl‐2 inhibitor; chronic lymphocytic leukaemia; drug sensitivity; targeted therapy.
© 2026 British Society for Haematology and John Wiley & Sons Ltd.