How I treat patients with CLL after prior treatment with a covalent BTK inhibitor and a BCL-2 inhibitor

The treatment landscape for chronic lymphocytic leukemia (CLL) has been revolutionized by the advent of novel agents, particularly covalent BTK inhibitors (cBTKis) and BCL-2 inhibitors (BCL-2is). This has resulted in significant improvement in outcome of patients with CLL many of whom experience a life expectancy comparable to general population. However, patients who are double-refractory, having progressed following exposure to both classes face limited options and poor outcomes. This manuscript presents a practical approach to managing double-exposed or double-refractory CLL, integrating clinical case discussions, trial data, and expert insights. For patients with intolerance to cBTKis, second-generation agents may remain effective. Similarly, re-treatment with venetoclax can be considered after prior fixed-duration use. In double-refractory disease, the non-covalent BTK inhibitor (e.g., pirtobrutinib) and CD19-directed CAR-T therapy (lisocabtagene maraleucel) are available standard-of-care options. Pirtobrutinib provides rapid disease control but often with limited durability, emphasizing the importance of early planning for consolidation with CAR-T or allogeneic stem cell transplant. Persistent disease after CAR-T warrants close follow-up and timely referral for transplant evaluation in eligible patients. While PI3K inhibitors are also available, their role is limited due to toxicity and modest efficacy. Investigational agents-including BTK degraders, bispecific antibodies, and novel cellular therapies-offer promise for the future. A nuanced, individualized treatment strategy that incorporates current therapies and emerging options is essential to optimize outcomes in double-refractory CLL.