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

ABSTRACT: The treatment landscape for chronic lymphocytic leukemia (CLL) has been transformed by the advent of covalent Bruton tyrosine kinase (BTK) inhibitors (cBTKis) and B-cell lymphoma 2 (BCL-2) inhibitors, leading to markedly improved outcomes and, for many, near-normal life expectancy. However, patients progressing after both classes of therapy (double-refractory) have limited options and poor prognoses. This review outlines a practical approach to managing double-exposed or double-refractory CLL, incorporating clinical cases, trial data, and expert perspectives. For cBTKi intolerance, second-generation agents may remain effective. Venetoclax retreatment is reasonable after prior fixed-duration use. In true double-refractory disease, noncovalent BTK inhibitors (eg, pirtobrutinib) and CD19-directed chimeric antigen receptor T-cell (CAR-T) therapy (lisocabtagene maraleucel) are standard-of-care options. Pirtobrutinib induces rapid responses, though often of limited duration, underscoring the need for early consolidation planning with CAR-T or allogeneic stem cell transplant. Persistent disease after CAR-T therapy warrants close monitoring and timely transplant referral in eligible patients. Phosphoinositide 3-kinase inhibitors remain available but are limited by toxicity and modest benefit. Emerging agents, including BTK degraders, bispecific antibodies, and novel cellular therapies, offer promising future directions. Optimizing outcomes in double-refractory CLL requires an individualized, nuanced strategy integrating available treatments with innovative approaches under investigation.