The Next Wave of CLL Therapies to Target Resistance

Despite major advances in targeted therapy, chronic lymphocytic leukemia (CLL) remains largely incurable. Resistance to currently available treatments is driving the development of new therapeutic strategies.

In an interview with Targeted Oncology, Nicole Lamanna, MD, of Columbia University Irving Medical Center, highlighted several emerging approaches—including Bruton tyrosine kinase (BTK) degraders, bispecific antibodies, and cellular therapies—that may help overcome treatment resistance and expand options for heavily pretreated patients.

Watch part 1 and part 2 of Dr Lamanna’s interview.

One promising class is BTK degraders, which represent a novel mechanism for targeting the Bruton tyrosine kinase pathway. Current therapies such as covalent and noncovalent BTK inhibitors bind to specific sites on the BTK protein, but resistance can emerge through mutations in these binding pockets. BTK degraders instead target the entire protein for destruction, potentially bypassing these resistance mechanisms. Early clinical data presented at the 2025 American Society of Hematology Annual Meeting have shown encouraging activity in heavily pretreated patients, including those previously treated with BCL2 inhibitors. These agents are still in development but may eventually move into earlier lines of therapy and combination regimens if results remain favorable.

Another area of interest is bispecific monoclonal antibodies, which are already approved for certain lymphoma subtypes, including follicular lymphoma and diffuse large B-cell lymphoma. Unlike traditional CD20 antibodies, bispecifics simultaneously engage both T cells and malignant B cells, bringing immune effector cells into close proximity with tumor cells to enhance cytotoxicity. Clinical trials are now evaluating these agents in CLL and in patients with Richter's transformation, an aggressive lymphoma that arises from CLL and remains an area of significant unmet need.

Cellular therapies are also evolving in CLL. The chimeric antigen receptor T (CAR T)-cell product lisocabtagene maraleucel (Breyanzi; liso-cel) has received approval for relapsed or refractory disease, though toxicity and response durability remain important considerations. Ongoing studies are exploring combinations of CAR T-cell therapy with BTK inhibitors to enhance efficacy and durability.

Together, these emerging modalities may help address resistance and broaden the therapeutic landscape for patients with advanced CLL.