ASH 2025 | Latest updates in cell therapy for CLL: real-world insights and strategies to improve CAR-T therapy

There were several important studies in cell therapy in CLL that were presented at this year’s ASH meeting. I would highlight that probably one of the most important studies was one led by Dr Huang at the Fred Hutch. This was a large, multi-center, real-world evidence analysis that we contributed patients to. And in her oral abstract presentation, Dr Huang presented evidence that the approved CD19-directed CAR T-cell product, lisocabtagene maraleucel or liso-cel, was associated with favorable outcomes, including a relatively high rate of complete response in patients with highly refractory CLL. Frankly, this was somewhat surprising given relatively low rates of complete response in the Phase I and II studies that ultimately led to its approval in this setting and raised questions about the real-world efficacy of liso-cel in CLL. And we need additional follow-up from this study to get more information about the durability of these responses, about the safety in a larger cohort of patients as we think about how to incorporate liso-cel in our treatment pathways for CLL. The question is, you know, clearly CLL has not had the same level of success with CAR T-cell therapies and cellular therapies in general, as have other hematologic malignancies, including large cell lymphoma, mantle cell, et cetera. And so one of the questions is, can we improve upon CD19-directed CAR T-cell therapy given as a single agent? And there have been a number of different efforts, including the addition of a covalent BTK inhibitor, such as ibrutinib. We have combination data from the liso-cel Transcend CLL study suggesting higher complete response rates when ibrutinib is given in combination with liso-cel compared with historical data from liso-cel alone. And we have significant preclinical and correlative data supporting potential for synergy between these agents. Other questions are, can we consider dual-targeted CAR T-cell products to potentially overcome the relatively lower complete response rates in CLL compared with other histologies. And there is interesting preliminary data that has been presented with a strategy in CLL. And finally, I would argue that simply the question of patient selection may have an impact on outcomes. Many of these studies that have been conducted include highly refractory patients, a majority of whom have received traditional cytotoxic chemotherapy, such as bendamustine and fludarabine, which have profound effects on T-cells. And so one question is, in a modern patient population who has never received bendamustine or fludarabine or other cytotoxic chemotherapy, who is receiving liso-cel or other CAR T-cell strategies after only having received targeted or immune-based therapies for their CLL, do we see differential efficacy outcomes? And I think more to come there as our patients today who have been treated with entirely modern therapy approaches are potentially eligible for CAR T-cell strategies.

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