ASH 2025 | Treatment landscape for dual-refractory CLL: current strategies and future directions

We have seen major advances in the treatment landscape for CLL over the last several years, with targeted therapies completely replacing chemoimmunotherapy in this disease. And yet, the population that remains in unmet need, who really is in need of better treatment approaches, are these dual refractory patients, patients who have been failed by BTK inhibitors, as well as BCL2 inhibitors such as venetoclax. This is currently a relatively small population, but it’s growing. There were several important studies targeting this patient population, one being data from multiple Phase III trials looking at the non-covalent BTK inhibitor pirtobrutinib and CLL. One, of course, focusing on a very different population, on a frontline population that was a randomized Phase III trial comparing pirtobrutinib and bendamustine rituximab. But perhaps more relevant was a randomized Phase III trial comparing pirtobrutinib and ibrutinib, which again supports its significant efficacy in a mixed population of both relapsed/refractory and frontline patients. Again, really reinforcing that this is an agent that has efficacy, substantial efficacy in CLL, and we’ve seen multiple previous studies that have established its efficacy in a covalent BTK inhibitor and BCL2 inhibitor refractory population with response rates upwards of 80%, making this a preferred option for patients with dual refractory CLL. Another interesting treatment option for these patients is, of course, CAR T-cell therapies with lisocabtagene maraleucel or liso-cel. As I just highlighted, we saw encouraging evidence, real-world evidence, of liso-cel in this population in the real-world setting, suggesting that treatment with lisocabtagene maraleucel is a viable treatment pathway with the potential for durable remissions and complete responses in patients with dual refractory CLL, really the current approved indication. And finally, there was significant data released at ASH on the use of BTK degraders in CLL, highlighting again, as we have seen from prior meetings, substantial efficacy with high response rates and encouraging safety outcomes, including in highly refractory CLL patients with both degraders developed by BeOne and the Nurix groups, both, again, with very high rates of response and encouraging safety outcomes. All of these together raise many questions. What are the optimal patient populations for each of these drugs and treatment approaches? Should we be moving these treatments earlier into the second-line setting and maybe even sooner? How do we do this? But I think that at a minimum right now, what we know is that these are all very encouraging options, including some FDA-approved options like pirtobrutinib and liso-cel for these dual-refractory patients. And again, with the degraders coming hopefully soon to the clinic.

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