iwCLL 2025 | The management of double-refractory CLL: current options and approaches being explored

So most people with CLL can now expect to have a normal survival. I think the groups of patients that may not expect that are very young patients who need treatment, and then patients with double-refractory CLL. So that’s CLL that has resistance developed to both a covalent BTK inhibitor and a BCL2 inhibitor, which is generally venetoclax. In this setting, the approved therapies that work are really pirtobrutinib, which again has a median progression-free survival of somewhere around a year and a half in this setting, which is probably less than someone’s expected lifespan for the vast majority of patients in that situation, and CAR-T with liso-cel, which can be effective. But again, if you’re looking at liso-cel alone, it’s only about 20% of the patients that get the complete remission where you’d expect a very long-term benefit. That increases to just over 40% if you add ibrutinib, but that’s not sufficient for a lot of patients. So I think this is the most difficult area for CLL. 

We’ve seen some other investigational therapies that have been used like BTK degraders. However, we don’t really know what the PFS is going to be there or how long that will control the CLL, and my guess would be not a decade. So, double refractory CLL, when I see patients with this, I always consider what’s their natural lifespan, how fit are they, and what can we accomplish for them? And really have a talk that’s different from the way I mostly discuss CLL with patients, where it could be something that does limit their survival, and think about strategies for how to avoid that. 

We do have patients in CLL that are very elderly and very, very unfit. And I know people don’t talk about that too much, but we have people in their late 80s or 90s with a lot of other comorbid health conditions that could not really undergo something like CAR-T, nor would they want to at this point in their lifespan. And while certainly pirtobrutinib will work there, it won’t work indefinitely, we have published our institutional experience using a combination of a covalent BTK inhibitor and venetoclax, mostly ibrutinib and venetoclax, in this population for patients who either don’t want to be or can’t be in clinical trials and have gotten very durable remissions. So I’m very interested in investigating how we might better use combination BTK/BCL2 inhibitors in this kind of double refractory space, particularly with something like pirtobrutinib, which works already there, you know, in combination with another drug. And we do have an investigator-initiated trial open with pirtobrutinib and venetoclax in covalent BTK inhibitor resistance. So not double refractory, but at least, you know, trying to delay, it’s a fixed duration, so delay the time to that developing. And I do think actually other combinations there will be effective. And that is definitely a space where I think some of the, if we’re successful at it, using things that can activate the immune system to fight the CLL would be very beneficial down the line.

This transcript is AI-generated. While we strive for accuracy, please verify this copy with the video.