EHA 2026 | Venetoclax plus ibrutinib delivers durable remissions after BTK inhibitor resistance in CLL

So I’m really excited at this meeting to share a long-term follow-up of a phase 2 study we actually started quite a while ago. And the whole goal of this study was to take patients who were taking the covalent BTK inhibitor ibrutinib, which at the time was the covalent BTK inhibitor we had available. And at the time of developing molecular resistance, actually add venetoclax to ibrutinib with a goal of eliminating molecular resistance and ideally giving patients some time where they didn’t have to take treatment. Still today, for patients whose CLL progresses on a covalent BTK inhibitor, the expectation is that they’ll be taking therapy most of the time. Even with approaches that are a venetoclax fixed duration there, the median PFS, which is actually unknown in this specific setting, is usually around two years. So you might get some time off therapy, but there’s not usually long durations of time. So we chose venetoclax for the intervention because it was the most effective therapy in a covalent BTK inhibitor progression setting. And we saw that the variant allelic frequency of BTK mutations and PLC gamma 2 mutations would decrease with that compared to other therapies we treated patients with in that time frame after ibrutinib. And now, of course, it is known in lots of settings that BCL2 inhibitor, BTK inhibitor combinations are effective, but then we mostly just knew they were safe and could be effective, and it really wasn’t as developed as a combination. So we had 28 patients that were taking ibrutinib, generally for quite some time, and the eligibility criteria was that they had to have a resistance mutation that was persistent with or without progressive disease. They were also allowed to discontinue the combination of venetoclax and ibrutinib after venetoclax was added at either 12 or 24 cycles, so that’s about 12 or 24 months, if they had a complete remission with no detectable CLL. What we found was the median progression-free survival with this strategy was 40.7 months, which is considerably better than the 24 months in a phase two trial of venetoclax monotherapy. So that was a really nice improvement. We also had half the patients discontinued due to response. I will say that not all of them discontinued due to the exact trial stopping criteria. A lot of this took place during the pandemic where we couldn’t do the assessments we wanted or some patients elected to discontinue due to difficulty returning for visits at the height of the pandemic. But we did have half that were able to be off therapy. Many of them are still not getting treated at longer follow-up. And those that did start a subsequent therapy, there was a median of about 22 months before they had to start a next-line therapy, and those are people who discontinued due to response. We also saw that the median PFS for those who discontinued treatment due to response was better than those who discontinued due to progression, which, you know, it’s an exploratory analysis, and this is a smaller study, but at least supports that stopping treatment in this setting is certainly feasible and isn’t really adverse for the patients. So I really do like this strategy of doing this combination. We did see that a lot of patients became mutation negative, which meant there was no detectable resistance mutation, and MRD negative, so no detectable CLL. We did see return of some of those resistance mutations when the disease was again detectable or occurred. So I don’t know that this is a strategy that will eliminate this molecular resistance to BTK inhibitors indefinitely, but certainly we can get deep remissions even in this space where people have molecular resistance. We did have a lot of the patients under the trial when they had some signs of disease progression. So we had both in there and we did kind of look at that as an exploratory analysis and those who had the intervention before kind of markers of overt disease progression did have a slightly longer PFS. The last thing I really want to say about this is that I think this strategy is very valuable, and we’re currently enrolling patients on a phase two trial of pirtobrutinib and venetoclax as a fixed duration therapy for patients who experience disease progression on a covalent BTK inhibitor, so ibrutinib, acalabrutinib, or zanubrutinib. So looking at this with a BTK inhibitor that is then effective in a resistant setting and venetoclax and having it be fixed duration for everybody. So I’m really excited about that trial too because I think it builds on the success of this trial and is likely to be even more effective.

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