EHA 2025 | Understanding mechanisms of resistance to BTK and BCL2 inhibitors in patients with CLL

So we’ve known for a while that over the years some patients can develop mechanisms of some resistance that render them no longer responsive to the therapies. Like I remember being in the room when we identified the first two patients that developed a BTK mutation at C481S. And that was back in the days, I think it was the year 2013, we had started the clinical trials in 2010. And we met with the leadership that was developing the drug and made a decision at the time to just wait a little bit longer because we were probably going to see more patients. And that was eventually what happened. And so over the years now, there’s much more data, it’s not only the C481S, there’s multiple other mechanisms of resistance that have been identified both for BTK inhibitors and BCL2 inhibitors. And we know that the emergence of these mechanisms of resistance causes us to then look into other novel targeted agents, such as like BTK degraders, which can target downstream and so overcome these known mechanisms of resistance. We see that these are emerging less in patients that are treated with fixed duration treatment strategies with novel targeted agents. So that’s one of the main reasons why I would be all open to do in a younger patient, like a double or a triple combination therapy is approved, you know, like right now it’s only approved in clinical trials. But it’s one of the main reasons why, in my mind, we need to have doublets available to be able to allow the patients to have treatment-free time so that they don’t keep hitting the same target and we don’t develop these mutations that will lead to resistance mechanisms over time and cause us to have then trouble later on because then once you finish hitting one target, then you are done and then you have to go to the next one. So, you know, like we know that, for example, one of the concerns that has emerged over the years is that one of the mutations seen with pirtobrutinib seems to be present also in patients that progress after zanubrutinib use. And so we still don’t know how that will impact. If it’s the zanubrutinib that is, you know, if you use it, then pirto might not work afterwards or may not work as well. or if it’s just, it has nothing to do with it. So still a little bit up in the air how we’re going to interpret this. But it’s interesting nonetheless, you know, like they didn’t see that mutation with ibrutinib, for example. But again, ibrutinib has other toxicities and that’s why it’s no longer preferred frontline regimen. So we’re still trying to understand and make sense of all these mechanisms of resistance, but definitely something to worry about for someone that is on continuous exposure to a drug, such as the continuous BTK use.

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