ESH CLL 2026 | Resistance to BTK degraders and combination strategies in CLL

Yeah, so my lab studies resistance to BTK inhibitors, which have really revolutionized the field for CLL treatment. And so my work kind of steps in with BTK degraders, and I look at resistance to BTK degraders specifically, and we identify this novel BTK mutation that causes resistance not just to BTK degraders, but we’re seeing that it actually causes resistance to all of the previously used BTK inhibitors as well, really creating this therapeutic need to find something to overcome this resistance mechanism. And so really today I’m just going to be talking about the mechanisms of resistance of that mutation and hopefully some ideas of the field where we could go to overcome this resistance. So we’ve done some preliminary work and we have a publication that’s currently under review showing that the potential of venetoclax combination with BTK-degrader might actually be able to overcome this resistance mutation, which is a little bit puzzling as far as the mechanism of how that’s working, because as I’ll talk about later, we show that the mutation actually prevents the BTK degrader from binding to BTK. And so it’s really interesting how the combination of venetoclax with the BTK degrader is able to overcome this resistance mutation. However, we are seeing the data across multiple different cell lines and models showing that this is something that’s happening, and we’re not seeing it with just venetoclax alone, so it’s not coming just from the venetoclax, it is coming from the combination. So we have some potential that we’re looking into, but we’re really trying to understand that mechanism of how that’s working, but we’re excited that that could be some potential. For this, it would be potentially for if you get BTK-degrader failure because of this A428D mutation it could specifically help to overcome this A428D. My personal thoughts that I am wondering is maybe could there be benefits of doing from the start instead of doing BTK degrader alone, doing a combination of BTK degrader and venetoclax, which we see a lot with the inhibitors that they do combination of venetoclax and a BTK inhibitor, which is something that there are trials that are at least, I don’t know if they’ve started yet, but I know that at least at the University of Miami, we have trials enrolling BTK degrader and venetoclax. So hopefully we’ll see some promising data there.

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