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ESH CLL 2026 | Resistance patterns with covalent vs non-covalent BTK inhibitors in CLL
Kerry Rogers, MD, The Ohio State University, Columbus, OH, discusses how resistance patterns can differ between covalent and non-covalent BTK inhibitors in chronic lymphocytic leukemia (CLL). She highlights the complexity of resistance evolution, emphasizing that multiple mutation patterns and non-BTK driver alterations can contribute to treatment resistance. This interview took place at the ESH CLL 2026 congress in Stockholm, Sweden.
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Transcript
So we do definitely, so far, see different mutations emerging with covalent BTK inhibitors like ibrutinib, zanibrutinib, and acalabrutinib, and the non-covalent ones, which really the data we have is for pirtobrutinib right now. And actually, even within the covalent BTK inhibitors, you can see some differences. Since they all bind at the C481 residue, you will see C481 mutations occur with those...
So we do definitely, so far, see different mutations emerging with covalent BTK inhibitors like ibrutinib, zanibrutinib, and acalabrutinib, and the non-covalent ones, which really the data we have is for pirtobrutinib right now. And actually, even within the covalent BTK inhibitors, you can see some differences. Since they all bind at the C481 residue, you will see C481 mutations occur with those. With pirtobrutinib, the non-covalent BTK inhibitor, it was designed to bind to mutant BTK. So you get emergence of like T474I, L523W, so you get these other mutations that emerge. But those mutations are actually seen with some covalent BTK inhibitor treatment as well. So I don’t know that it’s exclusive to pirtobrutinib. The other thing that’s important is that pirtobrutinib has really only been studied where we have resistance data when patients had already taken a covalent BTK inhibitor for the most part. So it’s not clear if some of these other mutations are actually occurring below the limit of detection or actually somewhere detected, but then before pirtobrutinib and then emerged during pirtobrutinib treatment. So I think the question now that’s going to be interesting is what do we see with pirtobrutinib resistance if it’s used as a first therapy? And, of course, these drugs are so effective it’s going to be a while before we have that, you know, because you have to treat people long enough that they develop resistance in their CLL. But the question might be less what are the differences between covalent and non-covalent BTK inhibitors and more like what mutations are going to emerge with each specific agent. And I think that depends on drug binding. We have also seen acquisition of driver mutations that are not in BTK at the time of resistance, like new TP53 mutations. I think there’s other mechanisms that aren’t just BTK mutations at play as well.
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