ESH CLL 2026 | Understanding and overcoming BTK inhibitor resistance in CLL

So, BTK inhibitors are obviously an extremely widely utilized class of drugs, and the main way to give them as a monotherapy is to use them until the CLL progresses during treatment. I mean, some people stop due to intolerance or other reasons, but a lot of patients will expect their CLL to be resistant to a BTK inhibitor at the end of their treatment with it. And one of the major mechanisms of resistance in CLL is mutations in BTK, the drug’s binding target, that make it so the drug doesn’t bind as well. So the covalent BTK inhibitors, ibrutinib, zanubrutinib, and acalabrutinib, bind and permanently inhibit BTK. And some of these mutations change the binding to reversible and allow continual B cell receptor signaling through BTK, which really means that the drugs don’t work as well. The most common mutation with ibrutinib was the first one we really kind of did work on, and that’s BTK C481S. However, there’s a spectrum of other mutations that will inactivate the kinase region, which is really confusing why that still allows signaling, but it does. It might be a scaffolding function of BTK. Or gatekeeper mutations like T474I, which mean that the drug really can’t bind to the active pocket. So with each of the drugs, we’ve seen a slightly different spectrum of these mutations emerge. BTK C481S is very common with ibrutinib, but then you’ll see these T474I mutations with acalabrutinib and actually different ones with zanubrutinib. So they do have overlapping mechanisms because all three of those drugs bind BTK at the same site, but you can see a slightly different mutational spectrum. That becomes really interesting when you think about the non-covalent BTK inhibitor pirtobrutinib, which was designed specifically to bind C481S mutated CLL, that you’ll actually see emergence of some of these other mutations in pirtobrutinib resistance. I think it’s really important to realize, though, that everyone taking pirtobrutinib, that we have this resistance mutation data for had their CLL exposed to a covalent BTK inhibitor first. So they actually went into pirtobrutinib treatment with sometimes multiple different BTK mutations. And then you’ll see the C481 ones decrease and other ones increase or new ones emerge. So you’ve got kind of this dynamic landscape of these mutations as the CLLs try to, as I explained to patients, like outsmart the BTK inhibitors. I think there’s a few ways to overcome this. The thing everyone thinks of is, oh, can we just sequence these based on what mutation emerges, which is a possibility. The issue is even if you get clearance of a mutation, it’s probably there below detection and will reemerge. So if you use ibrutinib, get C481S, it clears, and you get something else, not only is that mutation likely to confer resistance to ibrutinib, but if you go back to ibrutinib, probably that original mutation is going to return. And there will be multiple mutations, making it really hard to select a drug that will get around that. So I think it’s interesting to think about testing for these specific mutations and picking a drug based on them. We should definitely investigate that strategy. But I think that can be difficult. I think some newer drugs, so nemtabrutinib, which has been around for a while, which is less selective and also works with several mutations. Rocbrutinib, which we’ve done a lot of investigation on at Ohio State, which actually binds both covalently and non-covalently, binds most mutant forms of BTK and has effectiveness in BTK inhibitor-resistant CLL. Both of those are good strategies. There’s BTK degraders, which just remove the protein. So I think those are ways we can continue to target BTK even with these mutations. And then, of course, something that’s not really the focus of this topic, but there’s strategies that avoid needing BTK, like venetoclax and of course cellular immune therapies.

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