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SOHO 2026 | The transformative role of BTK inhibition in CLL: from ibrutinib to next-generation therapies
Kerry Rogers, MD, The Ohio State University, Columbus, OH, discusses the central role of BTK in the pathophysiology of chronic lymphocytic leukemia (CLL), highlighting how BTK inhibitors (BTKis) have transformed patient outcomes. She outlines the evolution from first-generation ibrutinib to the better-tolerated second-generation agents and discusses the potential of pirtobrutinib for patients who develop resistance to covalent BTKis. This interview took place at the 14th Annual Meeting of the Society of Hematologic Oncology (SOHO 2026) in Houston, TX.
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Transcript
I think it’s very difficult to understate how important BTK inhibition has been for the treatment of CLL. The more we learn about this, the more we see that B-cell receptor signaling is really a key driver of the disease in CLL. There’s not one mutation like in CML that really causes the condition, but we see that this B-cell receptor signaling, any way you block it seems to be therapeutically beneficial...
I think it’s very difficult to understate how important BTK inhibition has been for the treatment of CLL. The more we learn about this, the more we see that B-cell receptor signaling is really a key driver of the disease in CLL. There’s not one mutation like in CML that really causes the condition, but we see that this B-cell receptor signaling, any way you block it seems to be therapeutically beneficial. And so BTK, of course, is in the B-cell receptor signaling pathway, and it’s probably the most common target and the most effective. But if you block other proteins there too, like PI3 kinase or Syk, you still see a therapeutic benefit. So this is really central to what the CLL cells need to survive. And the outcomes with BTK inhibitors really have been outstanding. You’re seeing a normal survival for most, of course, not all, but most patients. You know, you’re seeing an expectation that people will have years of happy and healthy functioning. And these aren’t without drawbacks. You know, the first-in-class drug, ibrutinib, was transformative, but had cardiovascular risks and side effects that made it not suitable for everybody and did increase the burden of taking that. So I think we made some progress with the covalent BTK inhibitors, acalabrutinib and zanubrutinib, that have fewer cardiovascular side effects. Certainly in further study with pirtobrutinib, the non-covalent BTK inhibitor that’s very selective, you see probably the least side effects. And so that’s really valuable. The other kind of thing that’s happened is that when patients develop resistance in their CLL to BTK inhibitors frequently, it’s for mutating BTK so that the drug just doesn’t bind anymore. And we’ve seen that reestablishing a drug that binds there actually will reestablish the effectiveness. So pirtobrutinib binds BTK with a C481S mutation, and it continues to work. The C481S mutation confers resistance to ibrutinib, and now we’ve got BTK degraders that work after that. So I really think that seeing how across multiple lines of therapy continuing to hit that target is effective really just argues that this is one of the more effective ways to treat CLL and how central BTK is to the disease.
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