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ESH CLL 2026 | How BTK inhibitor selectivity influences toxicity in CLL
Gianluca Gaidano, MD, PhD, University of Eastern Piedmont, Vercelli, Italy, discusses how increasing selectivity among BTK inhibitors has improved the safety profile of therapies for chronic lymphocytic leukemia (CLL), particularly by reducing cardiovascular and bleeding events. He highlights how second-generation agents such as acalabrutinib build on the pharmacologic limitations of first-generation inhibitors. This interview took place at the ESH CLL 2026 congress in Stockholm, Sweden.
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Transcript
The selectivity of BTKi is something that has been improving over time. So the first-in-class ibrutinib targeted many innocent kinases beyond BTK. The second-generation covalent BTK inhibitors were already, so acalabrutinib and zanobrutinib, were already a bit more focused compared to ibrutinib. And then with the non-covalent BTK inhibitors, the profile of kinome targeting is even more selective...
The selectivity of BTKi is something that has been improving over time. So the first-in-class ibrutinib targeted many innocent kinases beyond BTK. The second-generation covalent BTK inhibitors were already, so acalabrutinib and zanobrutinib, were already a bit more focused compared to ibrutinib. And then with the non-covalent BTK inhibitors, the profile of kinome targeting is even more selective. So there’s a very high selectivity, which then translates in reduced side effects. And this is something very important from the biology of the kinome targeting compared to the safety profile, in particular for what concerns bleeding events, but even more important, I would say cardiovascular events, and in particular actual fibrillation and flutter.
Acalabrutinib has very high selectivity for BTK and at the same time it spares instead innocent kinases that are targeted by first generation BTK inhibitors. And that translates in, and this is well known, in a reduced rate of actual fibrillation or other cardiovascular events, in a reduced rate of hypertension also. And these are very important aspects in a population which is mainly made by elderly patients who already are predisposed to cardiovascular events. So this has been a major step ahead with acalabrutinib.
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