Breaking Down Frontline BTK Inhibitor Selection in CLL: Kerry Rogers, MD

When selecting a Bruton tyrosine kinase (BTK) inhibitor as initial therapy for chronic lymphocytic leukemia (CLL), the decision is currently straightforward from a regulatory standpoint: only covalent BTK inhibitors carry FDA approval for frontline use. Kerry Rogers, MD, associate professor at The James/The Ohio State University Comprehensive Cancer Center, broke down the nuances of that decision and where the noncovalent BTK inhibitor pirtobrutinib fits in.

Among the approved covalent options, acalabrutinib and zanubrutinib have emerged as the preferred choices, largely due to their improved cardiovascular safety profiles compared with ibrutinib. From a standard-of-care and insurance coverage perspective, Rogers noted, covalent BTK inhibitors remain the clear default.

That said, pirtobrutinib is generating attention. Data presented at the 2025 American Society Hematology annual meeting demonstrated improved progression-free survival (PFS) over bendamustine and rituximab in the frontline setting, a result Rogers described as expected given the field’s trajectory over the past decade. More notably, early signals suggest pirtobrutinib’s PFS may rival or exceed that of ibrutinib and possibly match acalabrutinib or zanubrutinib, with a favorable adverse effect (AE) profile driven by its noncovalent, selective binding mechanism and a markedly lower risk of atrial fibrillation.

“I think it would be appropriate for select patients where you don’t think they’re going to need many therapies in their lifespan,” Rogers said, “maybe because they’re older or people who really you think won’t need a BTK inhibitor badly, like venetoclax isn’t going to be an option and won’t tolerate that covalent one.”

However, sequencing remains a critical concern. Although pirtobrutinib after covalent BTK inhibitor failure is well established—it was developed in that setting—the reverse sequence is unproven. Whether covalent agents remain effective after pirtobrutinib exposure is unknown, and resistance mutations observed with pirtobrutinib raise questions about cross-resistance.

For younger patients with high-risk disease and long projected lifespans who may need multiple lines of therapy, Rogers advises caution about using pirtobrutinib up front. The risk of exhausting BTK inhibitor options prematurely is too significant given current data gaps. Pirtobrutinib as frontline therapy may be appropriate for older patients unlikely to require many future treatments or those for whom venetoclax is not an option and who cannot tolerate covalent BTK inhibitors.

Nemtabrutinib, another noncovalent BTK inhibitor, is less selective and carries more AEs, making it a poor candidate for frontline use absent a compelling efficacy advantage.