Bruton's Tyrosine Kinase Inhibitor Resistance and Treatment Sequencing in Chronic Lymphocytic Leukemia

At the 2026 LL&M Winter Symposium in Amelia Island, Florida, Jennifer Brown, MD, PhD, Dana-Farber Cancer Institute, Boston, Massachusetts, discusses mechanisms of resistance to Bruton's tyrosine kinase inhibitors (BTKi) in chronic lymphocytic leukemia (CLL), including mutations associated with both covalent and non-covalent agents. 

Dr Brown highlights treatment strategies to overcome resistance and emerging therapies aimed at improving long-term disease control.

Transcript:

Hi, I'm Dr Jennifer Brown from Dana-Farber Cancer Institute in Boston where I'm director of the CLL Center and institute physician, as well as the Worthington and Margaret Collette Professor of Medicine at Harvard Medical School. I'm here at Winter LL&M, where I gave a talk about BTK resistance mutations and clinical management associated with them.

If we think about what happens when you start a patient on a BTK inhibitor, a certain number of patients will come off very early on for an adverse event and those patients we consider exposed to a BTK inhibitor, but without progression. A small number of patients will develop transformation, and that's its own thing and needs to be managed as Richter's transformation but then over time, more and more patients will slowly develop resistance to BTK inhibition. That is associated with development of mutations that confer resistance. With the covalent inhibitors, the most common mutation is mutation of the cysteine 481 to a serine (C481S), which abrogates covalent binding. Ibrutinib becomes a non-covalent inhibitor with a little bit of activity, but acalabrutinib and zanubrutinib have no activity in that setting. This is why one should not retreat a patient whose disease has progressed on a covalent inhibitor with another covalent inhibitor.

Instead, we have either venetoclax, which can work regardless of mutation or pirtobrutinib, which also has been studied in all comers of patients whose diseases progressed on a covalent inhibitor and can also be used in that setting. The interesting aspect of pirtobrutinib is that it works against the C481S mutation, and we see that mutation go down significantly on pirtobrutinib. What happens is patients can develop resistance to pirtobrutinib, and that is most common with the T474 or L528W mutations, other mutations in the kinase domain of BTK.

Patients who do develop resistance to either covalent BTK inhibitors or pirtobrutinib tend to have what we call a multicolonal disease. They have multiple mutations, higher and lower-level mutations. What happens is they go from one BTK inhibitor to another, a new mutation can grow out if that one confers resistance to a given drug. Whereas if you take them off BTK inhibitors entirely, try venetoclax or something else, there's a chance that the mutations will go down because they're no longer under selection pressure– that's still a topic that we need to study further.

New drugs coming down the pipeline to work in this setting include another non-covalent inhibitor, nemtabrutinib, rocbrutinib, which is a dual covalent non-covalent inhibitor, as well as the BTK degraders. We hope that by using more time-limited therapy upfront and stopping therapy, we can avoid the selection pressure that leads to the development of resistance in the first place and then be able to reuse the same time limited regimen again.

Source:

Brown J. Updates in management of BTKi resistance and mutations. Presented at LL&M Winter Symposium; January 30-February 1, 2026. Amelia Island, Florida.