Bruton’s Tyrosine Kinase in B-Cell Malignancies: Advances in Targeted Therapy - Episode 5

Disease Progression and Resistance to BTK Inhibitors

Mazyar Shadman, MD, MPH, and Jonathon Cohen, MD, MS, talk about disease progression on BTKi and what mechanisms of resistance can occur.

Mazyar Shadman, MD, MPH: Ibrutinib, acalabrutinib, and we have zanubrutinib, another second-generation medication. Again, for all these drugs, the mechanism of action is very similar. For example, please talk about the resistance mechanism with ibrutinib, at least for CLL [chronic lymphocytic leukemia]. That’s the disease that’s studied more for treatment failure. There are mutations in CLL we have found that are responsible for most of the treatment failures. Maybe you should talk about that, and then we’ll move to the next BTK [Bruton tyrosine kinase] inhibitor, zanubrutinib.

Jonathon Cohen, MD, MS: One of the things that’s been interesting in CLL, we have identified several resistance mutations, the most common one being the C481S mutation, which does predict resistance to the available BTK inhibitors. This is one of the things that’s exciting about some of the newer ones we may talk about at the end that are in development because they may not necessarily be as impacted by this mutation.

One of the things though that’s interesting is that in mantle cell lymphoma, this has been studied and has not been nearly as prominent or as critical in development of resistance. There still is a lot more that we need to learn about mechanisms of resistance in mantle cell lymphoma. But for patients with CLL, there have been data that you can even see a trend for the emergence of a C481S mutation and predict relapse. But there’s still a lot that we’re learning about how to predict somebody’s impending relapse. Is that something that you’re doing in your own practice, or do you have any other methods that you’re using to follow patients who are on BTK inhibitors?

Mazyar Shadman, MD, MPH: In terms of following their resistance mutations?

Jonathon Cohen, MD, MS: Yes, sort of following in general for an impending progression.

Mazyar Shadman, MD, MPH: This is a practice that has been changing over time. When we first learned about the mutations, we started watching patients more closely if they had high-risk features like 17p deletion or complex karyotype. But then over time we learned that we’re not going to be changing treatment even if we find a mutation if the patient is not showing a clinical relapse because it’s not like we have 15 other options. The options are limited, and we should take advantage of each drug. What our practice is now, and what my practice is now, is if I see any signs that are concerning for progression, like rising lymphocytes that are consistent with CLL, or enlarging lymph nodes, or symptoms, then I will start looking for the mutations. But then I start planning for the next line of therapy.

Perhaps a few practical points, it’s absolutely important not to stop treatment unless you have a solid plan for the next line, and if possible, we should overlap and make sure that we’re not taking the patient off treatment if they have the resistance mutation. But no, we don’t check unless there is a clinical reason or suspicion to do so. One other practical point I wanted to mention because we did talk about the very similar MOA [mechanism of action] between the 3 drugs, which is binding to the Cys481S, location on the BTK. If we have a patient with disease progression on ibrutinib, or ACALA [acalabrutinib], or ZANU [zanubrutinib], we can’t be using the other 2 drugs for treatment. Basically, for a patient who has progression on ibrutinib, then acalabrutinib or zanubrutinib are not right answers in terms of the next line of therapy because they work the same way. At least for irreversible BTK inhibitors, that’s the same story. Of course, we talked about the different safety profiles, and switching between BTK inhibitors for that reason absolutely makes sense when it’s clinically necessary.

This transcript has been edited for clarity.