The Evolving Role of BTK Inhibitors in Treating Chronic Lymphocytic Leukemia - Episode 5

CLL Subpopulations: Whom Not to Give BTK Inhibition To

Ian Flinn, MD: I guess the other question is, who wouldn’t you give a BTK [Bruton tyrosine kinase] inhibitor to. You wouldn’t give it to somebody who you thought wasn’t going to respond to that drug. But in reality, we don’t really know who that person is up front. They’re just as likely to respond to ibrutinib or acalabrutinib as they are to venetoclax. Of course, there are those BTK mutations that occur. But those are mostly acquired aberrations that occur while patients are on it, and we don’t necessarily know that from the beginning that they’re not going to respond. So I can’t think of a genetic profile in which I wouldn’t be happy putting someone on a BTK inhibitor. How about you, Jan? Any thoughts there?

Jan A. Burger, MD, PhD: My thought on that is it’s maybe moving us a little in a different direction. But 1 thing we haven’t discussed yet is when making this choice, frontline venetoclax versus BTK inhibitor, the question always is, “Well, patients will possibly progress.” If you put somebody on venetoclax-based treatment, you give treatment for a year, but we I think can estimate many patients will eventually relapse. In that situation, we’re not sure what is going to work. Are they going to be sensitive to another dose or another round of a treatment with venetoclax? Are they sensitive to BTK inhibitors? Those data are emerging, and I think in a year or 2 we probably know what to do in that situation. But right now they’re just anecdotal data, basically. There are no systematic data that I know of that guides us how to treat a patient who progresses after receiving venetoclax frontline.

On the other hand, there’s a bit more data just because the BTK inhibitors have been around longer to say if the patient receives BTK inhibitor therapy, they usually respond. But then if a patient progresses, we know we can salvage them with venetoclax. I think for that reason, at least at this time, usually the choice in the frontline setting is still to go with a BTK inhibitor first and save venetoclax for second-line treatment. That’s a choice that may change at some point, but I think that’s also based on some data that we have that says you can quite effectively salvage a patient who progressed on BTK inhibitor later with venetoclax. Would you agree with that?

Ian Flinn, MD: The point is well taken. I guess I’m a little more comfortable with putting people on venetoclax as a frontline therapy. I think biologically all the data we have suggest that rationale. But I can understand why people would be hesitant to do that. We do have the RESONATE trial, the follow-up from that study where there’s more than 5 years, meaning 5½ years, of median follow-up. The long-term progression-free survival with ibrutinib and with acalabrutinib is really hard to argue in that setting. From a disease-control standpoint, it’s hard to argue with a BTK inhibitor. I worry a little more about some of the long-term adverse effects that accumulate in patients. And we do know that some patients, unfortunately, have to come off therapy. They’re intolerant of ibrutinib. Some will be switched to acalabrutinib and maybe can tolerate that or 1 of the other BTK inhibitors.

Transcript edited for clarity.