BTK Inhibitor Resistance and Progression

Ian Flinn, MD: Let’s segue and talk a little now about resistance. Unfortunately, ultimately the No. 1 reason people come off ibrutinib or acalabrutinib is not necessarily because they’re having an adverse event. It’s that ultimately the drug fails them, right? They progress. We know from a number of different publications now, there was the seminal paper that documented the cysteine 481 mutation, and the PLC-gamma mutation in patients with CLL [chronic lymphocytic leukemia] on ibrutinib.

Are you routinely testing your patients for these mutations? If you are, why are you doing that? And then when are you doing it? Are you doing it as you see someone’s counts go up? Are you doing it if they don’t achieve a CR [complete response] or they don’t have minimal lymphocytosis? How do you do that? Part of this is to try to talk to community physicians about when they should be doing this. What are your thoughts on that?

Jan A. Burger, MD, PhD: I think you first have to talk about the patient population, which patients are at risk for developing resistance to BTK [Bruton tyrosine kinase] inhibitors. The population at highest risk for developing resistance are those patients who carry a 17p deletion and/or TP53 mutation, especially if those patients had prior exposure to chemotherapy, even several lines of chemotherapy-based treatment. Those are the patients we had in the early trials where the remission duration or the median progression-free survival for those patients was less than 3 years. If you have a patient who fits into that profile, then you have to anticipate that their remission duration is going to be shorter than probably 2 or 3 years.

In those patients who are considered high risk for developing resistance, you would monitor the lymphocyte count. You would probably like to see those patients every 3 or 4 months, monitor their lymphocytosis. I think you are safe as long as those patients have a continuous decline in their lymphocytosis. But as soon as you hit a plateau, or if you notice that their lymphocyte count is starting to trend back up, that’s when you would want to see if those patients are developing resistance by testing. We can do that here in our lab by testing for BTK or PLC-gamma-2 mutations, because we know from past experience that those mutations are in about 8 to 9 of 10 patients associated with development of resistance.

Are they responsible for the biology of resistance? That’s another debate, but they are quite good indicators and they can precede the clinical resistance. But I think testing outside clinical trials, testing for these resistance mutations on a routine basis, that wouldn’t really have practical implications and would be more likely a clinical trial question but shouldn’t be done routinely. First, it’s a question of identifying which patients are at risk for developing resistance. That’s a smaller group of patients, particularly 17p deleted patients, but we shouldn’t totally restrict it to those.

It’s also those patients who had had a lot of prior exposure to chemotherapy, and 11q deleted patients also can relapse, patients who have complex karyotype abnormalities. But that’s usually not tested outside clinical trials. Yeah, I try to focus on the risk group of patients and then test it at a point that usually would be after 1 or 2 years of treatment when you see the lymphocyte counts plateauing or maybe starting to climb back up.

If that’s a clinical situation you see, 1 of the key things to re-emphasize is that physicians shouldn’t stop the BTK inhibitor, because the majority of the clone is still sensitive. If you stop at that situation and say, “Well, we will transition you to something else,” and you start them on the small dose of venetoclax but stop the BTK inhibitor, then patients sometimes can have pretty explosive worsening of their disease. For that reason, it’s good to overlap treatments rather than stopping the BTK inhibitor.

Ian Flinn, MD: Yeah, I think those are important points.

Transcript edited for clarity.