Bruton’s Tyrosine Kinase in B-Cell Malignancies: Advances in Targeted Therapy - Episode 8

Physician Preferences on BTKi

Mazyar Shadman, MD, MPH, and Jonathon Cohen, MD, MS, share their preferences regarding BTK-targeted treatment in B-cell malignancies.

Mazyar Shadman, MD, MPH: Is a second-generation BTKi [Bruton tyrosine kinase inhibitor] your choice these days for CLL [chronic lymphocytic leukemia] or mantle cell lymphoma, or is there a situation where you still go with ibrutinib? If you have all 3 available and financially, they’re not different.

Jonathon Cohen, MD, MS: For CLL, I’m most commonly utilizing acalabrutinib in practice, outside the setting of a clinical trial, and to your point, given availability of each. Now, I will say that there have been times when we’ve been able to get one agent instead of a different one at a cheaper cost to the patients, or there may be a patient assistance program that helps us out. But all things being equal, I have found that acalabrutinib has been my go-to in CLL more often than not. In mantle cell lymphoma, I have recently been using zanubrutinib more often than some of the others. I will say, at our own center we have some studies open exploring combination therapies, and those are using ibrutinib in that setting. And I have a number of patients who are receiving ibrutinib. But again, all things being equal, I’ve tended to go with one of the second-generation BTK inhibitors. Although I am still comfortable using ibrutinib, and if there’s a reason that a patient was a better candidate for that, those toxicities are generally manageable. And we’ve learned a lot about how to work with them over the years. What about you?

Mazyar Shadman, MD, MPH: Outside of clinical trials, for CLL it’s hard for me to come up with a scenario in which I would go with ibrutinib if I have access to acalabrutinib. You mentioned an important point, something we should be thinking more and more, at least I’ve been more careful about making decisions. The financial burden on the patient could be different. Sometimes I have patients for whom I may not be able to get one of these kind of next-generation drugs, and you’re waiting for weeks. I always tell them I absolutely feel comfortable moving forward to start treating with ibrutinib, and a lot of patients do well.

There’s absolutely no reason to delay treatment or causing anxiety or stress for the patient if for whatever reason we can’t get those next-generation drugs for them. Normally I go with the second-generation, which is acalabrutinib for CLL. For mantle cell lymphoma, same, I’ve been using either ACALA [acalabrutinib] or zanubrutinib. A lot of these decisions are based on our experience being involved in clinical trials, having more patients on one of these drugs. But for those of us who have been involved in most of these medications, I’m very comfortable with both second-generation drugs.

Jonathon Cohen, MD, MS: One thing that’s come up as we’ve gotten some of the data this year with the head-to-head trials, is if you have a patient who’s been on ibrutinib and doing well, would you consider switching them to one of these other agents based on the new data, or would you keep them on the ibrutinib if they’re still responding and tolerating it well?

Mazyar Shadman, MD, MPH: Absolutely not. I would continue. There’s no reason. And that’s a very important point because I get these questions now from patients.

Jonathon Cohen, MD, MS: Sure.

Mazyar Shadman, MD, MPH: They see these data, and that’s a common question. No, if somebody is on ibrutinib and they’re responding and the adverse effect profile is acceptable to the patient, no, absolutely. I would go even beyond that. We saw data from the ECOG trial, the FCR [fludarabine, cyclophosphamide and rituximab] versus ibrutinib/rituximab, I’m blanking on the number right now, E1912 I believe. That was a head-to-head trial with FCR versus ibrutinib/rituximab. We saw from that study that patients who stopped ibrutinib because of AEs [adverse events], and they stopped treatment without switching them to something else, there was a good progression-free survival after stopping ibrutinib. These patients had been on BTK inhibitors for a couple years.

The point is if I have a patient who, after being on BTK inhibitors for a while they develop an adverse effect and we decide to stop the BTK inhibitor, sometimes even watching those patients could be a reasonable approach, unless they have an indication for treatment or they have a high-risk feature in which we don’t want to take that risk. There are many patients who come off. No, I want to be very clear about that, that will never be my plan. When I start with a BTK inhibitor, we should go on by label, and the plan is to continue therapy. But for those patients who have to come off the drug, I will look at the indication for treatment, and maybe they can go without treatment for a months or even longer.

Jonathon Cohen, MD, MS: I have a patient who has CLL and has a number of other comorbidities, including a neurologic condition that precludes a number of different therapies because of some drug-drug interactions. And this patient eventually required therapy due to thrombocytopenia and was initiated on ibrutinib, and her platelets responded beautifully, and she responded very nicely. She developed some diarrhea, but ultimately had a GI [gastrointestinal] bleed, where we made the decision for her to come off therapy. And that was probably about 18 months ago, and her platelets are normal, her blood counts are normal, she feels great, her diarrhea has resolved since we discontinued the therapy.

That’s a key point, that just because you have to stop somebody’s therapy does not mean that you immediately have to go onto a different treatment. I would imagine this is where you’re coming from as well. These are not people who have been on therapy for 2 months and you’re just starting to see some benefit, and they have a toxicity. Those people probably do need to transition to an alternative agent. But the patient who’s been on it for 12, 18, 24 months or longer, who encounters toxicity or encounters maybe a new comorbidity or something that develops that makes it hard for them to continue therapy, many of those patients, I agree, can be observed without requiring treatment. Again, like I said, I’ve had some patients who have gone several years before we’ve had to start thinking about doing more treatment.

Mazyar Shadman, MD, MPH: Yes, I was referring, as we mentioned, to patients who have been on treatment for a long time. And again, just to be clear, because every once in a while, we do get patients coming with recommendations for taking ibrutinib or acalabrutinib for 2 years or 1 year and then stop. We don’t know if that’s the right way of giving these drugs. There are ongoing studies mainly combining BTK inhibitors with other agents and planning for maybe stopping or coming up with a finite duration. But for now, BTK inhibitors should be given indefinitely until progression or adverse effects. We are referring to patients who are in that specific situation that we just pointed out.

This transcript has been edited for clarity.