The Evolving Role of BTK Inhibitors in Treating Chronic Lymphocytic Leukemia - Episode 9

The Management of Cardiovascular Events

April 16, 2020

Ian Flinn, MD: I guess 1 of the more serious adverse effects to dial in on—and I’d love to get your take on your management because it varies, and it can vary from patient to patient and 1 institution and 1 investigator to the next—to me is the cardiac adverse effects.

The most prominent, of course, is atrial fibrillation and how to manage that. Not only do you stop the drug and start them on another drug, but if you keep them on the drug, do you have to keep them on anticoagulation? I usually do this in collaboration with a cardiologist. And the cardiologist will tell me, well, the person’s CHADS2 [chronic heart failure, hypertension, age, diabetes mellitus, stroke] score is this, so they’re at very high risk for stroke, and you really need to keep them on anticoagulation. On other instances, no, you can stop the anticoagulation. Now that we have acalabrutinib, if someone had atrial fibrillation on ibrutinib, I’ve generally tried to switch them off to acalabrutinib and then work on whether we need the anticoagulation. Of course, we also have to be a little careful about if there’s any drug-drug interactions with some of the anti-arrhythmic drugs that sometimes people are placed on, so working on that. What’s your take, Jan? Do you do something radically different from that, or is that similar to what you’re doing in your clinic?

Jan A. Burger, MD, PhD: I think that’s a perfect summary. I totally agree with all the points you’re making. For a while, we’ve been saying we need strict guidelines on how to manage cardiac adverse effects and atrial fibrillation with ibrutinib. But what you’re describing is exactly what we are doing, and it is such a case-by-case decision. At the time when we didn’t have acalabrutinib, we managed patients with a cardiologist on a case-by-case management plan to see if patients can be converted back to sinus rhythm. And then we reintroduced usually the BTK inhibitor at a lower dose, and we escalate it if necessary. And that sometimes works, but it doesn’t always work. I think, yeah, it’s a case-by-case decision when patients are co-managed with the cardiologist. Anticoagulation is discussed. They’re usually trying to convert them back to sinus rhythm if possible.

Now we have acalabrutinib, so it’s absolutely reasonable to bring it up to the patient to say, “Well, we have this other agent, which is more selective, which may have fewer cardiac adverse effects.” It’s not proven. Early data show that maybe the frequency of atrial fibrillation is lower, but that’s really early days. And we have much longer follow-up with the ibrutinib trials, so I’m not advertising acalabrutinib too much in that sense because it’s a randomized study. That’s the reason why they are doing this randomized study: to have stronger data. But it’s a good alternative, and if patients are interested, then I switch them over; otherwise, if they have high affinity and otherwise benefited a lot from ibrutinib, we can try to keep them on that. But it’s good to have more options and management of these adverse effects. And, yeah, it’s a case-by-case decision. Is that your read on the data too? Are you confident that there are fewer cardiac adverse effects with acalabrutinib? How would you read those data?

Ian Flinn, MD: I’m not confident that there are fewer cardiac adverse effects. The only thing that gives me pause in that whole thing is, well, the trials are often very different. So cross-trial comparisons are difficult. However, there is a trial in Waldenström macroglobulinemia where zanubrutinib, which of course is not indicated in CLL [chronic lymphocytic leukemia], but zanubrutinib was compared head-to-head. They have released outcomes. It’s not yet published, but they’ve released the outcomes. And the atrial fibrillation rate was a tiny fraction who got zanubrutinib compared with the patients who got ibrutinib. That’s a randomized trial—different disease but randomized trial—and so it was striking.

I would bet there is something to it, but I’m not sure if we can quantify yet. But at least that makes me think if someone has an adverse effect with ibrutinib, then, well, we should definitely try acalabrutinib. I don’t think having had ibrutinib worsens the outcomes for someone if they then go on to get acalabrutinib. I’m comfortable with that segue. I’m also comfortable with starting people on acalabrutinib. It has to whether they want a twice-a-day drug or once-a-day drug. If they already have a risk of some of these things, I might not go to acalabrutinib. And so I think it really has to be individualized. I don’t have 1 BTK inhibitor I use for all patients. I use different ones for different people.

Transcript edited for clarity.