Treating Adverse Events Associated With BTK Inhibitors

Dr. Rogers: Hi, I am Kerry Rogers. I'm an associate professor in the Division of Hematology at Ohio State University in Columbus, Ohio.

Graphic: How do physicians treat adverse events associated with BTK inhibitors?

Dr. Rogers: I think the way that physicians treat or approach adverse events with BTK inhibitors, very much, depends on what the adverse event is. Sometimes for things like headaches, taking caffeine, and taking ibuprofen with the medication if your platelets are good. There are actually a lot of patients who we see here, who respond very well to Excedrin with no aspirin in it. That requires a completely different management than an adverse event of say, bruising. So those things, like bruising or bleeding with BTK inhibitors, unless people are taking other medications that might be contributing to the bleeding, there's not a whole lot we can do to actually reduce the bruising that people experience. So it very much depends on the adverse event.

There are some adverse events or side effects that are so severe that I would say the majority of physicians would tell the person taking the drug to stop taking it, permanently discontinue it, or not take it again. That would be something like a life-threatening, abnormal heart rhythm or life-threatening, spontaneous bleeding, and I think that it would cause most physicians to say, "Oh, I think you should stop this drug."

Many things, like high blood pressure, could be managed with medications to control the blood pressure. Sometimes things like joint pains can be managed by reducing the dose of the BTK inhibitor, and some people feel better after that. So it really, very much, depends on the severity of the side effect and what other treatments are available for it.

Graphic: Can taking BTK inhibitors be interrupted, and if so, how will that impact the therapy?

Dr. Rogers: So BTK inhibitors are designed to be given indefinitely, and sometimes people do have to stop taking them temporarily. I think the most common one is that they have an increased risk of bleeding because they block or inhibit blood platelet function. People need to stop them so that they can safely get major surgery. Things like cataract surgery don't require stopping anticoagulants, so people can continue taking their BTK inhibitor, in most cases, and minor surgeries like skin cancer removal are not a big deal.

But if someone's getting major abdominal surgery, they should really stop their BTK inhibitor, or they're going to have a risk for excess bleeding during the procedure. And that seems to go okay for most people, and they're able to restart it without an issue. We usually recommend that people try not to interrupt their BTK inhibitor within the first six months of treatment so that they can get a nice response to their CLL before they have to interrupt it.

You can see a flare in the CLL after it's held. So if someone's been taking a BTK inhibitor for a couple of months, and then has to stop it for some reason, it's not uncommon for people to call and say, "Hey, my lymph nodes came back right away," or "I don't feel as good, and my lymph nodes are back." That's probably because this effective B-cell receptor signaling blockade ends as soon as the drug wears off, and some of the CLL cells that the drug told to leave the tissue and go into the bloodstream now home back to the tissue right away.

So these aren't bad problems. If people restart taking the drug, this tends to go away. We have seen some really poor effects for people whose CLL was becoming resistant to a BTK inhibitor, who then stopped it – they can get a really symptomatic flare of their CLL. So it's always good to check with your doctor before stopping a BTK inhibitor, just to make sure that the reason for stopping it is one that's important enough to do that right now.

Graphic: Would you change the dosage amount if a patient is experiencing adverse events?

Dr. Rogers: Yeah. So several of the BTK inhibitors – I think, actually, all of them – have a dose reduction scheme for adverse events. In some cases, that's really helpful, and people feel a lot better at a lower dose. For some things, that's actually not that helpful. Obviously, there are some adverse events that are so severe, you would not want to try restarting it at any dose. But for things like joint pains or muscle aches, it might be very worthwhile to consider a reduction in the dose. That's something that should be discussed with your healthcare team. People shouldn't just reduce the dose on their own. That's not a good idea.

Graphic: When would you recommend a patient switch their BTK inhibitor?

Dr. Rogers: There are three covalent BTK inhibitors that have the same mechanism, more or less, and that's ibrutinib (Imbruvica), zanubrutinib (Brukinsa), and acalabrutinib (Calquence). So those are the three BTK inhibitors that are approved for both the initial treatment of CLL and the subsequent treatment for people who really haven't had a BTK inhibitor before. Those have overlapping resistance mechanisms in the CLL cells. So if one of those stops working, switching to another one of those is probably not going to help the situation in any way.

For side effects though, switching between them does work quite well. Ibrutinib, which is a first-in-class drug, is generally thought of as having the most side effects because it's the least selective. I think that's probably true, and the data certainly supports that that's true. For someone taking ibrutinib, it would be very reasonable to switch to acalabrutinib, where there's actually a phase II study looking at this. For people who stopped ibrutinib for side effects, could you take acalabrutinib, most of them did very well. Or zanubrutinib, there's another study that's actually not just in CLL but across cancers. Could you switch to zanubrutinib if you don't tolerate ibrutinib or acalabrutinib, and that appears to work too?

The one I'm less enthusiastic about is switching to ibrutinib from one of the other two. But I think switching to either acalabrutinib or zanubrutinib for side effects, as a strategy, can definitely work. I would say, though, for side effects that were life-threatening, maybe you don't want to do that, or if it was a bleeding side effect that's pretty universal between them. There are some differences between the drugs, but acalabrutinib causes the most headaches. So for someone with intolerable headaches on acalabrutinib, switching to zanubrutinib would definitely be something I would consider recommending.

There's a recently approved BTK inhibitor, called pirtobrutinib (Jaypirca), that is approved under accelerated approval by the FDA for patients who have taken a covalent BTK inhibitor and a Bcl-2 inhibitor. That has a different mechanism than the other three, so when people use it should be very different than what I'm talking about, which is actually the covalent BTK inhibitors.