Safety and Efficacy of BTK Inhibitors in CLL

A discussion about managing toxicities associated with Bruton tyrosine kinase (BTK) inhibitors for chronic lymphocytic leukemia (CLL).

William Wierda, MD PhD: Let’s turn to toxicity and adverse effects. There were 2 important abstracts presented at ASCO [American Society of Clinical Oncology Annual Meeting] and EHA [European Hematology Association Congress] this year. Both were head-to-head phase 3 comparisons of irreversible inhibitors of BTK, ibrutinib vs acalabrutinib, and ibrutinib vs zanubrutinib. Acalabrutinib is approved. Zanubrutinib is not approved. On the NCCN [National Comprehensive Cancer Network] Guidelines, we have 2 options. One is ibrutinib as a category 1 and the other is acalabrutinib as a category 1. Dr Atallah, what are some of the toxicities you’ve seen with the BTK [Bruton tyrosine kinase] inhibitors? What are the things you worry about and talk about with patients when you start them on a BTK inhibitor?


Ehab Atallah, MD: I discuss toxicities with them. I specifically discuss the joint pain, bleeding, and atrial fibrillation. Although it’s not really a toxicity, we all know we need to explain to our patients about the lymphocytes going up so there’s no panic when they see their lymphocytes going up with the BTK inhibitor. These are things we need to watch for. I clarify the incidence of severe bleeding. Once you say the word bleeding, they wonder where the bleeding is from. You have to clarify that the severe bleeding is rare and it’s more commonly like bruising.

The acalabrutinib-vs-ibrutinib study showed that acalabrutinib, at least in terms of the efficacy, was about the same. But acalabrutinib did have a lower incidence of atrial fibrillation, arthralgias, and bleeding. Infections were about the same between both of them. The acalabrutinib is a twice a day, which is a little annoying, if I could say that for a pill that has to be taken for a long time. I consider that an annoying adverse effect, but when you compare it with atrial fibrillation and bleeding, it definitely has an edge there.

William Wierda, MD PhD: What tend to be the treatment-limiting toxicities that you’ve seen with ibrutinib and acalabrutinib? You mentioned arthralgias and atrial fibrillation. Is that treatment limiting?

Ehab Atallah, MD: If someone develops atrial fibrillation, what do I do with that? It varies. If I have another choice, I do switch. I don’t know if that’s the right thing to do, but I switch if someone develops atrial fibrillation. If I don’t have another option, I refer to cardiology and adjust. And of course, when someone gets atrial fibrillation on ibrutinib, we have to give anticoagulation. You get stuck there too. Do you increase the risk of bleeding or not in those patients? It gets a little more complicated there.

William Wierda, MD PhD: Let’s talk a little more in detail about the ELEVATE-RR trial. That was the head-to-head comparison of acalabrutinib vs ibrutinib. At the time, the population enrolled was considered high risk. It included patients with relapsed/refractory disease who had 17p deletion or 11q deletion. We don’t necessarily think of 11q as a high-risk feature with BTK inhibitor–based therapy—at the time they were—but 17p is clearly a high-risk feature. That trial did show noninferiority with acalabrutinib. Let’s talk a little more in detail about the differences in the adverse effects and toxicity profile. All-grade atrial fibrillation was higher for ibrutinib than acalabrutinib. John, what have been some of the challenges you’ve had with acalabrutinib? What toxicities are we seeing? There were a couple that were higher with acalabrutinib. How do you address those?

John Allan, MD: With all these BTK inhibitors, while the second-generation drugs seem to be better tolerated in general with fewer discontinuations and fewer cardiovascular events, they do have slightly different makeups and different selectivity. While they are pretty clean and very selective for BTK, they have some other kinds of inhibition. Even zanubrutinib and acalabrutinib are a little different from each other. They’re not all completely the same. We can’t get into this expectation that if you have a problem with 1, you’re never going to have any problems with the others. Because they do have some issues; with acalabrutinib in particular, it’s headache.

This headache is pretty restrictive to acalabrutinib. It’s a little there with zanubrutinib. You see headache with ibrutinib, but not to the same extent that we do with these other medications. Where you might fix the arthralgia, rash, or whatever it might be with ibrutinib, a patient will start to have complaints of a continual headache. Usually it goes away. It’s pretty self-limited. There are good data that show the incidence continues to decrease with time, but there are patients in whom it persists. It can be somewhat difficult to manage. You’re on a lot of Excedrin, caffeine, or sometimes even Fioricet. It really impacts patients’ lives, even though it may be low-grade, like grade 1 or 2.

We can’t expect that these drugs are all going to be free of toxicities. We do see atrial fibrillation. It’s not like 0. From the head-to-head studies, we see a relatively significant number of patients still developing atrial fibrillation and some cardiovascular outputs. With that said, you want to use drugs that typically have lower rates of those. Why have to deal with these problems if you don’t have to? The hypertension signal looks pretty good with these second-generation agents, where they do seem somewhat lower than what we see with ibrutinib. The incidence plateaus much earlier and doesn’t seemingly continue over time. You have to be wary of certain toxicities like headache and edema, which I’ve seen, and some of the other things that can be pesky that you don’t necessarily see with ibrutinib. Keep that in mind when you’re talking about these switches to potentially expect new things to show up.


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