BTK Inhibition: Disease State Effectiveness

Jan A. Burger, MD, PhD:You bring up an important question, and I think it’s really uncertain, as far as I’m concerned, as to why they necessarily work in 1 disease versus the other. For instance, think about large cell lymphoma. We know that the BTK [Bruton tyrosine kinase] inhibitors have activity. The group at the NCI [National Cancer Institute], Wyndham Wilson’s group, was the first that proved that ibrutinib had activity in patients with large cell lymphoma. It’s very short-lived and patients rapidly progressed there. It looked as if it was largely confined to patients with the ABC subtype. But when you think that pathway actually would be more activity, but the responses were not durable, at least as a single agent. I think I was really quite surprised how active these therapies were in CLL [chronic lymphocytic leukemia], and I was surprised to learn how active they are in diseases like chronic lymphocytic leukemia, more indolent disease, but still very responsive on the most responsive of the B-cell malignancies to BTK inhibitors.

I think we should talk a little about the different BTK inhibitors and their indications in different diseases. Let’s first talk about ibrutinib. Ibrutinib is an oral BTK inhibitor. It’s given once a day. It was the first-in-class molecule to be developed. It now has indications in chronic lymphocytic leukemia, mantle cell lymphoma, as well as Waldenström macroglobulinemia, so there is activity across these different diseases, both in the frontline as well as the relapsed setting.

It’s often criticized as being perhaps having a dirtier molecule when compared with some of the next-generation molecules, which are more specifically for BTK inhibition. As a consequence, there are some perhaps off-target toxicities that are important to know about. For instance, ibrutinib, we know there’s a risk of atrial fibrillation. The rates vary depending on the disease and the age group that’s being tested, but it can be as high as 15% in some patients with Waldenström macroglobulinemia; whereas in younger patients, it is perhaps as low as just a few percentage points. And so there are adverse events. We of course know that there’s bleeding phenomenon that occurs where patients bruise quite easily and perhaps are at risk for more major hemorrhages, more specifically when combined with other forms of anticoagulation. So that is something to take into consideration.

Transcript edited for clarity.