John P. Leonard, MD: Andy, let’s talk about the various treatments. I won’t call them dogs, but we’ll talk about their spots as we look at the different BTK [Bruton tyrosine kinase] inhibitors. Obviously, they are different in some ways, similar in other ways. How do you think about the differences from the laboratory preclinical standpoint and theoretical, technical standpoint? What do you really see practically in a patient?

Andrew D. Zelenetz, MD, PhD: The 3 approved BTK inhibitors—ibrutinib, acalabrutinib, and zanubrutinib—are all covalent, irreversible inhibitors of BTK, binding to Cys-481. This mechanism is reliable and highly effective. The drugs differ by their half-lives and by their kinome map. Acalabrutinib has the narrowest kinome of the 3. Zanubrutinib is in the middle, and ibrutinib has the most significant overlap, including overlap with things like ITK, which potentially does in vitro and inhibits ADCC [antibody-dependent cell-mediated cytotoxicity]. Maybe that’s why all the ibrutinib plus anti-CD20 antibody trials have essentially been negative, showing no improvement when you combine the 2. Neither acalabrutinib nor zanubrutinib have that effect in vitro, and they are the more logical combination if you want to add an anti-CD20 antibody.

We have other molecules coming down the pipeline. We’re going to talk a little about them later, including noncovalent inhibitors. They can be very useful when there are mutations, but they’re also very active on their own without the cysteine-481 serine mutation.

There are some other important differences. As was pointed out, there’s less drug-drug interaction with zanubrutinib. Like Tycel, it’s now my go-to for mantle cell lymphoma. I don’t have to worry about PPIs [proton pump inhibitors]. I don’t have to worry about if someone is on verapamil for hypertension. I don’t have to review with the clinical pharmacist—is it CYP34A, is it this, is it that? There’s much less drug-drug interaction, which makes it much easier to use.

John P. Leonard, MD: You referenced earlier safety from the standpoint of the adverse-effect profile. How would you generally think about zanubrutinib and acalabrutinib with respect to adverse-effect profile? We even have some comparative data.

Andrew D. Zelenetz, MD, PhD: We have head-to-head data enrolled in Waldenström macroglobulinemia with zanubrutinib showing a differential toxicity profile. Cardiac adverse effects are clearly less. AFib [atrial fibrillation] was essentially in the background with zanubrutinib but was significant with ibrutinib. But there’s more neutropenia that we see with zanubrutinib, and that’s a consistent finding in all studies except our CLL [chronic lymphocytic leukemia] study, which I don’t quite understand. But we can come back to that later.

But acalabrutinib causes some headache, but it’s usually self-limited. I tell people to get a Starbucks card and drink a lot of coffee because it’s very caffeine sensitive; they’ll feel better after having a cup of coffee or a can of Coke—not caffeine-free. But all these adverse effects are manageable. Also, based on the pooled toxicity data, acalabrutinib looks like it has fewer cardiovascular adverse effects. We’re waiting for the head-to-head comparison, but that should be coming pretty soon.

Transcript Edited for Clarity