BTK Inhibitors in MCL: AEs, Specificity, and Interactions


Michael Wang, MD: The class adverse effect with the BTK inhibitors? No. 1 is atrial fibrillation. The heart, it began atrial fibrillating. The heart rate, it’s the most dangerous adverse effect that a BTK inhibitor could render. So far it looks like the second-generation, acalabrutinib, has less atrial fibrillation and zanubrutinib has even less atrial fibrillation. Again, let me remind you, the number of patients treated, the follow-up time is not there. So far it looks like the atrial fibrillation is better with each newer one.

The second class of severe concerns of adverse effect is the bleeding. In the first generation, a BTK inhibitor is like aspirin. Bleeding is very often but nothing severe. Only when the patient falls down, could they have intracranial bleeding. That even killed a few patients in the ibrutinib. The acalabrutinib was much, much less reported. Why? Because we avoided those people who are on blood thinners, based on the success of the other drug avoiding adverse effects. Then zanubrutinib even has less bleeding, fewer patients treated, and less follow-up time. You see how difficult it is and how many factors there are.

Then there is infection. Infection rate is very high. It is certain number with ibrutinib. It’s not because of the drug, because 3 other chemotherapies may already affect the patient. They are more prone to infections. The ibrutinib looks a little bad because it treated too many patients. Acalabrutinib looks better. Zanubrutinib looks the best. I think we should use it more. We should keep an open mind, use it more, and gain more experience. We respect all the economic clinic data, but the real-world data we eagerly await.

All 3 main targets are to target the BTK, Bruton tyrosine kinase. However, they are small molecules. There are so many other targets in the cells, so they would invariably attack the main target but also affect other not-intended targets. The study to differentiate the 3 is called the Kinase Profile Study. According to the study, ibrutinib is the least selective; acalabrutinib is the better, more selective; and zanubrutinib is the most selective. That may be the intrinsic properties of different molecules. This is only in the test tubes. We have not tested the specificity inside the animal studies. In the cells we have not tested for the humans, which is more selective.

So far, in the test tube it looks like zanubrutinib is the most preferred. They said ibrutinib is a dirtier drug, but it has more immunotherapy properties. It’s approved for GVHD graft-vs-host disease, which is a transplant-related disease. Its immunotherapies can enhance CAR [chimeric antigen receptor] T-cell therapies. The others we don’t know because they are more selective. So being more selective has the benefit of fewer adverse effects and more potent efficacy, but it also may not have the immunotherapy properties. Don’t misunderstand me: zanubrutinib is a great drug. It is a welcome addition to the therapy regimens we already have. It is great news, not only for the Western patients but especially for the Asian patients and the patients who live in Australia.

Because the 3 BTK inhibitors interact with the kinases, they cannot be taken with other drugs. For example, for fungal infections you have to dramatically reduce the dose of each, lowering toxicities. You cannot drink citrus fruits. That will also affect the mechanism. All the 3 kinases share the same drug-drug interactions. Nowadays it’s easy: you just google what you can do and what you cannot do.

Transcript Edited for Clarity

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