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Considering BTK Inhibition's Role in Treating CLL and MCL



A review of the rationale behind Bruton tyrosine kinase inhibitors and their role in managing B-cell malignancies.


Michael A. Kolodziej, MD: The mechanism of Bruton tyrosine kinase [BTK] inhibitors is that they inhibit signaling downstream from antigen binding on B cells. That pathway has been known to be important since I was in medical school because there is a hereditary immunodeficiency disorder where children born with that defect can’t make antibodies and they lack the enzyme, the tyrosine kinase. So that enzymatic pathway is specifically targeted. Of course, inhibitors of tyrosine kinases are all over the place in oncology. When we think about, for example, probably the single most revolutionary therapy of our lifetimes, which is the treatment of chronic myelocytic leukemia [CML] with Gleevec [imatinib], Gleevec inhibits the tyrosine kinase. We see it in solid tumors now as well.

And so tyrosine kinases are very important. And it turns out that for a number of B-cell malignancies, inhibiting that enzyme is an excellent way to control the disease. I didn’t say cure the disease, I said control the disease. We don’t know, for example, whether you can stop the therapy after achieving a really good remission. We know, for example, in CML you can in some patients stop the Gleevec at one point or another. But in these diseases, we actually don’t know that, and historically they have been considered “incurable.” We will see I think some expansion of the BTK drugs into roles in other cancers, diffuse large B-cell lymphoma, for example. There’s a lot more that we don’t know about these drugs. We largely have not studied combinations of these drugs, all to be forthcoming.

At this point, BTK inhibitors have become the standard first-line therapy in chronic lymphocytic leukemia [CLL]. And again, that’s based on excellent phase 3 randomized clinical trials. They’re not for everybody. They’re absolutely the right thing for some patients. For example, we know that 17p deletions in chronic lymphocytic leukemia are really a bad thing, with terrible prognosis. We also know it’s an indicator that standard chemotherapy options do not work well. And so it’s very clear that those patients should be treated with the BTK inhibitors.

Regarding the role of BTK inhibitors in let’s call it standard-risk CLL, again, I think the evidence supports a first-line approach. What has happened though—and recently I was at a meeting where this was discussed in detail—is that there’s a little bit of hesitation in some patients because when you start ibrutinib, for example, it’s an open-ended proposition. You’re on it until you fail clinically, relapse or progress. It actually didn’t happen very often. More patients stop therapy because of toxicity than actually progress on therapy. And so the idea that you give chemotherapy for a short duration, with a defined start, defined stop, and defined cost, is attractive in some circumstances without a doubt. Even though there are randomized phase 3 data that show ibrutinib gives you a superior clinical outcome.

How the new BTK drugs are going to fit into this is really not completely clear because what we know is this for both acalabrutinib and zanubrutinib: Number 1) They are better at blocking that enzyme. They’re better than ibrutinib. Whether that will translate into clinical benefit, we don’t know. The second thing is, they’re more specific. A lot of the problem that we experience with ibrutinib is off-target problem. And let’s be clear, in addition to fatigue, which is by far the most common problem that people on ibrutinib experience, there are a couple of serious problems with ibrutinib. There’s bleeding and there are what’s broadly classified as cardiovascular toxicities. And that includes atrial arrhythmias and hypertension. Those are fairly common adverse effects, especially as time goes on.

The preliminary evidence is that acalabrutinib and perhaps even more so, zanubrutinib, have fewer of those toxicities. Again, probably because they’re more specific for inhibiting the BTK as opposed to ibrutinib. Whether those differences are going to wind up being clinically borne out, we will see.

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