Insights From: Brad S. Kahl, MD, Washington University School of Medicine; Steven P. Treon, MD, PhD, Harvard Medical School
Brad S. Kahl, MD: Honestly, right now, I think the established differences between first- and second-generation BTK [Bruton tyrosine kinase] inhibitors is so small that I’m not sure that you can make rational therapeutic decisions at this point. It’s not clearly established. It’s not clearly established that second-generation BTK inhibitors are markedly better tolerated. So honestly, I think we need more data. Right now I think you just stick to the FDA label. You have approvals. Take mantle cell lymphoma, for example. Approved for relapsed mantle cell are both ibrutinib and acalabrutinib. Zanubrutinib is not approved yet in relapsed mantle cell lymphoma, so your choices are ibrutinib and acalabrutinib.
I imagine a lot of physicians have experience with ibrutinib. It’s been around for several years now, probably less so with acalabrutinib. You might want to treat your next few patients with acalabrutinib and get some experience with it. See for yourself if you think it’s better tolerated than ibrutinib. I mean, the differences between these things are relatively small.
For CLL [chronic lymphocytic leukemia], acalabrutinib does not have a CLL indication yet. Ibrutinib does. That makes the decision making pretty easy. You’re going to give ibrutinib for relapsed CLL. Same with Waldenström macroglobulinemia. Same with marginal zone lymphoma. Having said all that, there will be more approvals for these other BTK inhibitors in the next 2 years. Acalabrutinib should get a CLL indication at some point. I expect zanubrutinib to get approvals at some point in different B-cell malignancies. Then we’ll have choices, then we’ll have options, and then we’ll have to think a lot harder about which BTK inhibitor for which patient with which disease. But at the moment, right now, it’s pretty easy because the approved indications are specific, and we don’t have a lot of competition within spaces.
Steven P. Treon, MD, PhD: I think what’s really important is to recognize that Waldenström disease has benefited by genomics. And it is really important for us to be able to get molecular diagnostics done on a particular patient, to understand the role of MYD88 as well CXCR4. And also to consider many of the innovative clinical trials that are currently coming about because of these genomic revelations, and clinicians can keep this in mind. I also think that clinicians really have the opportunity to play a very important role these days in the treatment of these patients, given all the new therapeutics and emerging therapeutics that are coming forward.
It’s important to keep in mind that the underlying genomics can, in fact, impact patient selection for BTK inhibitors. Those patients who] do not have the MYD88 mutation, and that’s about 5%, maybe 10% of all patients with Waldenström, may not be beneficiaries of BTK inhibitors. Those patients who have the MYD88 mutation can be considered. And for those patients who also have CXCR4 mutations, it’s important to keep in mind that the time to response may lag, particularly when BTK inhibitors are used as monotherapy.
At least what we’ve learned so far is that ibrutinib, which represents the first generation of BTK inhibitors, as well as newer BTK inhibitors, acalabrutinib and zanubrutinib, all demonstrate very high rates of activity in Waldenström disease. We’re seeing overall responses in about 90% of all patients. We’re seeing major responses that are between 75% and 80% of patients. And one has to keep in mind that these activity levels occur whether the patient is previously treated or presents for treatment for the first time. This is really important because it shows us that these BTK inhibitors are on target when you see this kind of level of activity.
And the adverse-effect profile overall, I think for all these drugs, when one considers them in context of many of the other therapeutics that we have for Waldenström, is really very good. We see very good tolerability. We see some minor differences, but overall BTK inhibitors have shown a very promising way forward for the treatment of Waldenström disease.