Selecting the Appropriate BTKi in Chronic Lymphocytic Leukemia


Comprehensive perspectives on clinical factors that help to inform the selection of appropriate BTK inhibitor therapy for patients with chronic lymphocytic leukemia.


Sonali M. Smith, MD: Nicole, with the availability of this new formulation of acalabrutinib, how will that play into your selection? If you’re going to use a second-generation BTK [Bruton tyrosine kinase] inhibitor, how will that play into your selection?

Nicole Lamanna, MD: I think it obviously puts it a bit more on an even footing because now you don’t have to worry about the PPIs [proton pump inhibitors]. Ibrutinib and zanubrutinib didn’t have that issue, and acalabrutinib now won’t have that issue as well with the new formulation. I believe they’re phasing out the other, altogether. Physicians do need to know about that, so they know there isn’t an interaction if they’re not aware of the new formulation. So it makes it easier. Now in terms of which newer agent to choose from, I think part of that will be for some patients already, as John already noted, even though zanubrutinib is in the NCCN [National Comprehensive Cancer Network] guidelines, there might be still insurance issues. Or insurance companies may say we prefer this one first vs this one, so some of that might still come into play.

Otherwise, I think both are very good agents, and the familiarity, I would love to see more data with zanubrutinib as a single agent. Because it was approved both as BID [twice a day] and a single agent, but most of our data are just BID, so twice daily. I think if it was once daily and those data were just as good, it would be much more convenient to give a once-daily drug vs twice daily for many of the patients out of convenience, and there’d be better compliance. But I think we’re going to be splitting hairs a bit if we’re going to be talking between the 2 agents about which one might be better for our patients. Although the hypertension, as Susan mentioned, is an issue too, the fact that it was not different from ibrutinib is something to keep in mind, for sure.

Sonali M. Smith, MD: Yes, and we have heard about some toxicities that occur with longer use. Atrial fibrillation and hypertension are the 2 that receive the most attention. Perhaps I’ll ask John to comment on the risk of hypertension and how that might play into your selection. We heard maybe a little allusion to it. But how does that play into your selection?

John N. Allan, MD: Yes, I think it’s an important toxicity to observe. This is something we’ve seen with longer follow-up with ibrutinib to be a very real effect of these drugs. And what we’ve seen with subsequent studies and subsequent agents is that it seems to be somewhat of a class effect. So BTK inhibitors in general can increase hypertension, and it is something that needs to be observed. In the ibrutinib data, it does seem to link to increased risks of other cardiovascular events. As hypertension is new or worsening in a patient, they have an increased risk of atrial fibrillation and even other potential arrhythmias, etc. This has been less studied with these newer, more selective agents.

With that said, these new selective agents also have shown hypertension. Acalabrutinib, in the head-to-head studies we’ve talked about, in the ELEVATE-RR study, does seem to have a lower rate of hypertension, about 9% to 10%, vs 20% or so, almost half the amount of patients are having hypertension in that study. Whereas as with zanubrutinib, as we’ve stated, it’s similar to what we see in ibrutinib. What’s interesting though, is that with these more selective agents, and with zanubrutinib in particular, despite the fact that they have similar rates of hypertension, you do not see higher rates of atrial fibrillation. So there are other effects that we don’t quite understand.

However, because we observe this as a major toxicity, it is something I pay attention to closely. As soon as I start to see it, I start to have these conversations with the patients to talk about initiating therapy or increasing hypertension medications that they’re already on. Getting them back to their cardiologist and/or their primary care doctor, so we’re working together, and thinking about the agents we’re using. Unfortunately, that’s the other limitation we have. I don’t know if we’ve identified an exact mechanism that is causing this high blood pressure, and via that, we don’t have a perfect regimen or agent that is proven to be better than another to manage it. So right now, it is something to observe, identify, and start to treat early. It is something that can lead to these other cardiovascular events if it is left uncontrolled.

Transcript edited for clarity.

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