Future Directions in Treatment of Chronic Lymphocytic Leukemia (CLL) with BTK Inhibitors - Episode 4

Treatment Selection Among BTK Inhibitors for First-Line CLL Treatment

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Ryan Jacobs, MD, and Bhavesh Shah, RPh, BCOP, provide insight on considerations when choosing a BTK inhibitor for initial treatment of chronic lymphocytic leukemia.

Bhavesh Shah, RPh, BCOP: Getting back to our discussion about BTK [Bruton tyrosine kinase] inhibitors, we have these first-generation BTK inhibitors, which believe it or not, I still do see a lot of ibrutinib [Imbruvica] being prescribed, and then now we’re seeing more of the second generation BTK inhibitors being more prominent, such as acalabrutinib [Calquence] and zanubrutinib [Brukinsa]. I just want to understand, for those patients for which you are considering a BTK inhibitor, how do you decide on which BTK inhibitor you’re going to start with?

Ryan Jacobs, MD: I want to just start out by saying it was really ibrutinib that led the way in this small molecule inhibitor-based renaissance that we’ve seen in treating CLL [chronic lymphocytic leukemia]. It is a great treatment. It has benefited so many patients, and it should be recognized as such, but now we do have other options. In terms of FDA [Food and Drug Administration]-approved options at this point in time, we have 1 other option that’s a second generation BTK inhibitor if you will: acalabrutinib. Early on we just had the kinome trees that we like to look at, and we could see that acalabrutinib had much less off-target kinase inhibition and just seemed like a cleaner drug. Then, clinically, we were maybe seeing less toxicities or lower grade toxicities in general in our clinics. We had these cross-trial comparisons that we could draw between the 2 and the matched, adjusted, integrated comparisons. Now, thankfully, we were able to—in manuscript form—just recently have the publication of the ELEVATE-RR [clinical trial] data, which compared ibrutinib versus acalabrutinib head-to-head in a high-risk relapsed CLL patient population. I feel like the conclusions that we drew from that study corroborated what we were thinking, which is that toxicities were lower with acalabrutinib, and discontinuation rates due to toxicities were lower. Specifically, atrial fibrillation, which was 1 of the secondary end points, was lower. Now, I think it’s reasonable to refer to acalabrutinib as a better-tolerated BTK inhibitor. When I talk about BTK inhibitors, I always say, it’s important to understand how these drugs are similar and how they’re different when making treatment decisions because how they’re similar is how they treat the CLL and their covalent inhibitors of Bruton tyrosine kinase. They do that by binding at the same C481S binding moiety. That’s why on this ELEVATE-RR study, which was a non-inferiority trial and that was the primary end point, it showed non-inferiority between the 2. You don’t efficacy-wise necessarily expect 1 to be superior to the other. Certainly, if you had a patient that had progressed on ibrutinib, I would not consider acalabrutinib as a treatment option for them because they should be resistant to acalabrutinib as well and most likely have a mutation at that C481S binding sign. Now we have head-to-head data to say definitively there are lower incidences of discontinuations due to adverse events with acalabrutinib, specifically lower rates of cardiac toxicity. I think it is reasonable at this point, and this is what I’m doing in my clinic, that if I’ve decided the patient’s going to be treated with a BTK inhibitor, then I start the conversation with acalabrutinib at this point. However, there are still situations where you might need another option other than acalabrutinib. The most obvious is the contraindication of taking a proton pump inhibitor with acalabrutinib. There are some patients that just really need their proton pump inhibitor. They can’t be downgraded to an H2 [histamine 2]-receptor antagonist, so ibrutinib is a great option to have for those patients. Sometimes you’ll run into situations, it has come up a few times for me, where there’s a contraindication like that to acalabrutinib, and maybe they’ve already been treated on ibrutinib and had a toxicity problem, and I’m looking for another option. That’s where it’s nice to have, in an off-label format, the ability to use zanabrutinib, which has had some data reported at this point about its efficacy in CLL and its tolerability. It’s not technically FDA approved yet, but it is now on the NCCN [National Comprehensive Cancer Network] guidelines, so I’ve been able to get it approved off-label in those select circumstances where I’ve needed it.

Bhavesh Shah, RPh, BCOP: I couldn’t agree with you more. I think really emphasizing the off-target impact of EGFR [epidermal growth factor receptor] and JAK 3 [Janus kinase 3] and R2, which really kind of bring to light some of these toxicities that you were talking about, such as atrial fibrillation, bleeding, and hypertension. It’s like we’re making these agents better and better to where we have more choices for patients. It’s amazing what some of the companies are doing, like acalabrutinib manufacturers reformulating acalabrutinib to actually be given with the PPI [proton pump inhibitor], because currently, you can’t. They developed the formulation, which is a maleate tablet formulation that actually you can give through a nasogastric tube or with a PPI, so it’ll be really interesting to get rid of the interaction that providers are always concerned about. I think it’s amazing for a manufacturer to go through lengths like that to actually reformulate because they know it’s such an important impact to patients on these medications. It seems like you’re definitely moving towards acalabrutinib, and if there are concerns about drug interactions, then zanabrutinib is kind of your other choice.

Transcript Edited for Clarity