Relapsed/Refractory CLL: Key Takeaways and Ongoing Challenges


Closing out their discussion on relapsed/refractory chronic lymphocytic leukemia, key opinion leaders consider important takeaways from the indirect comparison study of acalabrutinib versus zanubrutinib and identify unmet needs in the treatment landscape.


Alan P. Skarbnik, MD: So, what do you take away from this publication? What questions do you think come out of it and how that would impact your clinical practice and clinical practice in general? What are your thoughts?

Ryan W. Jacobs, MD:I think the big headline here is in the quest to try to find the best choice between second-generation BTK inhibitors. You can't necessarily say that 1 seems more effective than the other, or at least call into a significant amount of question whether 1 would be significantly different efficacy-wise. I don't think we necessarily ever thought 1 would be more effective, just given the similar mechanisms of action and how they covalently inhibit Bruton's tyrosine kinase. I think there was some level of surprise when the ALPINE data ultimately showed that PFS difference. And there are a lot of caveats there, obviously. This is helpful. I think we all inappropriately try to, indirectly in our own minds, compare across trials. This is a more formal way to do it, but still carry the same asterisk. I think it would be nice to someday get a direct comparison, but I think realistically we're going to be stuck with these and maybe some real-world comparisons, and we're going to have to draw our own conclusions. Where do you go from here? Do you find that the data supports efficacy, but are there differences with the toxicities that would maybe lead you to choose 1 over the other?

Alan P. Skarbnik, MD: Yes, I agree with you. Before we had the data and when we didn't know the superior efficacy of ibrutinib versus dose agents, those were the basis for our treatment determinations. What patient profile would potentially tolerate 1 drug versus another a little better? I think that can inform that. For instance, a patient who has bad migraines is unlikely to use acalabrutinib and can use zanubrutinib as an option. Someone who has preceding hypertension and I’m more concerned, I'll probably use acalabrutinib rather than zanubrutinib. It's good to have options, but I think that can inform our decisions a little better.

Ryan W. Jacobs, MD:Yes. I think in terms of implications, this makes us more comfortable in choosing either agent and trying to personalize that decision to the patient as best we can. At the end of the day, both appear to be good options.

Alan P. Skarbnik, MD: Absolutely. Any additional limitations with this finding? We commented on that already, but if there's something left unsaid, please feel free to add to it. What are your thoughts in the remaining areas of unmet need for relapsed/refractory CLL and what direction do you think our research is going?

Ryan W. Jacobs, MD:Yes. I think we've really covered the obvious limitations. It's not a prospective comparison. You referenced the different, greater level of ability to dose reduce zanubrutinib. That's not an easy comparison either. I think the obvious areas of unmet need for relapsed/refractory CLL are the "double refractory" or patients that have progressed on a BTK inhibitor covalent and venetoclax-based therapy. We are looking eagerly for that approval to come for pirtobrutinib. At least it is on the market now for mantle cell. If we can get it off-label, but it would be nice to have that on-label approval. The obvious area of future interest is going to be what do we do after non-covalent, covalent and BCL-2 inhibition? The data has encouragingly shown that our CLL patients are living as long as patients without CLL these days. There are going to be multiple treatment options that are needed.

Alan P. Skarbnik, MD: Absolutely. Adding to that, when we start having the combinations approved upfront, how are we going to treat those patients as well? Those are all very important questions. Just to remind everyone, pirtobrutinib is a non-covalent BTK inhibitor that has a different mechanism of binding, so, very interesting. Well, thank you very much to everyone for watching and this was, as always, very entertaining talking to you. Thank you, Dr. Ryan Jacobs, for joining me today.

Ryan W. Jacobs, MD:Thank you, Dr. Skarbnik.

Transcript edited for clarity.

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