BTK Inhibitors for Relapsed/Refractory Mantle Cell Lymphoma


Experts in hematologic malignancies review the role of BTK inhibitors and other therapies in patients with relapsed/refractory mantle cell lymphoma.


Alexey V. Danilov, MD, PhD: Now we will turn our attention to relapsed/refractory mantle cell lymphoma. Boyu, could you walk us through what regimens are used in relapsed/refractory MCL?

Boyu Hu, MD: Yes. In the second-line setting, we have our beloved BTK inhibitors, first generation, and these are all covalent BTK inhibitors, including ibrutinib, acalabrutinib, zanubrutinib, and also R2, [rituximab] with lenalidomide. Currently, it’s what you can get for the patients and what their insurance will approve, what you can get quickest for the patients. But I do think that [we can benefit from] some of the late-breaking [new data] this year, referring to CLL [chronic lymphocytic leukemia], given that [it’s a] cousin disease to MCL [mantle cell lymphoma]. [Particularly] with the ALPINE [NCT03734016] study, and zanubrutinib showing some better efficacy and previous safety over ibrutinib, we’re going to be preferring some of the second generation BTK inhibitors over ibrutinib. In fact, I do think that in the NCCN [National Comprehensive Cancer Network] guidelines, they have demoted ibrutinib in favor of the second-generation BTK inhibitors. Then, past the BTK inhibitors would be things like more chemotherapy, but also now we’re using more and more CAR [chimeric antigen receptor] T-cell therapy as well.

Alexey V. Danilov, MD, PhD: OK, but what kind of median PFS [progression-free survival], roughly? How long do patients stay on BTK inhibitors with relapsed MCL? Is it 2 years, 5 years? What’s your experience?

Boyu Hu, MD: Yes, it’s supposed to be around 3 years. I haven’t seen that much in the real world. There is a referral bias to academic centers for patients with more high-risk MCL. My experience has been a bit less than 3 years, but I think the median PFS on most of these studies was right around 30 to 40 months.

Alexey V. Danilov, MD, PhD: Thank you. Bijal, I’m going to exploit, a bit, your propensity to bias, like you said. Which one BTK inhibitor do you use in patients with MCL?

Bijal D. Shah, MD: I hope it’s not a propensity to bias, but we use all 3 in the beginning. As ibrutinib was coming, we learned from it. As acalabrutinib came, we learned from it. As zanubrutinib came, we learned from it. And it does appear, at least for our older patients, that zanubrutinib was better tolerated. We still see toxicity, and I don’t want to be ignorant of that. When patients fall, they hit their head, they bleed just as they would with the other BTKs. Atrial fibrillation, thankfully, is far less common with zanubrutinib, but it can be seen, particularly for folks who have a history of atrial fibrillation. Again, similar to the case that we discussed. Zanubrutinib has this unique toxicity of hypertension that seems to manifest earlier than we saw with the other BTK inhibitors. [But] I’m enjoying using it. I get fewer phone calls with zanubrutinib than with the others.

[What] I’m excited [about] is, hopefully, an impending approval for pirtobrutinib. And I had this conversation at ASH [American Society of Hematology annual meeting], where I was asked, “Are you going to then be using [pirtobrutinib] in your BTK refractory patients?” And I said, “No, I’m going to be using it in my BTK naive patients. I want to learn from it.” I want to try to see how this drug compares in terms of its benefits and toxicity, and I’ll learn. I’ll share with you next year.

Alexey V. Danilov, MD, PhD: Matt, do you still use ibrutinib in mantle cell lymphoma?

Matthew J. Matasar, MD: I do. I use all of them. They clearly have different toxicity profiles; their activity is perhaps a bit distinct. And it’s not just about toxicity, as we learned this year. But one important difference, which I have a bit of trouble predicting on a patient-to-patient level, is the financial toxicity of these agents. There’s a lack of transparency, at least for me and my patients, in terms of what the actual financial implications for a prescription of any of these 3 agents might be. Oftentimes, I have to work with my pharmacists and with third-party payers to figure out which of these agents might be the most affordable for that patient. The best drug of this class is the one that a patient can actually take. And realistic conversations with patients about affordability and means is critical to navigating this process.

Alexey V. Danilov, MD, PhD: Yes.

Transcript edited for clarity.

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