Personalized Therapy Approaches for Mantle Cell Lymphoma - Episode 10

Acalabrutinib in Relapsed Mantle Cell Lymphoma


John P. Leonard, MD: Now we have very recent data with the approval of acalabrutinib, a new Bruton's tyrosine kinase inhibitor for mantle cell lymphoma. We had some updated data presented here at this meeting. I think that there are some similarities between ibrutinib and acalabrutinib, and maybe some differences, although it’s unclear at this point. Andre, you’ve been involved in those studies. What is your take, at this point, within the limits of parallel trials at this point? What’s the efficacy of acalabrutinib? How do you see them compared in your practice? What is your approach?

Andre Goy, MD: Acalabrutinib is a second-generation BTK inhibitor that seems to be more specific. It has less off-target effect, and potentially explains some of the differences in the toxicity profile. There is also less inhibition of ITK, and less cardiac targeting from the off-target effects.

In the series of patients—over 100 patients in a context of relapsed/refractory mantle cell lymphoma whom had no prior exposure to ibrutinib, with a median of 2 prior therapies–the response rate was 80% with 40% complete response. The responses were brisk. The patients tolerated it well. We did not see any atrial fibrillation in the trial. I believe there are some small differences that may be confirmed in a real-world setting. Maybe there’s a bit of a bias for the population in this phase II trial. The complete response rate seems to be faster and sooner.

Obviously, this is not head-to-head against ibrutinib. I’m not aware that there is any data showing that you can get response with acalabrutinib in patients who have failed ibrutinib. One of the advantages, besides being more specific in terms of target and having less of a targeted effect, is the fact that it’s dosed as bid. It seems to have more persistent inhibition of BTK. That’s the results. This being said, it’s early. It would be difficult to say how different it’s going to be in the real world.

John P. Leonard, MD: What’s your experience with people that you have treated on trials? Is your sense that it’s different? I know it’s more or less anecdotal, but is there any sense of that?

Andre Goy, MD: As I said, the responses were brisk. The complete response rate appeared to be faster. With ibrutinib, the complete response rate was 20% at the beginning. It reached up to 40% after a year. It seems to be faster.

John M. Pagel, MD, PhD, DSc: To be fair, we have to recognize, as you alluded to, that they were different patient populations.

Andre Goy, MD: Less heavily pretreated, and the criteria for the response evaluation was dual criteria. That induces a little bit of a discussion on how to look at these data. That offers another BTK inhibitor. And again, that seems to have an easier safety profile.

Alexey V. Danilov, MD, PhD: In that study, I believe the MIPI score was also slightly more favorable than in the original ibrutinib study.

John P. Leonard, MD: I think this is an example of how we have 2 drugs, same class. There were other BTK inhibitors presented at the meeting, and maybe we’ll come back to that as well. Is more specificity better, less off-target effect? Is less specificity better? Is hitting ITK, for example, a better thing? And then again, obviously, the toxicity profile. Does that translate into clinical differences between the drugs? Time will tell. I think it’s interesting.

Stephen J. Schuster, MD: And even the dosing, John. We talk about BTK occupancy. Both ibrutinib and acalabrutinib are irreversible BTK inhibitors. Why do you have to give it twice a day? It binds. You’re 95% occupied and the cells will die. You take it on the next day and you’ll kill another fraction of cells. I think with the success of BTK inhibition, in a disease that has a moderate proliferation index, dose schedule may be important. You’re hitting the cells that are vulnerable. Sure, they’ll die. But the new cells that are generated don’t have BTK ligation. So, it may be that with the twice-a-day regimen, you need to compare apples to apples.

Transcript Edited for Clarity