Optimizing MCL Management: Sequencing and Combination Strategies


Panelists use an illustrative clinical case to highlight best practices in sequencing therapy for mantle cell lymphoma and discuss novel combination strategies under investigation.


Bijal D. Shah, MD, MS: I’d like to lead in with a case. Ian, I’m going to pick on you, but anyone can feel free to chime in. I try to think about cases that I’ve seen over the years and some of the challenges I’ve had. This is a more classic case, mantle cell lymphoma, gets a standard cytarabine-based induction, in this case a CHOP-DHAP [cyclophosphamide, doxorubicin, vincristine, prednisolone–dexamethasone, cytarabine, cisplatin] induction, followed by an autologous stem cell transplant, gets maintenance Rituxan. But still about 2 years later we’re starting to see a relapse, of a little earlier than we would want to see, particularly with the Rituxan component. We put him on a BTK [Bruton tyrosine kinase inhibitor]. The hope is we were going to see a 2-and-a-half, 3-year remission, but probably what we’re seeing now given this Rituxan resistance, this early resistance to chemotherapy and transplant, is only about 15 months. And now, we’re thinking about brexucabtagene. Does this make sense? Should we take a different approach, or are there other things like blastoid or TP53 mutations that might push you down a different pathway?

Ian W. Flinn, MD, PhD: Yes, I think there is a lot to talk about there. First of all, I think the initial approach that you’re mentioning, autologous transplant, rituximab maintenance, followed by a BTK inhibitor is a very standard approach for many patients with mantle cell lymphoma. But you also point out a couple of things. The responses were not quite what you want. The duration of remission is not what you had expected with rituximab maintenance after an autotransplant. Also, the BTK inhibitor was a little on the short side as well. At this point, there are not a lot of great options for this patient other than CAR [chimeric antigen receptor] T-cell therapy, I think, and so it falls naturally into that pathway.

You bring up a couple of other issues, TP53 mutations, should we be doing something different? The blastoid variant or the pleomorphic variant, should we be doing things there? I think that right now everyone is very concerned that we should be doing something different, but frankly are not aware about what we should be doing. Thus, these are the people that I try to steer hard toward clinical trials using some of these novel combinations with BTK inhibitors up front, that kind of thing. But I don’t know that we should be doing something there.

But in reality, what happens, at least in my experience, is that these patients don’t get as far as what you’re seeing here. They don’t get to 2 years after an autologous transplant. Sometimes they don’t get to a transplant at all, and so if you’re in that situation then you might want to go much faster to a CAR T cell. I think that we don’t know how much that’s going to change the natural history of it, but we do know what’s going to happen if you keep these people on the therapies that we have been using.

Bijal D. Shah, MD, MS: That’s a great point. Michael, are you avoiding autotransplants in your TP53-mutated patients?

Michael Wang, MD: Well, the current therapies including stem cell transplant have not been shown to be very effective in these high-risk patients. We know the old therapies don’t work. We don’t know the new therapy will work, but we need to try, to study those factors in clinical trial. Thus, the brexucabtagene autoleucel is really a new therapy for patients with these risk factors. We still don’t know how effective the therapy is in high-risk patients, but we are absolutely studying them in the trial, and this is how we make progress. It’s very exciting.

Bijal D. Shah, MD, MS: Absolutely. Brian, you heard Ian refer to a lot of combinatorial approaches that are now being pushed forward. Are there any that spring to mind as being particularly exciting?

Brian T. Hill, MD, PhD: Yes. Well, in the relapsed setting, we talked about the BTK inhibitors. I think one question that hasn’t really been addressed yet in a randomized fashion is whether anti-CD20 treatment actually adds to ibrutinib or acalabrutinib. That’s one combination that’s been explored, and we’ll see more data soon. The other agent that is very active in mantle cell lymphoma is the BCL2 inhibitor venetoclax, which is an oral agent, very active in CLL [chronic lymphocytic leukemia], which has some biologic similarities to mantle cell. We are seeing now combinations of the BTK inhibitors, such as ibrutinib with venetoclax as a doublet, and even some triplet data with anti-CD20 monoclonal antibodies and venetoclax and a BTK inhibitor. It’s an embarrassment of riches right now. We have so many options that it’s going to take effort to figure out which of these doublets or triplets is best, but certainly I think the future is bright with those combinations.

Bijal D. Shah, MD, MS: You think that myeloma and CLL are setting the paradigm then?

Brian T. Hill, MD, PhD: A little bit. I think mantle cell still remains a very relentless disease, as you’ve heard. And we know some of the high-risk features, but even in standard-risk patients, they almost invariably relapse.

Transcript edited for clarity.

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