John P. Leonard, MD: Another big category of agents that’s applicable, at least in trials, to many types of B-cell lymphomas, and is recently approved in mantle cell, is CAR [chimeric antigen receptor] T-cell therapy. Krish, tell us a little about the data leading to that modality’s approval in mantle cell.
Krish Patel, MD: CAR T-cell therapy was approved for relapsed/refractory mantle cell lymphoma just this year based on the ZUMA-2 trial, and that was a single-arm study of patients who had been previously treated with chemoimmunotherapy-containing CD20 and a BTK [Bruton tyrosine kinase] inhibitor. All the patients in the study had had prior BTK inhibitor exposure. The primary end point of that study was response rate. The response rates were very high, 80% or so and 60% complete responses.
A post-BTK setting, which several others have mentioned, can be very challenging, with really high response rates of at least 12 months and what looks to be encouraging progression-free survival. If we say that BTK inhibitors are commonly second-line therapy for those of us who have access to CAR T cells or patients who are eligible, this fits a post-BTK hole, so this has become our preferred therapy for patients after a BTK inhibitor.
John P. Leonard, MD: Andy, your take on CAR T in this setting?
Andrew D. Zelenetz, MD, PhD: Brexucabtagene autoleucel is a good drug. It’s approved. It’s pretty toxic. It is the same exact transgene as axicabtagene ciloleucel. There’s a lot of CRS [cytokine release syndrome], there’s a lot of neurotoxicity, and it’s tougher to give to older patients. Mantle cell lymphoma patients are older. It has not been as broadly applicable to our relapsed/refractory population.
We’ve been very lucky to have a couple of CAR T trials open, 1 of which is with lisocabtagene maraleucel that Lia Palomba just presented at ASH [American Society of Hematology Annual Meeting] with excellent efficacy, similar to brexucabtagene but far less toxic. In fact, many of the patients were dosed as outpatients. Not everyone stays in the outpatient setting. A good half of them get admitted and need additional therapy, but there’s no question that we’re seeing durable high-quality responses in the third-line mantle cell lymphoma patients with CAR T-cell therapy. We’re going to see improvements. We’re going to see products that hopefully will enhance the activity and improve it even further. My concern with the approved drug is a little about toxicity. It’s fine for younger patients, but some of the newer drugs that are emerging are a little kinder and gentler.
John P. Leonard, MD: Tycel, have you been using commercial CAR T for your patients so far in mantle cell?
Tycel Jovelle Phillips, MD: Since the approval, we probably had 10 patients who would have qualified. Only 1 has even worked toward being collected for various reasons. Some of the same issues have come up before with CAR [chimeric antigen receptor] T in general, but it hasn’t been as accessible as we would have liked, whether it’s because of insurance, space, COVID-19 [coronavirus disease 2019] cases, or patient preference. I do think, as John as pointed out, some patients do have concern about the toxicities at this point. Obviously, insurance still plays a big part as far as waiting for approval, which obviously leads you to do other things because sometimes you can’t wait.
John P. Leonard, MD: Krish, where is this going to put transplant? We heard that there are patients eligible who aren’t getting it for various reasons. One of the attractions of CAR T is that it’s in the ballpark of or easier than—and I don’t want to oversimplify or overgeneralize that, but 1 might argue that since we know transplant, at least autotransplant is limited in mantle cell lymphoma and allotransplant obviously has significant toxicities of its own. Will CAR T replace some of the patients getting either of those with mantle cell?
Krish Patel, MD: To echo Tycel’s concern, even though CAR T cell is definitely a different tool and offers something different from allotransplant and the toxicities, it maybe is challenged by some of the same access issues. Patients have to travel to the center to be able to receive that therapy. There’s the timing of it, and even when you have that therapy available in your own center, just like when you’re trying to get a patient to an allotransplant, you still have to control their disease while you’re waiting for your CAR T cells to come back. That can be challenging if the patient is progressing post-BTK inhibitor. As Andy mentioned, we still have a lot to do to improve on that therapy, but I foresee that there are fewer allotransplants that are likely to happen because there are some unique challenges with CAR T-cell therapy. But the long-term toxicities of allotransplant are quite a big trade-off compared with the short-term toxicities of CAR T cells.
John P. Leonard, MD: It seems as if there are very few patients who would get CAR T before they would get a BTK inhibitor, at least now. We’ll see. I’m curious if any of you have had any experience, before we move on, with CAR T in mantle cell in TP53-mutated patients. Have you seen responses there? Obviously, the data may be relatively limited, but has anybody formed any impressions about that in your algorithm?
Krish Patel, MD: I had a patient who was treated on the ZUMA-2 trial who had a TP53 abnormality but also had NOTCH mutations. This was a patient who received CAR T-cell therapy as a fourth-line therapy, and that patient has been in remission for almost 3 years and has done very well. So that’s encouraging.
Andrew D. Zelenetz, MD, PhD: Dr Maria Lia Palomba presented those data at ASH for lisocabtagene, and there was no difference in outcome by TP53 status.
John P. Leonard, MD: That’s 1 of the nice things so far about CAR T. As we’ve seen in large cell, it seems to me like CAR T can work in, for instance, the double hit, which is almost the bad-actor equivalent in large cell lymphoma as TP53 mutation is in mantle cell. It seems that CAR T can work there too, so it’s good to have something that seems to have some efficacy in that group of patients.
Transcript Edited for Clarity