Alexey V. Danilov, MD, PhD, presents a second patient profile of a 60-year-old patient with MCL, and the panel discusses using CAR T-cell therapy to treat MCL.
Alexey V. Danilov, MD, PhD: Let me show you another case. A 60-year-old man presented with symptomatic progressive lymphadenopathy. He has no other medical problems. He doesn’t take medications. PET [positron emission tomography]–CT shows diffusing lymphadenopathy throughout the body. [He has an] enlarged spleen. His SUV [standard uptake value] is 8. Bone marrow is involved by mantle cell lymphoma with a typical immunophenotype; Ki-67 is 30%. He has translocation 11;14 by FISH [fluorescence in situ hybridization]. He doesn’t have a TP53 mutation. He starts with R-CVP [rituximab, cyclophosphamide, vincristine, prednisone] in the community and achieves a PR [partial response].
Shortly after he presents with progressive masses around his eyes with this conjugate gaze, and he has trouble driving. The MRI of that area shows that he has up to 5-by-3-cm mass above the left orbit. There’s also a similar mass above the right orbit. Biopsy of the mass confirms MCL [mantle cell lymphoma]. He starts ibrutinib and achieves a PR within 3 months. The masses are smaller. They’re still there, but at least he can drive now. Some lesions have resolved; others are somewhat present. Then he quickly develops progressive lymphadenopathy and difficulty breathing through his nose. He has to breathe through his mouth.
A PET-CT demonstrates recurrent disease. He has a big mass in the sinus, which measures up to 7 cm in the nasopharynx. We give him XRT [radiotherapy], and ultimately we take him to CAR [chimeric antigen receptor] T-cell therapy. He gets brex-cel [brexucabtagene autoleucel], grade 2 CRS [cytokine release syndrome], tocilizumab, and pretty significant neurotoxicity. He was confused for about 2 weeks, but ultimately it subsided and resolved fully. Luckily a day plus 30, he’s in complete metabolic response. A few months later, he remains in remission. He’s doing great. He doesn’t have long-term sequelae, but it was a rough course nevertheless.
There’s lot of development in the targeted therapy space and mantle cell lymphoma. We’ve made significant advances in cell therapy as well. At ASH [American Society of Hematology Annual Meeting], we had another update of the ZUMA-2 trial in relapsed MCL. Boyu, what can you tell us about it?
Boyu Hu, MD: ZUMA-2 was the phase 2 study looking at CAR T within mantle cell lymphoma, using a different platform from Yescarta [axicabtagene ciloleucel]. They showed incredible data. We haven’t seen overall responses that high for a long time—80% to 90%, with a high complete response [CR] rate. In the responders, there were durable responses in those patients. The patients who were in CRs at 3 years we’re mostly still in CRs, which is incredible for this disease.
The other great part about CAR T is that it’s time-limited therapy. We’re trying to move past indefinite therapies, like BTK inhibitors. Patients who are younger don’t want to take a pill for the rest of their lives. Having time-limited therapy and getting 1 infusion of CAR T is great for patients in terms of quality life. The update from the data has shown that it’s a durable therapy. It’s here to stay. We should probably be thinking about incorporating it in earlier lines of therapy given how efficacious it is.
Alexey V. Danilov, MD, PhD: Bijal, Boyu mentioned that some patients still stay in CR 3 years later—almost half of patients. Do you think they’ve been cured now?
Bijal D. Shah, MD: No.
Alexey V. Danilov, MD, PhD: Maybe functionally cured?
Matthew J. Matasar, MD: No.
Alexey V. Danilov, MD, PhD: We need longer follow-up.
Bijal D. Shah, MD: I love CAR-T. It played a big role in the ZUMA-2 trial and in the real-world updates. But we have preclinical data showing that there are CD-19–negative cells—repopulating cells, stem cells, whatever you want to call them—that exist in the tumor microenvironment and can precipitate a relapse of that mantle cell lymphoma. I love it. I use it. I know of no other therapy that’s as active in a BTKi [Bruton tyrosine kinase inhibitor]–refractory space and in the blastoid TP53 space. It’s a very powerful therapy. But as much as I love it—I also have those 3- and 4-year patients—I still want to be cognizant that they need ongoing follow-up, and they’re likely to relapse over time.
Alexey V. Danilov, MD, PhD: Boyu, which toxicities are you worried about with CAR T cells, early vs late toxicities?
Boyu Hu, MD: The trials and real-world data have shown that neurotoxicity is still high in these patients, almost 50%. Even if it’s low grade, it can be a scary event. Cytokine release syndrome was relatively rare, but there were some high grades to that. The late toxicities of CAR T would be immunosuppression, hypogammaglobulinemia, and infectious issues as well. Even though [CAR T] is time-limited therapy, some patients suffer long term from the neurotoxicity and infectious complications.
Alexey V. Danilov, MD, PhD: Imagine you see a patient who comes from Hurricane, Utah, which is probably a [long] drive south from where you are. He gets CAR T-cell therapy, and he’s doing well. What do you tell him? He says, “When can I stop coming back seeing you? Is it 30 days, 100 days, 100 years? What’s it like?
Boyu Hu, MD: I don’t know if CAR T-cell therapy is truly curative. The majority of patients who relapse will probably relapse within the first year. But the more we’re seeing later relapses with CAR T, the more we have experience with it. Unfortunately, I don’t think there’s a time frame. I would see them very closely in the first year and then maybe be able to space it out after that. But these patients with mantle cell lymphoma, once we see them, are our patients forever. Besides allogeneic central transplant, I don’t necessarily know if there’s a truly curative option for these patients.
Alexey V. Danilov, MD, PhD: I agree. We need more follow-up on that.
Transcript edited for clarity.