The Expanding Role of CAR T Cells in Lymphoma and Leukemia - Episode 7

ZUMA-2 Trial Overview: Mantle Cell Lymphoma Impact

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Stephen J. Schuster, MD:It’s difficult to think of 11 lines of therapy for lymphoma. But I agree with what you said. Thinking of myeloma always makes me think of the lymphoma counterpart of myeloma, because a lot of the cases have the t(11;14) translocation, and there are also other molecular characteristics that were discussed at the current meeting.Proteasome inhibition works in mantle cell and works in myeloma. Lenalidomide works in both. There are clearly biologic and genetic pathologies.

David Miklos, MD: B cells, Steve?

Stephen J. Schuster, MD: Yes, but so are follicular lymphoma cells, which proteasome inhibition doesn’t do anything like large cell B cells and follicular B cells. There’s something about those mantle cells. Mark my words, maybe they’re memory B cells that are closer to the myelomas. I don’t know. I’m not a biologist. But the things that work in myeloma tend to work in mantle cell. Let’s move on to mantle cell lymphoma, because when Dr Michael Wang published in the New England Journal of Medicine what I think is a landmark article, if anybody would like to recap it, using a version of axi-cel [axicabtagene ciloleucel] where the T cells are separated from any circulating B cells to minimize CAR T-cell or malignant B-cell contamination of CAR T-cell product. It’s called KTE-X19, the ZUMA-2 trial (NCT02601313).

Loretta J. Nastoupil, MD: I treated a number of patients here, and I have some clinical experience. The patients failed BTK inhibitors in mantle cell lymphoma because there was not effective therapy. We’ve been looking at a number of different targeted agents. But this really does fit a need, particularly for those [who] are ibrutinib-resistant. But Caron, what was your impression of the study?

Caron A. Jacobson, MD: I was with a group of patients [who] had mentioned before, their survival was on the order of weeks to months. CR [complete remission] rates to subsequent lines of therapy were single-digits. And with KTE-X19 and multiply relapsed mantle cell lymphoma that had failed chemoimmunotherapy as well as a BTK inhibitor, you’re seeing CR rates of 67% with, at 12 months, you’re seeing somewhere around 60% of people maintaining their response, which is phenomenal, that’s really moving the bar forward. And we talked a lot about how long the follow-up is for large-cell lymphoma to see if these are durable responses. Mantle cell lymphoma is a different disease. It is a disease marked by inevitable relapses. We need longer follow-up of the series to know whether this is going to be a definitive therapy for a subset of patients or whether it’s a bridge to something like an allogeneic stem cell transplant. This moves the needle forward for a group of patients with a huge unmet medical need.

Matthew J. Frigault, MD: Caron, about one-third of those patients are blastoid variants, correct?

Caron A. Jacobson, MD: Yes. There are a number of patients with blastoid variant, a number of patients with p53 aberrations, complex karyotype, it’s a very high-risk group of patients, for sure.

David Miklos, MD: It’s worth pointing out, though, that there were significant challenges to managing the patients. They were able to get quite sick with very large tumor burdens, aggressive forms of CRS and neurological toxicities. The management on that trial being performed at centers that had already been experienced through the earlier ZUMA studies, ZUMA-1 (NCT02348216), those were still patients [whose cases were challenging}. And we all had to share our experiences in order to help some of those patients get through some of those toxicities.

Stephen J. Schuster, MD: When the bone marrow is involved and sinusoidal organs like spleen are involved, there’s much more toxicity with CAR T cells in any of the B-cell lymphomas. They’re much more like ALL [acute lymphoblastic leukemia]. And that’s mantle cell.

Transcript Edited for Clarity