Adult ALL and Data from ZUMA-3



David Maloney, MD, PhD: I want to transition to adults with ALL [acute lymphoblastic leukemia] for a minute. Obviously, we have tisagenlecleucel approved for up to the age of, I believe, 26, or through age 25. And that means if you’re 27 years old, you can’t get commercial tisagenlecleucel, which I think is terrible. We do know that CAR [chimeric antigen receptor] T-cells are very active in adults as well. Fred, do you want to update us a little on the KTE-X19?

Frederick Locke, MD: KTE-X19 is a CAR T-cell therapy tested in the ZUMA-3 trial for adult patients with refractory ALL. The interim results were presented by Dr Bijal Shah at the ASCO [American Society of Clinical Oncology] Annual Meeting earlier this year. Forty-one patients were treated across 3 dose levels, and both CR [complete response] and CRi [CR with incomplete hematological recovery] were 68%. In fact, it was 84% in the dose level that was selected for dose expansion. Interestingly, the overall severe grade 3 or higher CRS [cytokine release syndrome] rates were 29%, and grade 3 or higher neurological event rates were 38%. But in fact, those rates decreased over the course of the study as earlier interventions were utilized or suggested in this clinical trial. So it’s very encouraging that we may have a therapy headed toward FDA approval for adult patients with refractory ALL.

David Maloney, MD, PhD: I know the adult studies got off to a rocky start, both with the Penn studies and some of the Memorial Sloan Kettering Cancer Center studies as well where the CAR was associated with CNS [central nervous system] toxicity and cerebral edema. And so this has set the field back a little, but I think we’re now starting to see encouraging results. This definitely needs to be approved for adults. I think the oldest patient I treated for refractory ALL was age 81, and this patient had a complete remission from that. And so I think we desperately need this treatment, and I certainly encourage those studies to continue.

Frederick Locke, MD: These are patients without any other options.

David Maloney, MD, PhD: Is there a difference between CD28 and 4-1BB in this setting?

Max Topp, MD: Well, I think there are some data that the 4-1BB construct led to a long-term persistence of the T cells, so you could argue that the immune surveillance may contribute to the long-term control of disease. On the other hand, as you said, Fred, the data that were presented at ASCO was using CD28. And the data, at least in the response rate, is exactly the same as with the previous constructs with 4-1BB. We just have to wait on long-term outcomes regarding both of these pathways that we’re using currently to see...

Caron Jacobson, MD: Yeah, but as proof of concept, some of those 41 patients who were treated in ZUMA-3, the earliest treated ones, they were durable responses. So it does tell you that you can get durable responses.

David Maloney, MD, PhD: Yeah. I think we don’t really know the long-term follow-up.

Max Topp, MD: No, we don’t.

David Maloney, MD, PhD: There’s a perception that the toxicity is higher in adults than in pediatric patients. What do you guys think about that?

Frederick Locke, MD: Well, again, I don’t treat pediatric patients, but I can tell you that the toxicities in adult ALL patients getting a CD28-based CAR T-cell therapy can be severe, but that’s across the board with all CAR T-cell therapies. So again, earlier intervention. And in adults, we all worry about the severe toxicities. Adult patients are more likely to have comorbidities that make it more difficult to get them through these toxicities.

Max Topp, MD: And as Dr Jae Park showed, regarding the patients he treated in the MRD [minimal residual disease] situation, the toxicity profile was much lower than in the patients who were treated with full-blown relapsed disease. So it mirrors that we do need some kind of either early detection methods or a good debulking strategy up front to reduce toxicity for this approach.

Jason Westin, MD: I think, as mentioned before, some of the early concerns about toxicity in the adult patients were related to some of the cerebral edema deaths that occurred early on. We really haven’t seen very many of those cases that had severe toxicity since. So I think some of the early concerns may not be applicable today.

Caron Jacobson, MD: I think it’s really unclear what aspect of that study led to the incidence of cerebral edema. There were a lot of different variables that came to fruition, and it’s not clear that it was specific to the CD28 costimulatory domain.

David Maloney, MD, PhD: I think we’re all encouraged to see that clinical trials are beginning to proceed again in the adult population. We desperately need this therapy to be available for patients. I thank you for your attention to this section.

Transcript Edited for Clarity

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