Tisagenlecleucel Promising in R/R Follicular Lymphoma

Tisagenlecleucel (tisa-cel; Kymriah) produced a high overall response rate and complete response (CR) rate in adults with relapsed or refractory follicular lymphoma who had received two or more prior lines of therapy, according to results presented at the American Society of Hematology (ASH) annual meeting.

MedPage Today brought together three expert leaders in the field -- moderator Ian Flinn, MD, Loretta Nastoupil, MD, and Amitkumar Mehta, MD -- for a virtual roundtable discussion. This third of four exclusive episodes focuses on the phase II ELARA trial.

Following is a transcript of their remarks:

Flinn: Hello, I'm Ian Flinn from the Sarah Cannon Research Institute in Nashville, Tennessee. I'm joined today by Loretta Nastoupil from the MD Anderson Cancer Center and Amit Mehta from University of Alabama at Birmingham. We're going to talk about some of the exciting news that's come out at ASH 2021. It was a big year for lymphoma studies this year, and I think we have a great discussion.

Okay, so let's switch now, Loretta, and talk about a study that I believe you were involved with, the tisa-cel in patients with follicular lymphoma. We know that we already have an FDA-approved therapy, CAR T-cell, for patients with follicular lymphoma, with axi-cel [axicabtagene ciloleucel; Yescarta]. It does come with a significant adverse event profile -- is tisa-cel a better CAR-T cell for follicular lymphoma?

Nastoupil: So the ELARA [Efficacy and Safety of Tisagenlecleucel in Adult Patients With Refractory or Relapsed Follicular Lymphoma] results were updated and presented this year at ASH. ELARA looked at single-agent tisa-cel as a single-arm phase II study. It was a large global international phase II trial. Again, looking at patients that had failed at least two prior lines of therapy, including an alkylator in CD20. And these CAR-T protocols, whether you talk about ZUMA-5 or ELARA, they're enriched for those POD24 [progression of disease within 24 months from first immunochemotherapy] patients or those patients that are progressing quickly through treatment.

So despite moves to these patients having at least three prior lines of therapy, they're still a relatively young patient population, which again, sort of emphasizes that these are high-risk patients that are progressing quickly. And I highlight that because I think we're all struggling a little bit with what is the patient that we would consider the potential toxicity of a CAR-T, but we really want to harness the efficacy. Because I really do think that these are some of the most effective strategies in that third-line or later space outside of maybe bispecifics.

And we saw updates of ZUMA-5 this year, which now we have a medium PFS [progression-free survival] of nearly 40 months in these high-risk patients. We don't have as much mature follow-up with ELARA, but we see very high CR rates above 60%. And they do appear to be very durable -- again in a higher-risk patient population.

But I think what's really important about follicular lymphoma is we will trade off some toxicity for efficacy, but not nearly as much as we're willing to accept in large-cell lymphoma. And we also don't have that tempo of the disease that really we needed a CAR that is readily available in high successful rates of manufacturing.

So I do think that this now provides at least a window of opportunity for tisa-cel, because I think that window's closing in large-cell lymphoma.

Flinn: Amit, what about your thoughts on this? I mean, again we heard about the negative results in BELINDA with tisa-cel, but here is some pretty good data in follicular lymphoma. Arguably it is a better tolerated CAR-T cell than perhaps axi-cel. So do you think this is a great place for this drug to be used, or do you have concerns here as well?

Mehta: No, I think BELINDA, my thoughts were that the patient selection and design had some issues. But tisa-cel, as we know, in a third-line setting in follicular lymphoma, there is some merit to the results. So I do feel that it has a place in follicular lymphoma. And globally for follicular lymphoma, whenever we see a patient with follicular lymphoma we hate to say that, oh well, follicular lymphoma is still not curable, because it's a low-grade lymphoma.

I think these are all the opportunities, as Loretta mentioned, that there are long-term durable remissions, and potentially those patients are cured. So there is a lot of hope there for the cure, and hopefully that in the near future I can tell my patients that no, there is a place for hope in follicular lymphoma.

Flinn: Perfect. And Loretta, so one follow-up question for you. So one of the points of this study was to look at the differences in subgroups. You mentioned the POD24 had a substantial complete remission rate, albeit not as high as we saw in the greater population of patients. Why is that? If this is an immunological therapy, you would think it would overcome some of those aspects. Any insights into that would be appreciated.

Nastoupil: Yeah, I think the challenge is, and I'm guilty of this, sometimes POD24 identified patients that were progressing early following chemotherapy. And so the knee jerk reaction is to think, well let's change the mechanism of action. Maybe we can overcome that. Maybe that's a marker of poor response to chemotherapy. But I think it's just a marker of poor prognosis. Yes, there are therapies like CAR-T, like CELMoDs [cereblon E3 ligase modulators] that provide some efficacy, but it's not quite as good as the other patients who don't have POD24 status. But these studies are still enriched for that.

So I think the takeaway for me is they don't do as well if they have POD24 status, but they still do reasonably well. The other take-home message from the subgroup analysis in the study is that those patients who had five or more prior lines of therapy also didn't do as well.

So I think this now makes us revisit where does this fit in, in delaying it and delaying it until you sort of run out of options. You may not get as much benefit out of those autologous CARs that are done in patients that are heavily pretreated.

Flinn: Perfect. Thank you.

Watch episode 1: Will Bispecific Antibodies Challenge CAR T-Cell Therapy in Follicular Lymphoma?

Watch episode 2: Lemzoparlimab Promising in Tough-to-Treat Lymphoma

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