John M. Pagel, MD, PhD: Yeah, I think that is an exciting aspect. EZH2 inhibitors, in particular—it’s a drug in development known as tazemetostat. It is really perhaps the very first epigenetic agent that we have in follicular lymphoma and lymphoma. It’s being developed. Phase I studies have shown a very high response rate in patients who have a mutation in EZH2. It’s not something we typically look at. It is part of the m7-FLIPI [clinicogenic Follicular Lymphoma International Prognostic Index], but it’s not something we typically screen for. But there’s activity of significance in patients who have wild-type EZH2 with this oral agent, tazemetostat.

Patients with mutations in EZH2 response rate were somewhere in the order of around 80% or greater. It was extremely high. In the wild-type patients, it was modest but meaningful as well, in the 20% to 30% or so range. I think it’s an exciting drug. Not just because of that, but I think it’s extremely well tolerated. The adverse-event profile is almost nonexistent. It doesn’t cause really myelosuppression of significance, and there’s no GI [gastrointestinal] toxicity, there’s no rash, there’s really nothing that we’ve identified as a major safety signal with the drug.

What that likely means in follicular lymphoma is that it’s used in combinations. And the company that’s sponsoring that drug and promoting that drug is now going to be looking at it in combination with R² [rituximab-lenalidomide] as an obvious partner. So there will be a randomized trial, I’m sure, of R² [rituximab-lenalidomide] versus R² [rituximab-lenalidomide] and tazemetostat. And that’s maybe where the field is evolving. There are 3 drugs—now cost is becoming a problem—but I think this is a unique, interesting drug as well that will potentially be another tool that we can use in these patients.

Ian W. Flinn, MD, PhD: Pier Luigi, what about CAR T cells [chimeric antigen receptor T cells]? We had a study up in follicular lymphoma with CAR T cells, and frankly I had a really hard time finding the appropriate patient for...

Pier Luigi Zinzani, MD, PhD: It’s so difficult to finalize the patients eligible for CAR T cell. We have to remember that follicular lymphoma is a real indolent disease, and at the end of the day there is a small subset of patients potentially eligible for CAR T cell. CAR T cell could be, in follicular lymphoma, the new consolidation in term of autologous transplantation. You can use CAR T cell instead of autologous transplantation or allogeneic. But as we discussed before, it’s quite rare to use allogeneic transplantation in the setting of patients, and only in the young patients in second-line therapy can we try to use consolidation. So CAR T cell in this setting of patients is not like CAR T cell in diffuse large B-cell lymphoma, because this is a real an unmet medical need for a subset of patients.

Matthew Lunning, DO: I think another unmet medical need for CAR T cell in follicular lymphoma is the transformed follicular lymphomas.

Pier Luigi Zinzani, MD, PhD: Yeah.

Matthew Lunning, DO: It is unfortunate that in the development of a lot of the CAR T cells recently after transformation, I believe you had to have 2 further lines of therapy, you know? So you wanted to get them through those 2 lines of therapy very quickly because you knew that they were going to have a very short remission duration, especially if they had previously seen immunochemotherapy prior to their transformation. It’s a different disease when you have a de novo transformed follicular lymphoma, but in those people who have been previously treated. I feel that there are many patients who could have gotten CAR T-cell therapy but were unable to get it because they just progressed too fast and got too sick too fast.

John M. Pagel, MD, PhD: Yeah. But I would also say, remember CAR T cell therapy in follicular lymphoma is still completely investigational. And we have a long way to go to really understand.

Matthew Lunning, DO: Well, you had to pick the right population to study it in first.

John M. Pagel, MD, PhD: This is absolutely right. We have to really understand who we should be doing this in. And I think, again, we have all these other agents. I’m going to think about a PI3 kinase inhibitor before I’m going to take somebody to a CAR T-cell treatment that has, albeit a slow, low rate but does have potential for life-threatening complications.

Ian W. Flinn, MD, PhD: What about the off-the-shelf, the bispecifics? It’s not a customized product. It is an immunotherapy, it is engaging the T-cells. We have data which I think had very impressive results in patients with follicular lymphoma. We’re now getting smarter about how to give the drug with a stepped-up approach that gets around some of the cytokine release. Matt, any thoughts on that?

Matthew Lunning, DO: Well, you know, that’s the CD3, CD20 bispecific [T-cell] [engaging molecule], BiTE. I think the biggest impediment to it was previously everybody thinking it’s just blinatumomab again, right? It’s going to be continuous; now this I believe it’s a weekly dosing schedule.

Ian W. Flinn, MD, PhD: Three weeks.

Pier Luigi Zinzani, MD, PhD: Two weeks.

Matthew Lunning, DO: Yeah. Up and again it comes down to the effect of, how long do you need something like that? Are you going to get a lot of bang early on and then start to spread it out as you go along in the therapy? I think it’s going to be 1 of those drugs that’s going to be a finesse drug. You have to figure out the right schedule for the patients.

John M. Pagel, MD, PhD: I think you have to figure out the right bispecific too. That’s not the only 1.

Pier Luigi Zinzani, MD, PhD: Yeah. Many, many.

John M. Pagel, MD, PhD: There are many that are in development. And some of them appear very exciting. I am really excited to see where that develops, even perhaps more than a CAR T cell in follicular lymphoma.

Pier Luigi Zinzani, MD, PhD: And the safety profile is quite good if you compare with CAR T cell, in terms of CNS [central nervous system] and neurological toxicities fundamental for an indolent disease like follicular lymphoma.

Ian W. Flinn, MD, PhD: And to your point that you have to figure out which is the right 1, we were part of a study, and the neurological toxicity was worse than it was for CAR T cells. But that’s not been our experience with most, and it’s been much easier to give. And it’s been—according to the publications as well, which sort of verify that—the Regeneron Pharmaceuticals, Inc drug as well. I mean, I think there’s a lot of excitement in that area to use some of these bispecifics, and many more were in the pipeline. It’s certainly easier than trying to apheresis somebody, having this customized product for people.

You know, it’s hard to argue in large-cell lymphoma to get away from CAR T cell, where it’s curative. But in diseases that we’re talking about today, it sure seems a reasonable approach to me.

The other thing I’d like to talk about, Pier Luigi, is the venetoclax story in follicular lymphoma. If there ever was a disease that you thought was going to work, that was BCL2-mediated driven, you would have thought that follicular lymphoma would be the home for venetoclax.

Pier Luigi Zinzani, MD, PhD: Yes, absolutely. We did a trial comparing venetoclax plus rituximab versus venetoclax plus bendamustine and BR [bendamustine-rituximab]. But at the end of the day, the results are really negative because there is no difference in term of when you compare with venetoclax as a single agent. Because venetoclax is a single agent in relapsed-refractory follicular lymphoma. The overall response rate is 35%. But there is no increase of the response when you try to combine with rituximab or with the bendamustine plus rituximab because there is a toxicity. At least 50% of the patients discontinue the treatment because of hematologic toxicity.

We discussed this several times: what to do to. We could change the schedule, but it was too late for this trial. And in the future we will try again with another trial to reduce the dose of venetoclax. But at the same time, if you try to reduce the dose, it could be really difficult to have some clinical efficacy concerning the role of this drug.

As you said before, potentially because there’s a BCL2 inhibitor, that could be the best drug for follicular lymphoma. At the end of the day, it’s so difficult to combine to have an interesting result—in particular when you combine also only with rituximab—and it could be really difficult when you combine with conventional chemoimmunotherapy, like BR [bendamustine-rituximab].

Ian W. Flinn, MD, PhD: So now that we’re in the retrospective scope, do you have any speculation—I realize it’s speculation—about why this isn’t just dynamite, in terms of the combination?

Pier Luigi Zinzani, MD, PhD: I think the real problem in the CONTRALTO study was in the protocol. Because at the end of the day, the protocol was difficult to understand for all the investigators—what to do according to the different toxicity. In fact, in several centers they stopped venetoclax; in others they stopped rituximab; in others they stopped bendamustine. At the end of the day, it’s so difficult to have a subset of patients treated for at least a 3-fold cycle with bendamustine plus rituximab, plus venetoclax.

Ian W. Flinn, MD, PhD: So, you think if you had a different design…

Pier Luigi Zinzani, MD, PhD: You have to change the design.

Ian W. Flinn, MD, PhD: There’s still potential for venetoclax in this disease. It’s just not there yet.

Pier Luigi Zinzani, MD, PhD: We have only the first chapter. We will try to continue this...

Ian W. Flinn, MD, PhD: Okay, we’ll stay tuned.

Transcript Edited for Clarity