Targeting CD19 in Diffuse Large B-Cell Lymphoma - Episode 4

Transplant Ineligibility: Anti-CD19 Combination Therapy

Targeted Oncology

John Pagel, MD, PhD: I think they also really have preclinical data suggesting that these drugs can be potentially synergistic. So I agree, it’s a brilliant combination. Getting back to what we talked about earlier: this could be a very important combination of agents for patients who are not eligible for a transplant, or even have failed a prior transplant, don’t you think?

Ian Flinn, MD: Yeah, I do. I think that it’s clearly less toxic. So, giving it to patients in the relapsed/refractory population, no matter what your issue in terms of that, you know, which of the relapsed refractory patients. I think, particularly in people who aren’t eligible can withstand CAR T [chimeric antigen receptor T] cells. Using this drug (this therapy, I should say because it’s combined with lenalidomide), I think it has a lot of potential without just sort of continually beating on people with chelator immunotherapy. So, I think that’s certainly a huge potential for patients.

Sure, go ahead John.

John Pagel, MD, PhD: No, I agree. I think that the idea, when you’re resistant to chemotherapy or refractory to chemotherapy, as you say, continuing the same thing doesn’t make a lot of sense. And I think this was potentially a really nice salvage regimen, even for people who you are going to take to a transplant, if you can. Meaning those people who have had a reasonable first remission or something like that. Where do you see it fitting in?

Ian Flinn, MD: I think that that might work fine. I mean one of the things that, well the whole translate world is changing, right? So, we have these numerous different trials—the ZUMA 7 trial, the BELINDA trial and others, looking at whether we’re going to replace transplantation with CAR T cells—and so new CAR T cells, the second line. One of the issues that I think about in terms of transplant sensitivity in the past has always been chemosensitivity, since you’re just giving higher doses.

In the beginning, I might reconsider continuing to use a chemoimmunotherapy as a litmus, if asked whether someone should have a stem cell transplant. But if I’m not going to transplant, or if they failed a salvage regimen, and you didn’t think they could have taken the CAR T cells, then I would probably use this.

One of the things that I try to wrap my head around and figure out is how to sequence is that this is CD19 therapy. Regarding most of the CAR T cells, you saw the commercially available CAR T cells to date. So, there’s certainly a concern in that using a CD19 therapy, you might downregulate the expression of CD19 and then perhaps make CAR T cells less effective. So if my goal were to use CAR T cells, I think at least until we know more, I probably wouldn’t use this as a segue to that. What’s your thinking?

John Pagel, MD, PhD: We don’t have enough data, so I agree with you. You’ve got to really be cautious, and I’m glad you brought that up. There are some anecdotal data saying that you can get the MOR208 and then proceed to CAR T-cell therapy. You know that’s anecdotal, so you’re right. We need to wait for data; I agree with you completely. But I’d also point out, we had the same concern in the acute lymphoblastic leukemia space where we were worried about being able to use CAR T cells in patients who had had prior anti-CD19–based therapy with BLINCYTO.

And we found that it probably doesn’t affect the CAR T-cell approach, or the outcome. Let’s see what happens here. I agree with you. I’d proceed with a lot of caution if you’re trying to get to a CD19- directed CAR T-cell therapy. I think this is what you were saying: that this is a salvage therapy for people who don’t have great options otherwise. The ASH [American Society of Hematology] data presented in 2019 were really valuable to see. We’ll have to see the longer data and the upcoming randomized data. But that early data were pretty encouraging, I think, and I wonder what you think about that.

Ian Flinn, MD: Oh yeah, I agree with you completely. So just to remind everybody, this is the L-MIND study, which combined lenalidomide with MOR208: lenalida; the MOR208 was given a little bit of a load, and then it’s given weekly, and then it’s given every other week for about a year. And then, that’s combined with lenalidomide, which is I think given 3 weeks out of 4. Ultimately, if patients made it through a year or more, they could drop out and no longer receive the lenalidomide and continue on the MOR208.

I thought the results were really impressive. I think about 50% or more patients responded, and many had complete remissions. There were some very durable remissions from this group. I thought that was surprising, right? I wouldn’t have thought the results would have been that good.

John Pagel, MD, PhD: I was pretty impressed with it, too. As you said, the response rates were in a difficult patient population, these were people who were not going to get a transplant delivered, too. They had had up to 3 prior therapies, if I remember right. And as you noted, the response rates were about 60%, and about 30%, or a third of patients had a complete remission. And the progression-free survival rate was almost a year and a half in patients with relapsed or maybe even multiply relapsed large-cell lymphoma. That to me, is extremely encouraging. And I am even more excited about the fact that so many people reach remission, that if you looked at the people who got I think about a year, about three-quarters of the patients were still on therapy maintaining their remission. So you’ve got to get as many people to respond as possible. And, of course, understand that there are toxicities with the agent, which we should probably talk about. But I think the online data were really important for us to understand that we have some options now for using this drug in those patients.

Ian Flinn, MD: Yeah. I know that. I was impressed also with the fact that these patients, the follow-up was actually pretty mature, right? I think it was almost a year and a half of follow-ups on most of these patients. In a large-cell lymphoma that’s a relapsed-refractory large-cell lymphoma, that’s almost an eternity, right? So I thought those were good data as well.

Yeah, I thought the adverse event profile compared with chemoimmunotherapy was kind of what you would expect, right? You get some of the adverse events of the antibody—a lot of it’s the lenalidomide. But, of course, you have to keep it as a pair here. But, anyway, I thought that was impressive.

John Pagel, MD, PhD: Yeah. Actually, you have a fair amount of experience with it. From my experience, and really understanding the data, surprisingly perhaps, the infusion-related reactions were almost 0 with this engineered antibody—perhaps a bit surprising. I think there are only 80 or so patients in the trial. But regardless, if it’s close to 0, that’s telling you the antibody is pretty well tolerated. I think you’re right, the adverse events were really hematologic. There was about a third of patients who were neutropenic. There was some thrombocytopenia and anemia. But whether you combine it with a lenalidomide, that’s probably not that surprising; and maybe a lot of that was contributed to by the lenalidomide.

And if I’m not mistaken, if you had to approach patients with cytopenia in the trial, they would actually have a dose reduction of their lenalidomide, and they actually did very well when that happened.

My experience with this kind of combination is that the lenalidomide dose may be too high. I think you’re supposed to start at 25 milligrams daily. What do you think about that?

John, I agree with you regarding the dose in terms of, if you say if we extrapolate from the R-squared [Revlimid and Rituximab] regimen, it is higher. It is hard to get some of these higher doses of lenalidomide in, and perhaps dose adjusting based on toxicities is important, or even maybe starting out at a little bit of a lower dose.

The other thing that’s important in this data set as you look at all the different subgroups is that it really didn’t appear that there was a subgroup that didn’t benefit from this. Of course, the subgroups are small, as you mentioned. This is an 80-patient trial; so it’s hard to know if you got on to really small subgroups. But they all seem to do pretty well.

I agree. You know it’s small numbers, but those included the patients with more refractory disease, patients with higher IPI [International Prognostic Index]scores and patients who were, of course, refractory to rituximab therapy and a variety of other treatments. So, you know that’s getting back to where we started—those are the patients where we have a huge unmet need. Perhaps it’s not surprising that it works, even in those patients with more aggressive disease, because it has a completely different mechanism of action from cytotoxic chemotherapy that we have been using in this kind of setting for so many years. I hope we continue to get data that really convince us that patients with more aggressive disease benefit. Because again, we have a major unmet need there.

Ian Flinn, MD: I agree with that.

Transcript edited for clarity.