Future Directions of CAR T Therapy in R/R DLBCL


Andre Goy, MD, MS: Peter, you mentioned these patients are chemotherapy refractory, obviously, in that setting. But what type of non-chemotherapy option, what type of combination are you looking at or that you think is exciting to look at?

Peter Martin, MD: I think there is obviously a need for new therapies in people with refractory or relapsed lymphomas. Not everybody is a candidate for CAR [chimeric antigen receptor] T-cell therapy. For people who receive CAR T-cell, the majority of them will still unfortunately experience persistent lymphoma or recurrent lymphoma. There are a number of agents that are under evaluation. As Kami mentioned, the bendamustine-rituximab combination. I think the polatuzumab vedotin regimen is a reasonable option. I think we’re going to talk more later about the MOR208 [tafasitamab]-lenalidomide regimen. Historically, I can say that we have used lenalidomide-rituximab. Although it does not routinely result in responses, occasionally it surprises you, and some patients can do very well. So, we have used it frequently.

At ASH [the American Society of Hematology 2019 annual meeting] we have seen the continuation of the Pharmacyclics LLC PCYC-1123 trial, which was the combination of ibrutinib-lenalidomide-rituximab. That regimen clearly has activity. We saw it, and we just talked about it in the frontline setting. Now, I think there’s overwhelming data that it is an active regimen, so we have occasionally used that off-label. There are times when we will just use single-agent chemotherapy, gemcitabine in a palliative setting or bendamustine in a palliative setting, when the goal is to help somebody feel better. Anecdotally, I think that we’ve also tried a variety of things, including HDAC [histone deacetylase] inhibitors, demethylating agents.

Periodically, people get responses to some of these things, and although it’s hard to say that that’s the right thing to do all of the time, we will always have examples of somebody who does well. Some of these patients with large cell lymphoma seem to have a lymphoma that does not explode but rather trickles. Those are opportunities to try creative things. My bias is always to do that in the context of a clinical trial, but it’s not always feasible. In general, we’ve been pretty good at coming up with things to try for patients.

Andre Goy, MD, MS: …as a form of immunotherapy.

Peter Martin, MD: Yes, when you were talking about immunotherapy that was the one thing that sprang to mind.

Andre Goy, MD, MS: We have experience. We have done something in Chicago, the Northwestern group had looked at using PEMBRO [pembrolizumab] post-autologous transplantation, tried to take advantage of the better immunological…post-autologous transplantation, checkpoint inhibitors as single agent; the data were intriguing. So, we built upon this and we did IPI-NIVO [ipilimumab-nivolumab] post-autologous transplantation, and it’s a small number of patients. It’s 15 primary refractory patients or early relapse. These patients with EFS [event-free survival] at 18 months is 83%. There’s no question that there is toxicity, but that’s not an easy situation. I think there are ways, I think that allotransplant, I agree, although sometimes CAR T serves now as a bridge toward an allotransplant. That’s a separate story. But the autotransplant, there are opportunities to revisit it, not think otherwise just a…therapy. But there’s a way to reset the immune system and try to take advantage of immunotherapy because these patients have an enormous amount of T regs [regulatory T-cells] and immunosuppressive environment. So, I think that’s an opportunity.

Peter Martin, MD: I would say that in general, it’s better to do that in the context of a clinical trial than outside of a clinical trial. This is because, oftentimes, we’re surprised, right? In follicular lymphoma we combined lenalidomide with PI3 kinase inhibitors, thought it was going to be great, but it didn’t turn out that way. In multiple myeloma there was the whole checkpoint inhibitor, lenalidomide story that might turn out to be reasonable in other lymphomas or other diseases. However, in myeloma, it didn’t work out so great. We’re all pretty clever, but we should be careful not to be too clever.

Andre Goy, MD, MS: Absolutely. We talk about we are giving to our audience what’s coming up and what’s new because the field is really exciting. There is still an unmet need. In relapsed or refractory large cell lymphoma, we are in a situation where patients still have very poor outcomes, right?

Julio Chavez, MD: Yes, especially post-CAR T relapse. You mentioned the overall response rate or the CR [complete response] rate is initially good for CAR T cell therapy, but in patients who start relapsing, you can say the 3-month point, or 6-month point, the relapses post-CAR T are about 60% of the patients. The problem is they usually have other issues like thrombocytopenias, and they are not eligible for trials. So, it’s hard to put the patient with a post-CAR T relapse into a trial sometimes. We just have to figure out.

Grzegorz S. Nowakowski, MD: I think you nailed it because this is a very difficult population to deal with, but we are living in a post-CAR T-cell world—they are there, and they’re going to stay probably for some future. We need to learn how to deal with those patients who are relapsing post-CAR T-cell. Since we are developing our future clinical trials, we have to be open minded then to try to define what are the inclusion criteria.

Andre Goy, MD, MS: Really open minded with the counts.

Grzegorz S. Nowakowski, MD: Well, with some of the targeted agents, the platelet count.

Andre Goy, MD, MS: Absolutely.

Grzegorz S. Nowakowski, MD: Neutropenia is not as important.

Julio Chavez, MD: It’s important to advocate for the specific inclusion criteria. Some trials that require a hemoglobin of 10 g/dL; this isn’t possible.

Andre Goy, MD, MS: There’s no question that clinical trials have become too complex over time and not open enough, and they make it difficult to enroll and difficult to duplicate in the real world afterward.

Grzegorz S. Nowakowski, MD: The good thing about it is I think we have a better understanding also on the side of...agents is that some of those regulations are actually affecting development in those areas, and I think people appreciate this more now. I believe we’ll see a little bit of change in the landscape coming soon.

Transcript Edited for Clarity

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