How Should Treatment Be Sequenced for DLBCL, Follicular Lymphoma?

A roundtable discussion, moderated by Kami J. Maddocks, MD, of the James Cancer Hospital, Ohio State University Comprehensive Cancer Center, focused on treatment options for diffuse large B-cell lymphoma and follicular lymphoma, including novel emerging therapies and treatment sequencing considerations. Dr. Maddocks was joined by a panel that included Pierluigi Porcu, MD; Pamela Blair Allen, MD, MSc; and Jonathan W. Friedberg, MD.

In the next segment, the panel discusses treatment sequencing after CAR-T or transplant and the role bispecifics and other regimens may play.

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Dr. Maddocks: I think the majority of patients that are going to have the potential to receive CAR-T, probably people are choosing to give them CAR-T products because there’s a potential option for cure with that. Let’s just talk a little bit about do you see reasons for patients not responding or is there a way to predict patients who aren’t going to respond or who are going to relapse?

Dr. Allen: There are certainly patients that we have trouble getting to CAR T-cell therapy because the disease is just growing so fast and the manufacturing time and the slots and the logistics. I can’t say that we’ve had great success with any type of therapy in those types of patients where they’re so sick that you can’t get them to CAR-T, but having some of these other targeted agents I think is great, and once we have the availability for some of the bispecifics, that’s another place where I think that could be helpful.

Dr. Porcu: I think that some of the questions still revolve around the relative role of autologous stem cell transplant versus CAR-T. I don’t think that that kind of algorithm has been finalized, and CIBMTR data were recently published that seem to suggest that some of the patients did better with autologous stem cell transplant than patients who did not achieve a complete response compared to CAR-T. And so I think it’s open whether autologous stem cell transplant is going to go away in the second-line setting for DLBCL, but that would be interesting to see.

Dr. Friedberg: I think one interesting direction that we’re tackling in the NCTN is to try to have an early intervention that may make CAR T-cells work better. So the observation is that if you get CAR T-cell treatment in diffuse large B-cell lymphoma and you have an early complete remission, most of those patients do very well durably, but then there’s a group who has stable disease or partial response and maybe about 30% of them, 25% to 30% of them, will convert to a complete remission and do well, but the majority of them will experience disease progression, often relatively soon. So we feel that there’s a window of opportunity where if you do an early PET-CT, say between day 30 and 60 and you’re in that partial response category, you might be able to give them something else to convert them to a complete response. And we’re about to open a trial that’s going to look at a couple of different strategies, either a bispecific with mosunetuzumab, either polatuzumab or the combination, and compare that to the standard now, which is to wait and see what happens. And that’s a relatively small trial to get some experience, but I think the concept speaks to ways that you might be able to have combinations or sequences with CAR T-cell therapy that could improve outcome.

Dr. Porcu: Almost like an early consolidation sort of idea.

Dr. Friedberg: Exactly. And it’s for a defined treatment period as well.

Dr. Maddocks: I think patients who progress after CAR-T or don’t respond can be very challenging to find other treatments for; some of it is just if they have rapid progression of disease, some of it is counts can be a real issue, but maybe each of you can just comment on what treatment options you try to pursue after CAR or how you think about sequencing the different options, because as you’ve said a few times, there’s lots of options and nobody’s doing the same sequencing.

Dr. Allen: So if we’re talking about standard of care options and not having clinical trials, part of it depends on, as you said, what their blood count looks like and what their prior therapies and how far out from CAR-T. So if it’s a while out from CAR-T and they haven’t had an autologous transplant, for example, that is something that you could still potentially consider. If it’s earlier, then things like tafasitamab are things that we try sometimes.

Dr. Porcu: They’re not approved, but the data with the bispecifics look very interesting and there are responses after CAR T-cell failure, so hopefully we’ll have one or more of those drugs available soon. And I agree also with tafasitamab/lenalidomide for patients who fail CAR-T, I’m not aware of data, I don’t know if any here at the tables was aware of that, but I think that was something to try. And then the sequencing is really going to be a key here in terms of trying to alternate between CD20 targeting versus CD19 targeting.

Dr. Maddocks: And that may be somewhere where real-world data might come in to play because people are doing whatever and nice to see some real-world data on what we’re seeing with outcomes post, because I think CD19 sequencing is a big thing or CD20, and can these agents be sequenced? How are they sequenced?

Dr. Friedberg: I think as you said though at the beginning, for many of these patients it’s very difficult to get anything just because many of them are progressing quickly after CAR-T. They’ve had a lot of treatment in a short period of time; they still may be recovering from toxicities of the CAR T-cell therapy, and given the kinetics of the disease, that may become our major unmet need.

Dr. Allen: That’s been I feel like generally my experience is when they’re relapsing, it’s quick and their counts are low and there’s just really not a whole lot that you can do.

Dr. Maddocks: So there’s not really an answer to this, but do you think as we move CAR-T earlier into lines of therapy, now second-line approval that’s being investigated in high-risk frontline that that’ll change this, that it’ll be easier to, or just more difficult to treat these patients?

Dr. Allen: Yeah, I think that if they haven’t been heavily pretreated then certainly the treatment after CAR-T is going to be a lot easier.

Dr. Porcu: Yeah, I agree. I think one of the challenges in terms of the standard of care menu so is that we see these patients are going from frontline chemoimmunotherapy to second-line chemoimmunotherapy to third-line chemoimmunotherapy and then at some point their myelosuppression becomes so severe and hard to recover that even putting them on clinical trials is very, very difficult at that point because they don’t meet the eligibility criteria.

Dr. Maddocks: This is an area in follicular where there’s probably not as much experience, but any thoughts on has anybody treated follicular patients post-CAR progression and effective agents or sequencing in that situation?

Dr. Porcu: I have not.

Dr. Allen: I have not.

Dr. Friedberg: Our patients have done pretty well, I have to say, who’ve gotten CAR and it’s a select group. I would speculate that given what we talked about before with tolerability being better, that it will be easier to potentially do something else for those patients. And I think again, it’s likely to become a reality very soon that we’ll have a bispecific where there are data suggesting significant responses after CAR T-cell treatment. So my guess is that would be the likely sequence that we will see.