Use of CAR T Therapy in R/R DLBCL



Andre Goy, MD, MS: I want to deep dive a little further into the novel therapy, and I think 1 of the buzzwords of the ASH [American Society of Hematology Annual Meeting & Exposition] is CAR T [chimeric antigen receptor T-cell therapy] again. There are close to 300 abstracts of ASH at least on CAR T. I want to talk a bit more about this and talk about what is currently approved. Dr Chavez, can you remind our audience what is currently approved?

Julio Chavez, MD: Chimeric antigen receptor therapy, or CAR T-cell therapy, is currently approved for diffuse large B-cell lymphoma [DLBCL] after at least 2 lines of therapy. There are 2 agents approved for diffuse large B-cell lymphoma: tisagenlecleucel and axicabtagene ciloleucel. They actually showed good overall responses in patients who have poor prognostic disease, including high a IPI [International Prognostic Index] score, and patients with primary refractory disease and who were refractory to their last therapy, including those in lymphoma. Definitely CAR T cell therapy changes the paradigm of treatment of diffuse large-cell lymphoma on patients who actually didn’t have any other options.

Andre Goy, MD, MS: It’s interesting that for salvage therapy, first of all, there are 40% or so who really benefit with very durable response over...the last update on the ZUMA-1 trial. But all the standard prognostic factors that we see in lymphoma—bulky, never prior therapy, really doesn’t affect double-hit—still have a high response rate. What is your experience on the use of this commercially? For approved therapy, we know that there’s a tisa-cel [tisagenlecleucel] and axi-cel [axicabtagene ciloleucel], and we know that they have slightly different toxicity profiles, issues with Medicare reimbursement, and all that. What is your experience, Dr Maddocks? Do you want to talk about outpatient versus inpatient? What has been your experience at The Ohio State University?

Kami Maddocks, MD: The majority of our patients are treated inpatient. All the patients are treated inpatient. For the KYMRIAH [tisagenlecleucel] product, we do have a few patients who have been treated outpatient, but I think everybody standardly is being treated inpatient, just with the risk of toxicity. We’ve seen some issues with the neurotoxicity and the cytokine release, especially when patients have a lot. Now that it’s approved, they’re a lot sicker—some of them, when they’re getting the therapy at our institution at least—and so they’re monitored a lot more carefully after infusion.

Andre Goy, MD, MS: Even in the real world, we have been a bit more preemptive in jumping on TOCI [tocilizumab] and steroids, and it seems like this was not uncommon that patients would routinely go to the ICU [intensive care unit] initially, and now this is much more manageable on the floor, and it makes it much easier.

Kami Maddocks, MD: Yeah. I think there’s even an abstract that will be presented this year. There was some concern about using steroids early on, that it might mitigate the effects of…

Andre Goy, MD, MS: There are data showing that.

Kami Maddocks, MD: Yeah, CAR T that the patients do, it doesn’t harm efficacy, and it actually improves the neurotoxicity and cytokine release when it’s used earlier on.

Andre Goy, MD, MS: It’s interesting; it didn’t change. The abstract will be presented in more detail, but it didn’t change the T-cell amplification, and it improved the clinical experience but didn’t change efficacy. What are the other compounds in the pipeline that we can talk about? I mean, we all have presentations on the TRANSCEND-NHL-001 study. We’re not going to go into the detail of the data. But what do you think, and how we move forward when having already several options of CAR T cells? How do we pick a CAR T therapy for the treatment of a patients? For our audience, it will be important for us to explain about referring a patient for CAR T early, because probably immunologic fitness, general inflammation...matters. But T-cell fitness matters probably even more. So if we refer this patient early, they probably would be better. How do you decide on a treatment, Nathan?

Nathan H. Fowler, MD: You brought up great points, Andre, about how there’s a lag. I’ve heard this described as brain to vein versus vein to vein. When you think that a patient needs a CAR T cell, it takes quite a while before you can actually get insurance approval, before you can figure out logistics. There can sometimes be as long as a 2-week to 4-week delay before you can actually get this type of treatment approved by Medicare or insurance. Then from that time, it’s another 3 weeks, usually at a minimum, from the time you’re apheresed.

Andre Goy, MD, MS: Usually a couple of months in large-cell lymphoma.

Nathan H. Fowler, MD: In large-cell lymphoma, it’s 2 months. You really hit the nail on the head. If you have a patient who’s relapsing early, you need to think about CAR T cells and start getting the patient prepared immediately. As you mentioned, we have 2 and probably soon 3 of these drugs on the market. All of them cost, as far as I can tell, about the same amount of money. The efficacy when I look at them looks similar. The durable CR [complete response] rate—which is what you really should be watching for these, the 6-month CR rate is really how you should compare these different drugs—is fairly similar. Then it comes down to the adverse-effect profile. The neurotoxicity, at least from 2 different trials, does look to me a little less with the KYMRIAH product. But again, these are different study populations. It took patients a little longer to go on trial with some of those early studies. So it’s hard to know whether this was because of how they graded them, patient populations, or how they treated them. Right now, I would say it’s dealer’s choice—maybe there’s a little less neurotoxicity with 1 of the products.

Andre Goy, MD, MS: Dr Chavez?

Julio Chavez, MD: Yeah, I agree with all the points with already 3 products available for CAR T-cell therapy for DLBCL. Cross comparison of trials is a little difficult because...the protocols are different, the co-stimulators are different, the kinetics of each CAR T cell probably is different. That leads to the toxicity also. For instance, the… onset of CRS [cytokine release syndrome] for axicabtagene ciloleucel is about 2 days. It’s hard to justify outpatient treatments, so nobody will treat an outpatient with axicabtagene ciloleucel. But this is different in Maraleucel [liso-cel] because their toxicity onset is usually a little later, in the range of 3, 4, 5 days, so there is an opportunity of doing outpatient therapy.

But also pointing out what Nathan mentioned, the grading is different too. The reported data on the JULIET study was using the University of Pennsylvania criteria for CRS and neurotoxicity. They were different. That’s why sometimes you have challenges choosing. The way I choose a product, 1 or the other, is based on our center experience. At Moffitt Cancer Center and The University of Texas MD Anderson Cancer Center as well, mostly we’re doing axicabtagene ciloleucel as opposed to tisagenlecleucel, so we’re very comfortable. There was a learning experience when we started the ZUMA-1 studies. We were concerned with the steroid, so we have few tools to treat neurotoxicity of CRS. But the more we learn about the effect of steroids on CAR T-cell therapies, doctors were a little more aggressive treating those conditions. That’s what’s in the real-world data. The use of steroids and tocilizumab is a little higher, and the toxicity is similar. It probably tends to be a lower toxicity.

Finally, something I want to point out is the fact of early referrals, data presented focusing on commercial axicabtagene ciloleucel outcomes. The most important factor for patients doing bad with CAR T-cell therapy was their performance status and has to be with how soon we can get the patient there. It’s important for clinicians to identify this, like a primary refractory DLBCL or the early relapse to refer to a CAR T center.

Transcript Edited for Clarity

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