CAR T in Transplant-Eligible and Transplant-Ineligible DLBCL

EP: 1.Standard of Care for Relapsed/Refractory DLBCL

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EP: 2.CAR T in Transplant-Eligible and Transplant-Ineligible DLBCL

EP: 3.L-MIND Study in R/R DLBCL

EP: 4.RE-MIND Study in R/R DLBCL

EP: 5.Phase 2B SADAL Trial in R/R DLBCL

EP: 6.Treatment of R/R DLBCL: Beyond CAR T Therapy

John M. Burke, MD: You bring up CAR [chimeric antigen receptor] T-cell therapy. Let’s talk about that. We’ve now had CAR T cells available for a couple of years. Dr Chavez, let’s start with you. What is your approach? How do you select patients for CAR T-cell therapy? How do you select patients who are not candidates for CAR T-cell therapy? What advice would you give to community doctors like me, where you look at a patient and say, “This is not a candidate for CAR T-cell therapy?” Are there such patients? How do you approach the choice between the different agents that are available? Last, a nice topic Greg brought up would be minimizing toxicities in the modern era with CAR T-cell therapy. It’s a meaty discussion about CAR T-cell therapy. Let’s get into that.

Julio Chavez, MD: Those are good questions. Chimeric antigen receptor therapy is approved for diffuse large cell lymphoma refractory after 2 lines of therapy. The question of who is eligible for CAR T therapy is the million-dollar question because there is no guidance. If you read the label of the FDA, it just says patients had to have DLBCL-NOS [diffuse large B-cell lymphoma, not otherwise specified], primary mediastinal B-cell lymphoma, transformed follicular lymphoma, or high-grade B-cell lymphoma, and the patients had to have 2 lines of therapy. It doesn’t even mention what lines of therapy. You can have R-CHOP [rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone]. You can have antibody. Then you mentioned CAR T, but there is no guidance of who will be the best patient to retrieve it.

We’re trying to use eligibility criteria of clinical trials—for instance, ZUMA-1, which led to the approval of axicabtagene ciloleucel. However, as we know, trials exclude patients who otherwise would be eligible, so patients who had CNS [central nervous system] involvement, a stroke, or a prior thrombosis. Those are the things that we see commonly that we feel that the patients can be treated with CAR T, but they were excluded from trials.

We did multicenter analysis with Mayo Clinic and The University of Texas MD Anderson Cancer Center, like a retrospective review of cases of CAR T-cell patients treated with diffuse large B-cell lymphoma. We looked at variables outside the clinical trials—patients who had comorbidities such as chronic kidney disease, thrombosis, and active thrombosis. It didn’t actually affect the efficacy and the toxicity. The most important factor was performance status, actually. Performance status was the strongest predictor of poor survival and toxicity. My recommendation, because we don’t have clear rules for which patients are eligible, it’s not age and not really comorbidities. It’s mostly performance status, so we recommend doctors identify the high-risk patients—as Dr Fowler mentioned, primary refractory patients or those with lymphoma—who don’t respond to therapy and refer them early.

Community doctors know when CAR T is indicated. But sometimes when you see a patient who you know will not respond to standard salvage chemotherapy, I would refer for CAR T evaluation—especially a primary refractory double-hit lymphoma that relapsed.

In our clinic in CAR T, we assess the patient. We look at their labs. We do a physical examination. We look at the prior history. Essentially, it’s performance status of how well the patient feels, how well the patient is at the time you see it, so you can actually predict how well they’re going to perform in the future. This is because, unfortunately, the CAR T-cell therapy is not available right away. There is a process. It has to be approved by the insurance. They have to schedule apheresis, and then you have to wait for manufacturing time. The fastest CAR T is axicabtagene ciloleucel, and it takes about 17 days.

Let’s say I see a patient today. I tell him or her, “You will be dealing with CAR T if everything goes smoothly within a month.” That month is critical how to keep the patient stable. My recommendation is to refer patients with high-risk diffuse large cell lymphoma to a CAR T-cell evaluation.

In regard to the available options for CAR T-cell therapy, we have 2 options approved so far. We have axi-cel—axicabtagene ciloleucel—and tisagenlecleucel. There are differences in the structure of the CAR T-cell. One, the difference is a costimulatory. The costimulatory is CD28 in axi-cel [axicabtagene ciloleucel] 4-1BB. In tisagenlecleucel, we cannot say that more than 1 is better than another because they weren’t compared head-to-head. However, in my experience, I feel the tisagenlecleucel is less toxic, so I tend to use tisagenlecleucel in older patients or patients who have more comorbidities because the neurotoxicity, the CRS [cytokine release syndrome], is less.

With tisagenlecleucel, in patients who have high tumor burden disease, you don’t tend to see a very good response, so that’s why for patients who have high tumor burden—we can see it in about half the patients—we tend to use more axicabtagene ciloleucel, because the CD28 works a little faster. However, that is my own experience. I don’t know if others have a different experience. There were not comparator head-to-heads, but that’s the way I assess how to choose which product. If a patient has an aggressive disease, you know that with axicabtagene ciloleucel you’re going to have in a shorter period of time than tisagenlecleucel. That takes around 23, 24 days. As opposed to tisagenlecleucel, that is almost a week earlier, so that’s also something to keep in consideration.

In terms of lisocabtagene maraleucel, it’s another 4-1BB, a CAR T cell. The way it’s made is that it has a 1:1 CD4/CD8 T cells that improve the chance to have a better memory of naïve T cells that have better expansion, especially more persistence. That’s the rationale of using this type of technology. It’s not approved, but we expect it to be approved with the same label. The question is if you are adding another product, then how are you going to choose? It’s going to be based on the safety profile basically and the familiarity of the doctor. We want to treat patients with the safest product. So far, the toxicity profile looks manageable, a little similar to other CAR Ts, so we just have to be more aware of how to use this product, to use it in real life.

John M. Burke, MD: I have an open question for anybody who would like to answer. Is there a difference between the effectiveness of these products, and is there a difference between the toxicity profiles? Did we just get better over time at managing the toxicities? Can you guys comment on how we are managing those toxicities differently maybe now than in the early days of CAR T-cell therapy?

Nathan H. Fowler, MD: I think we are getting better at managing them. Very early on we didn’t recognize what a lot of the toxicities were, so there was a delayed response. For example, many of these patients now, when they develop certain levels of neurotoxicity or cytokine release, we move them directly to the ICU [intensive care unit] for very close observation. Before, unfortunately, many of these patients really decompensated before we got aggressive. Many times, that monitoring includes MRIs, neurological consults, lumbar punctures, and aggressive uses of steroids and anti–IL-6 when patients start to show signs of decompensation.

From my impression, even moving that early intervention ahead 1 or 2 days often changes the outcome. We were using steroids and anticytokine drugs before, but we intervene with them a little earlier and we monitor patients closely. I think the outcomes are better because we’re better at recognizing the adverse events.

Grzegorz S. Nowakowski, MD: I would agree here completely with Nathan. We definitely are better at recognizing the toxicity. Also, what has changed is that people now have more experience in many centers that treat a volume of CAR T-cell patients and a specialized team that focuses on care of those patients. They’re very good and skilled now at recognizing those toxicities earlier.

I would bring another issue too for a lot of patients. Particularly for the older patients or patients willing to travel for different reasons, sometimes social reasons, this really gets to be an access problem. This is because we have those centers, which do perform CAR T-cell therapy and have a relatively high volume of patients. On the other hand, in a lot of smaller community types, this therapy is not available. For many patients, that’s a significant barrier. We’re trying to overcome those barriers and provide the social support and financial support and as much medical support as we can. But a lot of those older patients will not be able to consider actual therapy, which requires significant travel or hospitalization. That’s another thing to change, even as we are getting better in recognizing toxicity.

John M. Burke, MD: Good, OK.

Transcript Edited for Clarity