Early Split Between Responders and Others Shown With CAR T in DLBCL

Two phase 3 clinical trials of chimeric antigen receptor (CAR) T-cell therapies have supported their use in patients with early relapsed or primary refractory diffuse large B-cell lymphoma (DLBCL). In a Community Case Forum event in Los Angeles, California moderated by Ann F. Mohrbacher, MD, associate professor of clinical medicine at Keck Medicine of USC, reviewed the trials and the differences in their design and outcomes. In particular, she highlighted the gap between patients who responded well to treatment vs those who did not, how this can be overlooked by following the median efficacy outcomes, and stressed the lingering cytopenias and other adverse events (AEs) to look out for.

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This article is part 2 of a 2-part series from a Case-Based Roundtable event.

Targeted Oncology: What data supported the use of CAR T-cell therapy vs second-line standard-of-care in DLBCL?

Ann F. Mohrbacher, MD: ZUMA-7 [NCT03391466] is what put this on the map of using CAR T cells instead of transplant in that group of patients early relapsing in less than a year, or the primary refractory ones—that was the criteria for ZUMA-7. It was a prospective randomized trial of over 350 patients, and half of them were assigned to axicabtagene ciloleucel [axi-cel; Yescarta] with the standard lymphodepletion chemotherapy, and the other half to standard of care, a lot of which was gemcitabine plus oxaliplatin—it's not necessarily the most aggressive salvage—and then they were reevaluated. In the case of the non–CAR T patients, they were sent off to transplant if they were a full responder, which was not a high proportion of them, and the outcomes were clearly very different. The axi-cel, in terms of event-free survival [EFS], was much more successful at getting them into remission and staying in it [HR, 0.42; 95% CI, 0.33-0.55].¹ The curve doesn't quite plateau; a few of those deaths might even be infectious deaths or complications, but the gap arrives early and is sustained between the two.

I don't think looking at median overall survival [OS] is very important. It's more all or nothing. You're either out of [remission] in 6 months and you've relapsed, or you're likely to stay in it. That's where you get these EFSs that are really sustained, going down from 50% to 40%, from 1 to 4 years, but they're down to less than half of that to start with [20% EFS at 1 year] in the patients who had standard of care. The OS mostly reflects that, but remember that we did have several salvage options, some of which would be even going back to CAR T after the fact, or a late salvage of other therapies and so on. The OS differences aren't as dramatic, but they're clearly different early on, and they are sustained through time [HR, 0.73; 95% CI, 0.54-0.98].

[EFS] seems to underreport the late deaths, too. What about the person who dies of a bacteremia 4 months afterwards? That should count; EFS isn't the same as progression-free survival. Some people are still dying of late CAR T infectious problems or pancytopenia.

What were the safety outcomes reported in the ZUMA-7 trial?

Grade 3 cytokine release syndrome [CRS] is not very common [6%]; almost everybody has some CRS [92%].² It tends to be in the first 3- to 7-day period. In some of the ones who get it, it's going to last all the next week. They use tocilizumab [Actemra] in about two-thirds of these patients, steroids less commonly because we're trying not to shut off these CAR T cells, and vasopressors practically never because that would be for grade 3 or 4 toxicity. Neurotoxicity is pretty common to have, [consisting of] a little bit of confusion [in 60%]. Those tend to happen a little later and last a little longer when they happen, but most of them are less than grade 3, and steroids are a little more effective for that. Serious infections [were reported in 14%, but] I think this is an underestimate. I think the hypogammaglobulinemia occurs later, so I think they're underestimating this and not measuring it correctly. But [69%] have grade 3 neutropenia early on, and in some people it's very persistent.

How did EFS and OS outcomes differ for primary refractory vs early relapse?

It's better that you were a full responder before.³ But again [we see] the same pattern. Most people are going to make it or not by 6 months. You're either benefit from CAR T and most stay with that benefit, or you do not, and you do or don't [respond] on your standard of care. But the primary refractory patients are definitely going to do better with CAR T than they are with standard of care, and so are the patients with early relapse.

On OS, we play catch-up with some of these patients. The [standard of care] curve pulls up. Why is that? Because they do get to bispecifics and CAR T later to come back and [improve OS]. [The curves are close in primary refractory patients], but remember, some of these patients would have gotten a CAR T or bispecifics after they relapsed. They would have gotten a third or fourth line, usually.

How did the TRANSFORM study (NCT03575351) investigate CAR T-cell therapy?

The TRANSFORM study is the updated version of the lisocabtagene maraleucel [liso-cel; Breyanzi] trials. This one was taking people with PET-positive residual disease, relapsed or refractory within 12 months. They had to have had standard R-CHOP [rituximab (Rituxan), cyclophosphamide, hydroxydaunomycin, vincristine sulfate (Oncovin), and prednisone] and they could be eligible for transplant. This was basically doing the same thing that ZUMA-7 did, except that they did allow bridging therapy. They did allow crossover if they were flunking after 2 rounds of their salvage chemotherapy. It turns out 63% of patients did cross over and get CAR T, and that's a real-world way of doing things, in some ways.⁴ Sometimes you have to give them chemotherapy.

They looked at their outcomes in the follow-up, and they still did better when they had been assigned frontline to the CAR T arm, because these are the patients who do poorly because they're refractory or early relapses, and they tend to come out of remission extremely quickly on the standard-of-care arm, in [roughly] 2 months. So, can they cross over and get [similar outcomes] for overall survival? Possibly; sometimes you have to start the chemotherapy. Their disease is too rapidly growing to wait and get their CAR T authorized, but once they get into that remission, the median EFS is incredibly long on the CAR T arm [29.5 months].

Liso-cel may be a choice for patients who [need a therapy with] a little less toxicity. The rate of neurological grade 3 events was very low, which was good, and the overall rate was only about 11%.⁵ They tend to be a little on the late side, but do not last as long with liso-cel, so it's probably a slightly gentler CAR T cell. They didn't have to use as much tocilizumab, and very little steroids were used. Again, I think they're underestimating the hypogammaglobulinemia [11%]. Lots of people have cytopenias, but I don't think they're monitoring carefully for the hypogammaglobulinemia.

What are the key takeaways from these 2 trials?

Just summarizing the 2 together, these are both the randomized trials of standard of care vs CAR T. They both had 3 to 4 years of follow-up.^1-4 For EFS, I think the average is not the meaningful thing. The EFS rate was little lower at 4 years in ZUMA-7. But if you go back and look at the curves, I don't think these are that different. Most people with standard care are out of remission within 6 months. That's why that number is so low at 3 and 4 years on either trial.

Progression-free survival is similar, but we're comparing 3 years to 4 years. I don't think they're very different from each other. OS of 3 years to 4 years looks like it’s going to be rather similar between the 2 of them. Why is it so good in the standard of care? Because I think a lot of these people got a CAR T or bispecifics afterwards and caught up. One is not better [than the other trial] because you’re comparing the 3-year to the 4-year [outcomes]; the ZUMA-7 trial was done longer ago. I think the chance [of fatal AEs] with the CAR T is lower, so that will help your EFS. For OS, I think there's only about a 9% difference between them…There's still not a perfect plateau. When you get out past 3 years, a few people still drop off.

How prolonged are cytopenias based on earlier CAR T trials?

Most patients are still neutropenic at treatment, but the axi-cel looks a little less than liso-cel.^6-9 When you get 1 to 3 months out there, still a quarter of patients are neutropenic and thrombocytopenic. Even after 3 months, my patients want to come back.

At 1 month vs 3 months vs 12 months, most people have recovered, but not 100% and still in that 3 to 12 months, there are a lot of people still neutropenic and a little thrombocytopenic too. Beware of that, because that's what you're managing [later].

What other long-term toxicities are of concern?

Second primary malignancies are very concerning. Although this is only 3%, there was a concerning uptick with leukemias with all of these very powerful agents, including the myeloma ones.¹⁰ That is probably because they're given a lot of chemotherapy before this, and you're driving a lot of inflammation, which drives leukemia and myelodysplastic syndrome. There are other kinds of cancers they get, but there's barely an uptick in any of them, except maybe some of the skin malignancies. Most of these are people in their 60s and 70s. They get cancers and you have to stay on top of that.

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_{DISCLOSURES: There were no known relevant disclosures.}

_References:

_{1. Westin JR, Oluwole OO, Kersten MJ, et al; ZUMA-7 Investigators; Kite Members. Survival with axicabtagene ciloleucel in large B-cell lymphoma. N Engl J Med. 2023;389(2):148-157. doi:10.1056/NEJMoa2301665}

_{2. Locke FL, Miklos DB, Jacobson CA, et al; All ZUMA-7 Investigators and Contributing Kite Members. Axicabtagene Ciloleucel as second-line therapy for large B-cell lymphoma. N Engl J Med. 2022;386(7):640-654. doi:10.1056/NEJMoa2116133}

_{3. Westin JR, Oluwole OO, Kersten MJ, et al. Axicabtagene ciloleucel (axi-cel) versus standard of care (soc) in patients with primary refractory or early relapsed large B-cell lymphoma (LBCL). Transplant Cell Ther. 2025;31(2 suppl):S209-S210. doi:10.1016/j.jtct.2025.01.323}

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_{5. Abramson JS, Solomon SR, Arnason J, et al. Lisocabtagene maraleucel as second-line therapy for large B-cell lymphoma: primary analysis of the phase 3 TRANSFORM study. Blood. 2023;141(14):1675-1684. doi:10.1182/blood.2022018730}

_{6. Locke FL, Ghobadi A, Jacobson CA, et al. Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1-2 trial. Lancet Oncol. 2019;20(1):31-42. doi:10.1016/S1470-2045(18)30864-7}

_{7. Abramson JS, Palomba ML, Gordon LI, et al. Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study. Lancet. 2020;396(10254):839-852. doi:10.1016/S0140-6736(20)31366-0}

_{8. Abramson JS, Palomba ML, Gordon LI, et al. Two-year follow-up of lisocabtagene maraleucel in relapsed or refractory large B-cell lymphoma in TRANSCEND NHL 001. Blood. 2024;143(5):404-416. doi:10.1182/blood.2023020854}

_{9. Jain T, Knezevic A, Pennisi M, et al. Hematopoietic recovery in patients receiving chimeric antigen receptor T-cell therapy for hematologic malignancies. Blood Adv. 2020;4(15):3776-3787. doi:10.1182/bloodadvances.2020002509}

_{10. Elsallab M, Ellithi M, Lunning MA, et al. Second primary malignancies after commercial CAR T-cell therapy: analysis of the FDA Adverse Events Reporting System. Blood. 2024;143(20):2099-2105. doi:10.1182/blood.2024024166}