Prompt Management of CRS After CAR T for DLBCL Is Essential
Early relapsed or primary refractory diffuse large B-cell lymphoma (DLBCL) is a setting that requires aggressive intervention. Trials of chimeric antigen receptor (CAR) T-cell therapy have shown its clear efficacy in this setting. In a Community Case Forum event in Pittsburgh, Pennsylvania, Nathan Denlinger, DO, MS, assistant professor in the division of hematology at The Ohio State University College of Medicine in Columbus, Ohio, reviewed trial data including the phase 3 ZUMA-7 trial (NCT03391466), the design of which stands out for not allowing on-protocol crossover, enabling it to show a more clear overall survival benefit. Denlinger also discussed the toxicities of CAR T-cell therapy and how management has evolved over time and differs between the 2 products approved in this setting.
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This article is part 2 of a 2-part series from a Case-Based Roundtable event.
Targeted Oncology: What were the key aspects of the design of the ZUMA-7 trial?
Nathan Denlinger, DO, MS: This [trial investigated] the original CAR T product, axicabtagene ciloleucel [axi-cel; Yescarta] vs standard of care in the second line. It’s a CD28 costimulatory product, so it’s got higher expansion, a little more toxicity, and some people feel like more efficacy—the data are tough to decipher between products. They enrolled patients with large B-cell lymphoma whose disease relapsed within the first year. Primary refractory was defined as no complete response to first line therapy, and patients were randomly assigned either to axi-cel or a standard-of-care platinum salvage like R-ICE [rituximab (Rituxan), ifosfamide, carboplatin, and etoposide] or R-GDP [rituximab, gemcitabine, dexamethasone, and carboplatin/cisplatin], followed by an autologous stem cell transplant. No crossover was allowed on this trial. So even if you had to go through with the other [regimen], you weren’t allowed to get CAR T. The primary end point, event-free survival [EFS], was the time from randomization to the earliest date of disease progression, new lymphoma therapy—[such as] if they had a manufacturing failure and had to get new therapy—or death.
What were the 5-year outcomes reported from this trial?
The outcomes were dramatically different: [a median of 10.8 months with] axi-cel vs [2.3 months with] standard of care.1 This trial was pivotal for us in the transplant world, because we used to do either [transplant or CAR T], and now we’re thinking, if you relapse within 1 year, we’re just going to do CAR T. It saves us a lot of time and effort. EFS was markedly improved, and there was also an overall survival benefit [median not reached with axi-cel vs 31.1 months with standard of care]. This overall survival benefit is probably one of the biggest reasons why we are still using it. You don’t see that a lot these days in some of the newer trials. We just don’t find trials that can produce an overall survival benefit in a study that didn’t allow crossover. That is a reason why people are looking at this and [seeing that it shows] better overall survival.
What are the most notable toxicities with axi-cel?
Some of the toxicity associated with CAR T is cytokine release syndrome [CRS]. I describe it to patients as fevers, rigors, and chills, [as if] they are septic or have an infection. I [say] to patients that when you have the flu, it’s not the flu virus that’s making you feel sick, it’s your immune system fighting the flu virus, and that’s what CAR T is. It’s your immune system ramping up, causing these symptoms. We’re much better at treating it nowadays.
The rate of grade 3 CRS was only 6%,2 and we don’t see grade 3 CRS in our hospital very often anymore, because we’re very good at getting on top of these things. Immune effector cell–associated neurotoxicity syndrome [ICANS] or neurotoxicity is still a very big issue; that’s still the main toxicity that we worry about and the one that we haven’t figured out how to prevent or fix with great certainty. [There was] a 60% rate of that, so that’s a high number of patients who are [experiencing] confusion, which makes it not the most appropriate patient for an 83-year-old with dementia with an ECOG performance status of 2. There are different things we do, but we still have a fair number of patients with grade 3 ICANS. We are very good at treating it. In this trial, only 1 patient died due to [treatment-related] grade 5 toxicity. But this is a serious AE, and one we still need to work on for CAR T.
When you hear about other CAR T-cell therapies, [such as] ciltacabtagene autoleucel [Carvykti], and other targets, from my standpoint, this neurotoxicity is specific to CD19 CAR T for lymphoma and leukemia. A lot of people have different theories, but I think it’s an on target, off tumor [toxicity]. It’s something to do with targeting CD19. CD20-type CAR Ts and other CAR T products don’t have this type of neurotoxicity, so it’s something that we deal with specifically for lymphoma and leukemia.
We see infections with CAR T and they [may] get hypogammaglobulinemia, so a fair number of our patients will end up needing intravenous immunoglobulin. They’re getting recurrent upper respiratory infections, somewhere like 20%. We’ll see cytopenias for a little while after [CAR T].
How are you using tocilizumab (Actemra) to treat CRS?
We now use tocilizumab almost in the first line. If they have a fever for more than a day, we give them tocilizumab; we don’t let them suffer. If they’re a young, healthy patient and they have a light fever and they’re not very symptomatic, we watch it for a day and see if it’ll just resolve. But then if it doesn’t, after a day, we just give them tocilizumab and a lot of times it just knocks it out. We figured out that tocilizumab doesn’t hurt the CAR T cells, so why are we holding it back? Usually, the sooner we get on top of things with tocilizumab and steroids, it doesn’t let the CRS get out of control. We see better outcomes with more aggressive upfront treatment for toxicity.
We admit everybody as soon as they have a fever. There are some programs around the country that do outpatient management for grade 1 CRS, such as a dose of tocilizumab or 10 mg of dexamethasone in the clinic. We don’t do that. We just bring them in. For some patients with lisocabtagene maraleucel [liso-cel; Breyanzi] where we’re doing outpatient [administration], we’ll bring them in, see they’re afebrile for 24 to 48 hours, and we just let them go. For axi-cel, we usually do it inpatient, and 90% of the time they’re going to get a fever. We don’t know how fast it’s going to go, but we have lots of different algorithms, and we’ve been doing it a lot now.
How did primary refractory or early relapsed status affect outcomes in ZUMA-7?
There was an [analysis] that broke out primary refractory and early relapse in ZUMA-7.3 With primary refractory, they just do a little bit worse; with early relapse, they do a little bit better. So there’s a little bit of difference there.
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DISCLOSURES: There were no known relevant disclosures.
References:
1. Westin JR, Oluwole OO, Kersten MJ, et al. 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. 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(suppl 2):S209-S210. doi:10.1016/j.jtct.2025.01.323