Outpatient CAR T-Cell Therapy: ZUMA-24 Study of Axi-Cel Safety

As chimeric antigen receptor (CAR) T-cell therapy becomes approved for more indications, its accessibility becomes of greater and more pressing importance. Recent research efforts have focused on fine-tuning the CAR T experience before, during, and after infusion to make the process as seamless as possible, reducing burdens on patients, providers, and health care facilities. Additionally, regulatory actions, like the FDA removing the risk evaluation and mitigation strategies (REMS) for CAR T-cell therapies earlier this year, expand upon these research efforts.

In an interview with Targeted Oncology, Lori Leslie, MD, discussed the phase 2 ZUMA-24 study (NCT05459571), which was investigating whether the CAR T-cell therapy axicabtagene ciloleucel (axi-cel; Yescarta) could safely be given in the outpatient setting with prophylactic steroids and early toxicity management for the treatment of diffuse large B-cell lymphoma (DLBCL).

Leslie, hematologist and medical oncologist at Hackensack University Medical Center in Hackensack, NJ, explained that the study yielded positive results, with lower rates of hospitalization, intensive care unit admittance, and duration in hospital with no drop in efficacy. Further, the safety profile of outpatient axi-cel in ZUMA-24 was improved compared with inpatient administration, likely due to the prophylactic and early management strategies. All incidences of cytokine release syndrome (CRS) were grades 1 and 2, and neurologic events like immune effector cell-associated neurotoxicity syndrome (ICANS) occurred at rates comparable to inpatient axi-cel administration. Regarding quality of life, patients reported an increased quality of life above the baseline mean by months 3 and 6 following infusion, indicating a clinically meaningful improvement.

Here, Leslie discusses the rationale of the study, its findings, and next steps in this line of research.

Targeted Oncology: What was the rationale for this study?

Lori Leslie, MD: CAR T-cell therapy has changed the landscape of relapsed/refractory DLBCL dramatically in the past few years. It was first approved in 2017 for patients who had extensive prior treatment and no other treatment options and was very effective there. It’s been moved up in the landscape and is now approved in second-line and beyond DLBCL in certain situations. We are now actually even studying it in the frontline setting.

Throughout all this experience, some of the main barriers to CAR T administration are the possible [adverse] effects, which include cytokine release syndrome, over-activation of the immune system, as well as ICANS or neurologic toxicities. With experience, as time's gone on, we've realized that we can intervene earlier and do even preventative treatment with tocilizumab [Acemtra] and or corticosteroids to help mitigate the risk of some of the more severe toxicities. And as CAR T has been more predictable in terms of [adverse] effects due to these more proactive measures for toxicity management, we hypothesize that maybe not all patients need to be in the hospital for their entire CAR T experience. Historically, patients were in the hospital to get their cells and be monitored for toxicity for about 2 weeks.

ZUMA-24 is looking at a systematic way of reviewing outpatient CAR T based on real-world experience when using these more preventative measures. These were patients that were otherwise eligible for the approved indications for CAR T-cell therapy, axi-cel specifically in this study, for DLBCL. They got the cohort 6 management, which is the prophylactic corticosteroid, on the first few days of their infusion. Then patients were infused outpatient, and they were monitored at least daily at the treatment center. Some centers folded in telemedicine visits in the afternoon or monitoring in a full-day room. The primary outcome was looking at the rates and severity of CRS and ICANS. Other secondary measures were length in the hospital and patient-reported outcomes. Later, we looked at cost of care.

This is a way to try to make CAR T a bit more tolerable from a[n adverse] effect perspective, patient experience perspective, and cost of health care perspective.

What were your findings? Was anything particularly surprising?

We found, as we had seen in other studies, cytokine release and neurotoxicity was relatively common, occurring in 90% and 80% of patients overall. But most of those were less severe. It seemed that the corticosteroid use was able to mitigate that risk of more severe toxicity, such that there were no grade 3 or higher CRS events. In terms of the neurologic events, most of them were grade 1 to 2, with a small proportion of patients having grade 3 or 4 compared with historical percentages. It was a favorable reduction in the rates of more significant neurologic toxicities as well with those earlier interventions.

The CAR T was administered outpatient but, of course, at the provider's discretion, [patients] could be admitted to the hospital for management. The majority of patients did end up getting hospitalized. But we did also find that the hospitalizations were briefer on average than what was experienced previously, when there was basically a 2-week mandatory hospitalization.

That also could impact the cost of care and the use of inpatient resources, which is really important because CAR T approvals are expanding across hematologic malignancies and even into tumors. So, so we have more and more tumor types that are potentially eligible for CAR T. The space to actually administer CAR T solely inpatient is limited, so sometimes you have to time and delay treatments because there's physically no space to have more patients. By doing outpatient CAR T, hopefully we will free up some of that very valuable inpatient resource to allow continued expansion of this novel therapy.

What questions do you still have?

Though we've made great advancements in learning how to manage CAR T toxicity and who may be at higher risk of certain CAR T toxicities, it's certainly not perfect. Significant toxicities still occur, and patients still need to be in the hospital. I think moving forward, especially as we move these therapies as early in the frontline in certain diseases, further fine-tuning about how to risk-stratify patients in terms of what [adverse] effects they may have. [We also have] to further fine-tune our CAR T constructs so that we can have enhanced tumor killing with less over-activation of the immune system. We’re doing that with allo[geneic] CAR Ts, different targets, and other combination therapies that can mitigate the risk of some of these toxicities. There is still a lot of work to do, but it is really a hopeful space.

REFERENCE:

Leslie LA, Baird JH, Finn IW, et al. Outpatient axicabtagene ciloleucel for relapsed/refractory large B-cell lymphoma: ZUMA-24 primary analysis. Am J Cancer Res. 2025;15(8):3417-3433. ISSN:2156-6976/ajcr0166149