Low Rates of Late-Onset CAR T-Cell–Related CRS/ICANS Support Shorter AE Monitoring Periods

Olalekan O. Oluwole, MD

The relatively early onset and resolution of neurologic toxicities following axicabtagene ciloleucel (axi-cel; Yescarta) administration among patients with relapsed/refractory large B-cell lymphoma (LBCL) supports the potential for decreased post-infusion monitoring periods and even outpatient CAR T-cell therapy administration, according to Olalekan O. Oluwole, MD. 

Since the development and subsequent regulatory approvals of CAR T-cell therapies for patients with LBCL and other malignancies, investigators have worked to determine the optimal length of monitoring for neurologic adverse effects (AEs) that prioritizes patient safety and quality of life (QOL), Oluwole noted in an interview with OncLive®. In the pivotal phase 3 ZUMA-7 trial (NCT03391466), which supported the 2022 FDA approval of axi-cel for the treatment of adult patients with relapsed/refractory LBCL, the respective rates of grade 3 or higher cytokine release syndrome (CRS) and neurologic effects in patients who received axi-cel (n = 170) were 6% and 21%.1,2

Based on the incidence rates of neurologic AEs among patients receiving CAR T-cell therapy, the axi-cel prescribing information requires patients to be monitored daily for 7 days at the infusion center and to remain within close proximity of a certified health care facility for a minimum of 4 weeks following infusion.3

At the 2025 Transplantation and Cellular Therapy Meetings, Oluwole and colleagues presented findings from a retrospective analysis investigating the rates of CRS and neurologic toxicities that persisted in patients with relapsed/refractory LBCL who received axi-cel in the ZUMA-7 trial and the phase 1 ZUMA-1 trial (NCT02348216).4 This study showed that at 2 weeks post-infusion, 53% of patients from the ZUMA-7 cohort had achieved durable resolution of CRS/neurologic AEs (defined as resolution lasting at least 3 consecutive days). Between 2 and 4 weeks post-infusion, 1 patient had developed a grade 1 neurologic AE.

In the ZUMA-1 cohort, at 2 weeks post-infusion, 56% of patients had achieved durable resolution of CRS/neurologic AEs. Between 2 and 4 weeks post-infusion, 3 patients had developed a neurologic AE.

“[The fact that most] patients already had complete resolution [of neurologic AEs] and [few] had any form of new-onset [toxicities 2 weeks post-infusion] opens the door for consideration,” Oluwole emphasized. “Do these patients need to stay [for monitoring] at the academic center for a month?’

In the interview, Oluwole discussed the rationale and design of this study, the implication that patients may not need prolonged hospital monitoring following CAR T-cell therapy infusion, and how the evolution of CAR T-cell therapy has ushered in refined AE management practices and considerations for outpatient administration.

Oluwole is an assistant professor of medicine at Vanderbilt Hematology Clinic, Vanderbilt Health in Nashville, Tennessee.

OncLive: What was the rationale for investigating the incidence of CRS and other neurotoxicities at and beyond 2 weeks following axi-cel infusion?

Oluwole: CAR T-cell therapy is a one-time infusion. As the CAR T cells go into the body, they engage the tumor and produce a lot of inflammatory cytokines, which is part of how they eliminate the tumor. They work right away, because they are fully active at the time of infusion.

We expect most of the AEs to happen early. That was what we have always observed. However, the FDA requirements for [CAR T-cell therapy] administration require us to monitor patients for approximately 28 days close to the treatment center. Now that we’ve done a lot of [CAR T-cell therapy infusions], we asked: Is it truly what we thought that most of the AEs will happen and resolve quickly, or do [patients] still have [a high] risk [of developing these AEs] going far out to 28 days? [We wanted to evaluate] what we have observed among the patients we have treated and whether the risks truly [persist] for the whole 28-day period or just a portion of that time.

What patient population was included in the study you and your colleagues conducted?

These were patients with LBCL. That is the patient population in which we use CAR T-cell therapy most often. We needed to examine a uniform group to find the answer we needed. We could have extended this study to [include patients with] mantle cell lymphoma, acute lymphoblastic leukemia, or multiple myeloma, but fewer of those patients have been treated with [CAR T-cell therapy]. It made sense for us to eliminate a variety of diseases and just evaluate LBCL.

What were the key findings from this study?

More than half of the patients had developed CRS and/or neurological effects, and they were already discharged from the hospital within approximately 2 weeks post-infusion. It was interesting to see that beyond 2 weeks, no patients had new onset [of neurologic AEs]. A few patients may still have been recovering [from these AEs], but most had completely recovered.

How might these findings affect the future management of CAR T-cell therapy–related toxicities?

Many of these patients are farmers, office workers, and other professionals. Many have to relocate to where they receive CAR T-cell therapy. Relocation is not trivial, and patients always need a caregiver. There are assistance processes, foundations, and other methods to cushion the financial effects [of receiving CAR T-cell therapy], but there isn’t any reasonable alternative to patients being outside of their own homes.

[These findings show that] for select patients, perhaps it might be reasonable to not monitor them that closely at the academic center. Maybe they can go back home early. Maybe we can use telemedicine and other means to allow them to get an additional semblance of a return to normal in their lives.

How has the management of CAR T-cell therapy–related neurotoxicities evolved since the advent of these therapies in clinical development and practice?

All the [neurologic AEs] are directly related to CAR T-cell therapies. The approved CAR T-cell products are autologous. They [contain] mature T cells. They control the immune system; they talk to other cells in the immune system—monocytes and macrophages—and the whole [of their mechanisms of action] is what causes all these AEs.

We cannot prevent T cells from recruiting the rest of the immune system, but we can intervene early. We can use corticosteroids and tocilizumab [Actemra] earlier to reduce the AEs without affecting the efficacy of the CAR T cells. We have learned over the past year or two that earlier intervention has led to reductions in these toxicities and a shortened time that patients have these toxicities. That is partly reflective of what we saw in this retrospective analysis: by 2 weeks after the CAR T-cell [infusion], most of these AEs are over.

What does the future look like for CAR T-cell therapy application and administration?

[Approximately] 6 or 7 years ago, it was impossible to consider outpatient CAR T-cell therapy. However, everybody wants to do this now, and it is interesting to see how the toxicity management and our comfort level of care with patients [receiving CAR T-cell therapy] have evolved. We’re [developing] so many more new products that it is unrealistic for us to keep all patients in the hospital, and QOL is better outside the hospital, so it is refreshing to see that outpatient [CAR T-cell therapy ideas are] gaining momentum. We are also now finding out that it might be possible to expand [CAR T-cell therapy] research to diseases that are not cancer, such as autoimmune disorders.

References

1. FDA approves axicabtagene ciloleucel for second-line treatment of large B-cell lymphoma. FDA; April 1, 2022. Accessed March 25, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-axicabtagene-ciloleucel-second-line-treatment-large-b-cell-lymphoma?utm_medium=email&utm_source=govdelivery
2. Westin J, Oluwole OO, Kersten MJ, et al. Primary overall survival analysis of the phase 3 randomized ZUMA‑7 study of axicabtagene ciloleucel versus standard‑of‑care therapy in relapsed/refractory large B-cell lymphoma. J Clin Oncol. 2023;41(suppl 17). doi:10.1200/JCO.2023.41.17_suppl.LBA107
3. Yescarta. Prescribing information. Gilead. Updated June 2024. Accessed March 25, 2025. https://www.gilead.com/-/media/files/pdfs/medicines/oncology/yescarta/yescarta-pi.pdf
4. Incidence of cytokine release syndrome and neurological events in patients with relapsed or refractory large b-cell lymphoma at and beyond 2 weeks following axicabtagene ciloleucel infusion. Presented at: 2025 Transplant and Cellular Therapy Meetings; February 12-15, 2025; Honolulu, HI. Poster 311.