Reduced Incidence of ICANS and CRS After 2 Weeks Post-CAR T Supports Shortened Monitoring Period in DLBCL

After 2 weeks of treatment, CAR T-cell therapy was found to elicit hallmark adverse effects (AEs) such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) less frequently in patients with diffuse large B-cell non-Hodgkin lymphoma (DLBCL), supporting a more abbreviated toxicity monitoring period, according to a findings from a retrospective study published in Blood Advances.¹

Patients with DLBCL who underwent CAR T-cell infusion therapy (n = 475) experienced any-grade CRS at a rate of 60% and any-grade ICANS at a rate of 32.4%. In the first week post CAR T infusion, new-onset CRS and ICANS occurred at rates of 57.5% and 25.4%, respectively. During the 8 to 12 days following infusion, these rates dropped to 5.4% and 9.3%, respectively.

Most patients who developed CRS or ICANs did so within the first 2 weeks after infusion, with no new-onset CRS being reported after this period and new-onset ICANS occurring at a rate of only 0.7% after this time. Based on these findings, study authors contended that data support downgrading the 4-week monitoring period following CAR T-cell infusion to 2 weeks with the option to extend, as well as advocated for a shortened driving restriction.

“As a clinician that administers CAR-T, I’ve had many patients who have not been able to receive it because of barriers to access,” study author Nausheen Ahmed, MD, MBBS, said in a news release.² “I have patients who are traveling for 6 or even 8 hours to get treatment.”

Ahmed is an associate professor of hematologic malignancies and cellular therapeutics, assistant director of cellular therapeutics, and medical director of the BMT Survivorship Program at the University of Kansas Medical Center, in Kansas City.

The FDA previously established the Risk Evaluation and Mitigation Strategy (REMS), which requires patients who receive CAR-T cell therapy to remain within 2 hours of their authorized treatment center for at least 4 weeks post-treatment. Patients are also mandated to refrain from driving for at least 8 weeks after treatment. Notably, most authorized treatment centers have even more stringent criteria, requiring patients to stay within 30 minutes to an hour from their authorized treatment center and to have a dedicated caregiver.²

There are presently 3 CAR T-cell therapies approved by the FDA for the treatment of patients with hematologic malignancies: axicabtagene ciloleucel (Yescarta; axi-cel), tisagenlecleucel (Kymriah; tisa-cel), and lisocabtagene maraleucel (Breyanzi; liso-cel). Prior research has concluded that patients who receive these agents are at risk of developing CRS or ICANS, both of which can be fatal.

The first-of-its-kind study examined the onset and duration of CRS, ICANs, and other causes of death following CAR T-cell therapy beyond relapse in patients with DLBCL across 9 centers from March 2018 to May 2023. Most patients received a CAR T-cell agent in the third-line or later (69.8%). Patients received axi-cel (n = 216), tisa-cel (n = 158), or liso-cel (n = 101).

Furthermore, the objective of the study was to determine if the CAR T monitoring period and driving restriction could be shortened in order to increase accessibility to the agent class.

Additional findings from the study showed that after 12 days post-infusion, there were no cases of new-onset CRS and 1 case of new-onset CRS, which occurred in a patient treated with tisa-cel. After 2 weeks, infections were the most common cause of death, developing in 14.5% of patients within the first 28 days following CAR T infusion. Moreover, 2 infection-related deaths were reported in the first 28 days following infusion, with 5 such deaths occurring between 29- and 90-days following infusion. During the period closely following CAR T infusion, bacterial infections were the most common with viral infections becoming more common after 4 weeks.

Study authors noted that their research was limited by individual guidelines for patients that impacted eligibility and management of CRS and ICANS. Additionally, some variables, such as late-onset neutropenia and hypogammaglobulinemia, patient-reported outcomes, and caregiver education practices, were unable to be captured.

“We are learning that infection may be driving a lot of the non-relapse mortality and toxicity within the first few months after CAR-T infusion, so we have to shift our focus to preventing and managing infections after those two weeks,” Ahmed said in the press release.²

“Instead of the authorized treatment center trying to keep the patient locally for a long time, we could collaborate with and train community hematologists/oncologists and referring physicians to identify, initiate treatment for, and collaborate with the authorized treatment center to manage infections and other less common AEs.”

References

1. Ahmed N, Wesson W, Lutfi F, et al. Optimizing the post-CAR T monitoring period for axicabtagene ciloleucel, tisagenlecleucel, and lisocabtagene maraleucel. Blood Adv. Published online July 23, 2024. doi:10.1182/bloodadvances.2023012549
2. FDA-mandated CAR-T monitoring period could be halved. News release. American Society of Hematology. July 24, 2024. Accessed July 24, 2024. https://www.eurekalert.org/news-releases/1051856