CAR t-cell therapy-related cytokine release syndrome and neurotoxicity: Real-world outcomes from a comprehensive cancer center Free

Background: Chimeric Antigen Receptor T-Cell Therapy (CAR-T) is used in the treatment of relapsed/refractory hematologic malignancies, such as multiple myeloma, B-cell lymphoma, and acute lymphoblastic leukemia. Despite the durable, efficacious clinical responses, these therapies are associated with a serious adverse effect profile, most notably, cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). In the CAR-T clinical trials, rates of CRS and neurotoxicity have ranged from 50-90% and 20-80%, respectively, across different products. Given these concerns, more real-world studies need to be conducted to investigate the safety outcomes in broader, general populations.

Objective: The purpose of this study was to compare real-world outcomes from a comprehensive cancer center to the pivotal trials that led to the FDA approvals of various CAR-T products.

Methods: This is a retrospective cohort study conducted in adult patients (≥18 years old) with hematologic malignancies who received FDA-approved CAR-T therapy at USC Norris Comprehensive Cancer Center between January 2022 and December 2024. Treatment options included ciltacabtagene autoleucel, brexucabtagene autoleucel, and axicabtagene ciloleucel. Those enrolled on investigational protocols were excluded from the study. The primary outcome was the incidence of CRS and neurotoxicity/ICANS, graded and scored by the treating physician according to the American Society of Transplant and Cellular Therapy (ASTCT) criteria. Secondary outcomes included use of tocilizumab, corticosteroids, vasopressors, anakinra, intrathecal chemotherapy, dasatinib, and thiamine; length of stay; survival at 100 days and 1 year. Data were collected through chart review of the electronic medical record and analysis included descriptive statistics.

Results: 53 patients were included in the study. Most patients receiving axi-cel experienced grade 1 or 2 CRS, with only three patients experiencing grade ≥3 CRS. The incidence of CRS was lower here compared to ZUMA-1 and ZUMA-5. Axi-cel had the highest rate of neurotoxicity in our study. The incidence of grade 1 or 2 neurotoxicity was similar to trials, but grade ≥3 was lower here. Most patients receiving brexu-cel experienced grade 1 or 2 CRS, with only one patient experiencing grade ≥3 CRS. The incidence of CRS was lower here compared to ZUMA-2 and ZUMA-3. Patients experienced a more diverse range of neurotoxicity, but the rates were still lower than in the trials. Patients receiving cilta-cel had a lower incidence of CRS than in CARTITUDE-1 and had no neurotoxicity. None of our patients experienced grade ≥4 CRS and only one patient experienced grade 4 neurotoxicity. For supportive care, approximately 75% of the patients received tocilizumab and 50% received dexamethasone, with a few patients needing anakinra and vasopressors.

Discussion/Conclusion: CAR-T is associated with CRS and neurotoxicity/ICANS, though most cases were grade 1-2 and required minimal supportive care in our study. The incidences of CRS and ICANS were slightly more favorable than what was seen in the pivotal trials, possibly due to the higher and earlier utilization of tocilizumab and dexamethasone. These findings validate the safety profile of CAR-T outside of the clinical trial setting and showcase our institution's ability to provide safe outcomes in our patients.