Early Intrathecal Therapy Appears Feasible, Efficacious for ICANS in R/R B-cell Non-Hodgkin Lymphoma

Patients with relapsed/refractory B-cell non-Hodgkin lymphoma who experienced grade 3 or higher immune effector cell–associated neurotoxicity syndrome who were treated with early intrathecal therapy experienced improved survival.

Early intrathecal therapy may help combat grade 3 or higher immune effector cell–associated neurotoxicity syndrome (ICANS) and decrease treatment-related mortality for patients with relapsed/refractory B-cell non-Hodgkin lymphoma, according to a study published in JAMA Oncology.

ICANS resolved in all 7 patients, and findings from the temporal course indicated that the improvement was associated with intrathecal therapy. The estimated 1-year progression-free survival (PFS) and overall survival (OS) was 57.1%, and the median follow-up for surviving patients was 611 days from the time of CAR T-cell infusion. Four patients had steroid-refractory ICANS. Investigators reported an estimated 1-year PFS and OS of 18.8% for all patients and 0% for those with steroid-refractory ICANS. As of the last follow-up, all living patients remained in complete remission.

“Intrathecal therapy may be a valuable central nervous system-directed treatment for high-grade and/or steroid-refractory ICANS and an alternative to systemic immunosuppression, potentially reducing treatment-related mortality associated with CAR T-cell therapy. Further prospective investigation is indicated to validate these findings,” investigators of the study wrote.

This study used data from 2 clinical trials (NCT03019055 and NCT04186520) examining CAR 20/19 T cells in relapsed/refractory B-cell malignancies. Data were also used from patients who were treated with commercial CAR T-cell therapy. The analysis included those who developed high-grade ICANS after treatment with either anti-CD19 CAR T-cells or bispecific lentiviral anti-CD19 and anti-CD20 CAR T-cells between 2018 and 2021.

A total of 74 patients were analyzed who received CAR T-cell therapy, 15 of whom developed high-grade ICANS following treatment. The mean age was 64.9 years and 8 patients were men. Additionally, 8 patients were treated with axicabtagene ciloleucel (Yescarta) and 7 were treated with an investigational agent.

Of those who developed high-grade ICANS, 7 patients were steroid-refractory and were treated with intrathecal therapy within 5 days of development. In 6 patients, CAR T-cells were detected in the cerebrospinal fluid.

Additional treatment with anakinra (Kineret) was included for patients with steroid-refractory ICANS. Patients received a median cumulative corticosteroid dose of 713 mg of dexamethasone equivalents for a median duration of 35 days. From the onset of high-grade ICANS, it took 6 days to resolved to grade 1 ICANS. After administration of intrathecal therapy for high-grade ICANS, investigators reported that it took a median of 2 days to resolve to grade 2 and a median of 5 days to improve to grade 1. All patients treated with anakinra died of infection complications. Intrathecal therapy was not administered to 7 patients, and 1 patient received late intrathecal therapy 24 days after developing ICANS.

A total of 2 patients with non-steroid refractory ICANS were alive and in complete remission at the last follow-up. Moreover, 3 patients with steroid-refractory ICANs received additional treatment. Those with steroid-refractory ICANS had a median duration of treatment with corticosteroids of 50 days and a median cumulative dose of 962.5 mg of dexamethasone equivalents. Steroid-refractory ICANS did not resolve for 2 patients, and it took 13 and 22 days, respectively, for it to improve to grade 1 in the remaining 2 patients.

Reference

Zurko JC, Johnson BD, Aschenbrenner E, et al. Use of early intrathecal therapy to manage high-grade immune effector cell-associated neurotoxicity syndrome. JAMA Oncol. Published Online March 10, 2022. doi:10.1001/jamaoncol.2022.0070