Use of Early Intrathecal Therapy to Manage High-Grade ICANS (2024)

Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy is effective in treating relapsed or refractory B-cell non-Hodgkin lymphoma. However, high-grade (≥3) immune effector cell-associated neurotoxicity syndrome (ICANS) remains a treatment-limiting complication.^1,2 ICANS is currently managed primarily with corticosteroids. Despite their efficacy, greater cumulative doses of corticosteroids are associated with inferior progression-free survival (PFS) and overall survival (OS) among patients.³ However, current alternatives to corticosteroids for ICANS are not widely used or particularly efficacious.^4,5

We have increasingly used intrathecal hydrocortisone with or without intrathecal chemotherapy to treat patients with high-grade and steroid-refractory ICANS.⁶ We report a series of patients with relapsed or refractory B-cell non-Hodgkin lymphoma and high-grade ICANS, detailing outcomes of those who received early intrathecal therapy with steroids compared with those who did not.

The Medical College of Wisconsin Institutional Review Board approved this case series and waived informed consent because it did not involve direct contact with patients. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.

For this study, we used data from patients enrolled in 2 clinical trials (NCT03019055 and NCT04186520) and from patients receiving commercial CAR T-cell products. We performed a retrospective review of patients with relapsed or refractory B-cell non-Hodgkin lymphoma who developed high-grade ICANS after treatment with (1) commercial anti-CD19 CAR T cells or (2) bispecific lentiviral anti-CD19 and anti-CD20 CAR T cells between 2018 and 2021.

Survival curves were constructed using the Kaplan-Meier method. Continuous variables were compared using the Mann-Whitney test. Statistical significance was defined as P < .05 in a 2-sided test. All analyses were performed using GraphPad Prism version 9.3.1 (GraphPad Inc).

Of 74 patients who received CAR T-cell therapy, 15 (20.3%) developed high-grade ICANS. These 15 patients had a mean (SD) age of 64.9 (10.8) years; 8 (53.3%) were men and 7 (46.7%) were women. In terms of treatment, 8 (53.3%) were treated with axicabtagene ciloleucel and 7 (46.7%) were treated with an investigational agent.

Of the 15 patients with high-grade ICANS, 7 (46.7%) had steroid-refractory ICANS; they were treated with early intrathecal therapy within 5 days of developing high-grade ICANS (Table). CAR T cells were detected in all 6 cerebrospinal fluid specimens tested (a sample was not available for 1 patient). All 7 patients recovered from ICANS, with the results of the temporal course suggesting improvement associated with intrathecal therapy. The estimated 1-year PFS and OS was 57.1%, with a median follow-up of 611 days (range, 184-953 days) from CAR T-cell infusion among surviving patients (Figure, A). All living patients remained in complete remission at last follow-up.

Three patients received additional treatment (anakinra) for steroid-refractory ICANS. The median cumulative corticosteroid dose was 713 mg (range, 446-914 mg) of dexamethasone equivalents (Figure, B), and the median total duration of corticosteroid use was 35 days (range, 22-43 days). From the time a patient developed high-grade ICANS, it took a median of 6 days (range, 1-15 days) to improve to grade 1 ICANS. From the time of intrathecal therapy administration for high-grade ICANS, it took a median of 2 days (range, 1-5 days) to improve to grade 2 and a median of 5 days (range, 1-11 days) to improve to grade 1 (Table). All patients who received anakinra died of infectious complications.

Seven patients did not receive intrathecal therapy for high-grade ICANS, and 1 received late intrathecal therapy (ie, intrathecal hydrocortisone 24 days after developing ICANS). Of these patients, 4 (50.0%) had steroid-refractory ICANS. Estimated 1-year PFS and OS was 18.8% for all patients and 0% for patients with steroid-refractory ICANS (Figure, A). Two patients with nonsteroid-refractory ICANS were alive and remained in complete remission at the last follow-up (range, 308-580 days). Three patients with steroid-refractory ICANS received additional treatment (2 received cyclophosphamide and 1 received anakinra). Patients with steroid-refractory ICANS had a median duration of 50 days (range, 23-62 days) of corticosteroid use and a median cumulative dose of 962.5 mg (range, 876-1083) of dexamethasone equivalents, both greater than that for patients treated intrathecally (Figure, B). Of 4 patients with steroid-refractory ICANS, the syndrome did not resolve for 2 (50.0%) and it took 13 and 22 days for improvement to grade 1 in the other 2.

The results of this case series suggest that early intrathecal therapy is feasible and has clinical efficacy in the management of high-grade ICANS. For patients with steroid-refractory ICANS in this study, the duration and cumulative dose of corticosteroids was lower, the time to recovery to grade 1 ICANS was shorter, and PFS and OS were greater among patients who received early intrathecal treatment. This data set is limited by the heterogeneity of the patients, disease, and ICANS treatments. However, our findings suggest there is a correlation among early intrathecal treatment and improved clinical outcomes.

In conclusion, 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.

Accepted for Publication: January 7, 2022.

Published Online: March 10, 2022. doi:10.1001/jamaoncol.2022.0070

Corresponding Author: Nirav N. Shah, MD, MS, Blood and Marrow Transplant and Cellular Therapy Program, Division of Hematology and Oncology, Medical College of Wisconsin, 9200 W Wisconsin Ave, Milwaukee, WI 53226 (nishah@mcw.edu).

Author Contributions: Dr Shah had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Zurko, Hari, Shah.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Zurko, Hari, Shah.

Critical revision of the manuscript for important intellectual content: Johnson, Aschenbrenner, Fenske, Hamadani, Hari, Shah.

Statistical analysis: Zurko.

Obtained funding: Hari.

Administrative, technical, or material support: Zurko, Johnson, Aschenbrenner, Fenske, Hari.

Supervision: Hamadani, Hari, Shah.

Conflict of Interest Disclosures: Dr Johnson reported receiving research support from Miltenyi Biotec. Dr Aschenbrenner reported receiving personal fees for serving on speakers’ bureaus for Astellas, Kite, Sanofi Genzyme, and Incyte and on advisory boards for Astellas, Incyte, Omeros, EUSA Pharma, and Janssen, all outside the submitted work. Dr Fenske reported receiving research funding from Novartis, Portola, Curis, and TG Therapeutics; and receiving consulting and/or speaking fees from Adaptive Biotechnologies, ADC Therapeutics, AbbVie, AstraZeneca, BeiGene, Bristol Myers Squibb, Biogen, CSL Therapeutics, Karyopharm, Kite (Gilead), Kyowa, MorphoSys, Pharmacyclics, Sanofi, Servier Pharmaceuticals, TG Therapeutics, and Verastem, all outside the submitted work. Dr Hamadani reported receiving research support and/or funding from Takeda, ADC Therapeutics, Spectrum Pharmaceuticals, and Astellas; receiving institution research funding from Janssen R&D, Celgene, Merck, MedImmune, Seattle Genetics (now Seagen), and Millennium Pharmaceuticals; receiving consulting fees from Incyte, ADC Therapeutics, Omeros, MorphoSys, Kite, Genmab, Seagen, Gamida Cell, and Novartis; and receiving speakers’ bureau fees from Sanofi Genzyme, AstraZeneca, BeiGene, and ADC Therapeutics, all outside the submitted work. Dr Hari reports receiving grants and personal fees from Bristol Myers Squibb/Celgene, Takeda, Amgen, and Janssen; receiving personal fees from Legend, Sanofi Genzyme, Karyopharm, AbbVie, and GlaxoSmithKline; and being employed by Iovance, all outside the submitted work. Dr Shah reports participating on advisory boards and receiving personal/consulting fees for Kite Pharma, TG Therapeutics, Miltenyi Biotec, Lilly, Bristol Myers Squibb, Epizyme, Legend, Incyte, Novartis, and Umoja; and receiving research funding and honoraria from Lilly, Miltenyi Biotec, Epizyme, Novartis, and Umoja, all outside the submitted work. No other disclosures were reported.