Abstract
This case series describes the use of early intrathecal steroid administration to manage high-grade and steroid-refractory immune effector cell-associated neurotoxicity syndrome among patients with B-cell non-Hodgkin lymphoma.
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.
Methods
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).
Results
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.
Table. Demographic and Clinical Details of 7 Patients Receiving Early Intrathecal Steroid Treatment for High-Grade ICANS.
| Patient No. | Histologic results | CAR T-cell therapy | Day of initial ICANS | Day maximum ICANS grade reached (grade) | Treatment other than steroids for ICANS | Intrathecal hydrocortisone treatment day | Intrathecal chemotherapy treatment day | Time from intrathecal therapy to grade 1 ICANS, d | Follow-up length (disease status, survival/cause of death), d |
|---|---|---|---|---|---|---|---|---|---|
| 1 | DLBCL | LV20.19 | D6 | D16 (3) | NA | D20 and D24 | D21 | 7 | 953 (CR, alive) |
| 2 | DLBCL | LV20.19 | D6 | D8 (4) | NA | D9 | NA | 5 | 835 (CR, alive) |
| 3 | DLBCL | Axi-cel | D10 | D10 (3) | NA | D13 | NA | 2 | 387 (CR, alive) |
| 4 | MCL | LV20.19 | D5 | D5 (3) | 200 mg Anakinra thrice daily for HLH (D16) | D7 | NA | 2 | 46 (PR, died of GNR sepsis) |
| 5 | DLBCL | LV20.19 | D14 | D15 (3) | 200 mg Anakinra thrice daily for 3 d (D18) | D19, D49 | D21 | 11 | 57 (CR, died of pneumonia) |
| 6 | tSMZL | Axi-cel | D6 | D9 (4) | 200 mg Anakinra thrice daily for 3 d (D14) | D10 | D12 | 6 | 31 (NA, died of GNR sepsis) |
| 7a | tFL | Axi-cel | D8 | D14 (4) | NA | D10 | D14 | 1 | 184 (CR, alive) |
Abbreviations: Axi-cel, axicabtagene ciloleucel; CAR, chimeric antigen receptor; CR, complete remission; D, day; DLBCL, diffuse large B-cell lymphoma; GNR, gram-negative rod; HLH, hemophagocytic lymphohistiocytosis; ICANS, immune effector cell-associated neurotoxicity syndrome; LV20.19, lentiviral anti-CD20 and anti-CD19 CAR T cells; MCL, mantle cell lymphoma; NA, not applicable; PR, partial response; tFL, transformed follicular lymphoma; tSMZL, transformed splenic marginal zone lymphoma.
This patient received intrathecal hydrocortisone for persistent grade 2 cytokine release syndrome on day 10, which initially resolved then recurred on day 14 as grade 4 ICANS. The syndrome then resolved to grade 1 by day 15 after the administration of intrathecal chemotherapy plus hydrocortisone.
Figure. Survival Outcomes and Early vs No or Late Intrathecal Steroid Administration to Treat High-Grade ICANS .
A, Progression-free survival among patients with high-grade immune effector cell-associated neurotoxicity syndrome (ICANS), comparing 7 who received early intrathecal steroid treatment vs 8 who received no or late intrathecal steroid treatment. B, Cumulative steroid use among patients with high-grade steroid-refractory ICANS, comparing 7 who received early intrathecal treatment vs 4 who received no or late intrathecal treatment. P values were calculated via the Fischer exact test. IT indicates intrathecal.
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.
Discussion
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.
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