Use of Intrathecal Chemotherapy for Corticosteroid-Refractory Icans in B-Cell Lymphoma Patients Treated with CART

Introduction Immune cell-associated neurotoxicity syndrome (ICANS) is a common complication of autologous anti-CD19 chimeric antigen-receptor T-cell therapy (CART) in patients with B-cell lymphoma (BCL). Corticosteroids are an effective treatment for its management, but refractory cases are increasingly observed, and no standard treatment is currently available. Objectives As migration to the central nervous system (CNS) of CAR T-cells, monocytes and related cytokines has been shown to contribute to ICANS, local treatment with intrathecal (IT) chemotherapy could be a safe and effective approach for patients with corticosteroid refractory-disease. Methods Patients with BCL developing grade 3 or higher ICANS with standard of care CART, not responsive to maximal corticosteroid for at least 48 hours, were prospectively treated at a single center with IT chemotherapy between January and August 2023. ICANS was graded according to ASTCT criteria. On the day of IT, concentration of CAR T-cells was measured by flow cytometry both on peripheral blood (PB) and cerebrospinal fluid (CSF), and a 13-cytokines panel (including interleukin 1, 2R, 4, 5, 6, 8, 10, 12, 13, 17, interferon gamma and tumor necrosis factor alpha) was measured on PB. Results Nine patients were included in the analysis. Median age was 68 (range, 32-80) and 8 (89%) patients were male; 4 (44%) patients had mantle cell lymphoma and 5 (56%) large B-cell lymphoma; the infused CART product was brexu-cel and axi-cel in 4 (44%) patients each, and liso-cel in 1 (12%). Before CART infusion, 2 (22%) patients had a history of CNS involvement, 2 (22%) required dose reduction of lymphodepleting chemotherapy, and 2 (22%) received prophylactic anakinra. Median day of ICANS onset was day 5 (3-26), and IT was used after a median of 6 (2-12) days from its onset. Before IT, the median cumulative dose of dexamethasone was 410 mg (30-951), and 5 (56%) received anakinra. On the day of IT, median serum LDH was 310 U/L (227-5490), ferritin 1880 mg/L (411-34643), and CRP 6.3 mg/L (1.3-34.6); median PB and CSF CAR T-cell concentration was 135 cells/mcL (0-1340) and 21 cells/mcL (2-66), respectively. Eight (89%) patients received 100 mg of IT cytarabine (7 with 100 mg of hydrocortisone) and 1 (11%) received 12 mg of IT methotrexate (with no hydrocortisone). After IT, the median cumulative dose of dexamethasone was 351 mg (140-1182), and 6 (67%) received anakinra. ICANS resolution was achieved in 5 (56%) patients, after a median of 8 days (1-9); among the 4 non-responders, a 2nd IT was attempted unsuccessfully in 3 cases. No significant association between PB/CSF CART or PB cytokines concentration and response to IT was observed. Conclusion IT chemotherapy can represent an effective treatment strategy for corticosteroid-refractory ICANS; larger prospective studies are needed to optimize its schedule and to identify biomarkers of response and resistance.