Intrathecal Chemotherapy: An Alternative Treatment Strategy to Prolonged Corticosteroids for Severe CAR T Associated Neurotoxicity

Chimeric antigen receptor T cell (CAR T) therapy has become a breakthrough treatment option for patients with relapsed and refractory malignancies. Complications, such as neurotoxicity often associated with cytokine release syndrome (CRS), are self-limiting but can be life threatening or fatal. Recently, grade 3-4 neurotoxicity has shown to lower overall survival, with prolonged courses of corticosteroids having no improvement in outcomes. With the lack of efficacy and increased toxicity of high dose corticosteroids, different strategies are needed. At The James Cancer Hospital at The Ohio State University, patients with severe neurotoxicity who have not responded to corticosteroids or have rebound neurotoxicity while on corticosteroids, have been treated with intrathecal (IT) triple chemotherapy (e.g. methotrexate 15mg, cytarabine 40mg, hydrocortisone 50mg). Here, we describe 7 patients who received CD 19-directed CAR T therapy with axicabtagene ciloleucel for non-Hodgkin lymphoma and developed grade 3-4 neurotoxicity. Three patients (43%) had prior CNS disease and 6 patients (86%) had progressive disease at time of CAR T therapy. One patient received CAR T therapy on clinical trial. All patients developed CRS with a max grade of 2 and a median onset of 1 day (range, 0-6). Five patients (71%) received tocilizumab and 2 patients (29%) received siltuximab for persistent CRS. Grade 3-4 neurotoxicity developed in a median of 7 days (range, 5-11). Ferritin levels peaked after high dose corticosteroids and/or tocilizumab was given. Four patients (57%) had no response to corticosteroids and the 3 patients (43%) who initially responded, developed rebound neurotoxicity after corticosteroids were tapered. All patients received 1 dose of IT chemotherapy and had grade 3-4 neurotoxicity at time of administration. Median time to IT chemotherapy from onset of neurotoxicity was 11 days (range, 3-21). Overall, 5 patients (71%) responded to IT chemotherapy with total resolution of neurotoxicity in a median of 11 days (range, 1-18). Administration of IT chemotherapy allowed corticosteroids to be discontinued in a median of 11 days (range, 1-20) in responders. Four patients that were intubated due to severe neurotoxicity were extubated in a median of 3 days (range, 2-5) after IT chemotherapy. The 2 patients that did not respond died from infection. Five patients are still alive with 3 patients in complete response, 1 patient in partial response and 1 patient with progressive disease. Ferritin levels did not correlate with resolution of neurotoxicity. The outcomes of this cohort present a promising alternative to prolonged courses of corticosteroids, which can cause significant toxicities and increase the risk for opportunistic infections. Treatment of severe neurotoxicity with IT chemotherapy that is unresponsive to corticosteroids warrants further evaluation in prospective clinical trials.