A phase 2 study of prophylactic intrathecal chemotherapy to prevent high-grade immune effector cell–associated neurotoxicity syndrome

Abstract Background: Immune effector cell-associated neurotoxicity syndrome (ICANS) is a serious and potentially fatal toxicity associated with chimeric antigen receptor (CAR) T-cell therapy. Current management strategies rely on corticosteroids and supportive care, but effective prophylactic interventions remain limited. While prophylactic corticosteroids and cytokine-directed therapies like the IL-1 receptor antagonist anakinra have been explored, they carry potential risks and inconsistent efficacy. Disruption of the blood-brain barrier by cytokine surges is a key contributor to ICANS pathophysiology, and retrospective studies suggest that intrathecal (IT) chemotherapy combined with IT corticosteroids may mitigate neurologic toxicity. However, to date, IT chemotherapy has not been prospectively studied in the prophylactic setting. Study Design and Methods: This is a single-center, open-label, phase 2 trial evaluating the prophylactic use of IT methotrexate (12 mg), cytarabine (50 mg), and hydrocortisone (50 mg) in patients receiving standard-of-care axi-cel or brexu-cel for relapsed/refractory large cell or mantle cell lymphoma respectively. The study focuses on these two products due to their higher incidence and rapid onset of ICANS. Eligible participants are ≥18 years of age, have an ECOG performance status ≤2, and must be treated in an inpatient setting. Exclusion criteria include patients with acute lymphoblastic leukemia, prior allogeneic transplant, active central nervous system (CNS) malignancy, and neurologic comorbidities such as uncontrolled seizure disorder. A total of 22 participants will be enrolled (allowing for attrition), with 20 evaluable for the primary analysis. IT chemotherapy is administered on days +2 and +5 (±1 day) post-CAR T-cell infusion (which occurs on day +1). Participants are monitored for 30 days post-infusion. Cerebrospinal fluid (CSF) will be collected during IT therapy for exploratory biomarker studies. Objectives: The primary objective is to evaluate the efficacy of IT chemotherapy in preventing grade ≥3 ICANS by day +30 post-CAR T-cell infusion. Secondary endpoints include incidence of any-grade ICANS, IT-related adverse events, corticosteroid use, and anakinra use. Exploratory endpoints include time to onset and duration of ICANS and hospitalization duration. Biomarker Studies: CSF will be collected at baseline and after the second IT treatment to evaluate the impact of IT chemotherapy on T-cell amplification and cytokine production in the CNS. Flow cytometry will assess T-cell subsets and CAR T-cell presence. Cytokine profiling will be performed using a 13-cytokine panel and a multiplex immune assay to quantify inflammatory and immune-related proteins. These analyses aim to correlate neuroinflammatory signaling with clinical outcomes. Impact: This study has the potential to establish a low-cost, low-morbidity strategy for the prevention of ICANS, which remains a major challenge and unmet medical need in the administration of CAR T-cell therapy. If effective, this approach could reduce the need for systemic corticosteroids, which are associated with significant morbidity. Further, prophylactic intrathecal therapy may be generalizable across existing and emerging CAR T-cell platforms, expanding eligibility to patients who might otherwise be excluded due to a high risk of neurologic toxicity.