Chimeric antigen receptor (CAR) T cells have emerged as a promising class of cell-based immunotherapy in refractory malignancies. Neurotoxicity represents a common and potentially life-threatening adverse effect of CAR T cells, and clinical experience is limited. Here, we describe the clinical presentation and management of 25 adult patients who presented with neurotoxic syndromes after CAR T-cell therapy at the Massachusetts General Hospital. This cohort includes 24 patients treated with CD19-directed CAR T cells for non-Hodgkin lymphoma (n = 23) and acute lymphoblastic leukemia (n = 1), and 1 patient treated with α-fetoprotein–directed CAR T cells for hepatocellular carcinoma (n = 1). Twelve of the 25 patients (48%) developed grade 1-2 neurotoxicity and 13 patients (52%) presented with grade 3-4 neurotoxicity. We found that lower platelet counts at time of CAR T-cell infusion were associated with more severe neurotoxicity (P = .030). Cytokine release syndrome occurred in 24 of 25 patients (96%). Serum levels of ferritin peaked with onset of neurologic symptoms, and higher ferritin levels were associated with higher neurotoxicity grade. Grade 3-4 neurotoxicity correlated negatively with overall survival (OS) (P = .013). Median OS of the entire cohort was 54.7 weeks. Eight patients (32%) with grade 3-4 neurotoxicity were deceased at database closure, whereas none died with neurotoxicity grade 1-2. High pretreatment lactate dehydrogenase was frequently encountered in lymphoma patients with grade 3-4 neurotoxicity and correlated negatively with progression-free survival (P = .048). We did not find evidence that steroid use ≥7 days altered the patient’s outcome when compared with <7 days of steroids. Management of CAR T cell–mediated neurotoxicity warrants evaluation in prospective clinical trials.

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The optimal therapy for primary mediastinal B-cell lymphoma is a subject of ongoing debate, with no accepted standard of care. We performed a retrospective analysis of 63 patients in the modern era treated with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP), with or without radiation. Median age was 37 years (range 20-82). Eighty percent had limited stage disease and 71% were bulky. By age-adjusted International Prognostic Index (IPI), 15% were low-risk, 52% low-intermediate, 27% high-intermediate and 6% high-risk. Some 77% of responding patients received consolidative radiotherapy. Overall and complete response rates were 79% and 71%. Primary induction failure occurred in 13 (21%) patients. Five-year PFS and OS were 68% and 79%, respectively. Adverse prognostic features included increased IPI, advanced stage, advanced age and multiple extranodal sites. These data demonstrate an unacceptably high rate of primary refractory disease on R-CHOP, particularly among patients with high-risk features. Novel treatment approaches are needed that reduce primary refractory disease and reliance on mediastinal radiation in young people.