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Clinical presentation, management, and biomarkers of neurotoxicity after adoptive immunotherapy with CAR T-cells

Philipp Karschnia, Justin T. Jordan, Deborah A. Forst, Isabel C. Arrillaga-Romany, Tracy T. Batchelor, Joachim M. Baehring, Nathan F. Clement, L. Nicolas Gonzalez Castro, Aline Herlopian, Marcela V. Maus, Michaela H. Schwaiblmair, Jacob D. Soumerai, Ronald W. Takvorian, Ephraim P. Hochberg, Jeffrey A. Barnes, Jeremy S. Abramson, Matthew J. Frigault and Jorg Dietrich

Key points

  • Neurotoxicity after CAR T-cells is associated with cytokine release syndrome, serum levels of inflammatory markers correlate with severity.

  • Grade 3-4 neurotoxicity is a negative prognostic factor for overall survival, and a short course of steroids appears not to alter outcome.

Abstract

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 one patient treated with AFP-directed CAR T-cells for hepatocellular carcinoma (n=1). Twelve of the 25 patients (48%) developed grade 1-2 neurotoxicity and thirteen 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=0.030). Cytokine release syndrome occurred in 24 out 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 (p=0.013). Median overall survival of the entire cohort was 54.7 weeks. Eight patients (32%) with grade 3-4 neurotoxicity were deceased at database closure, while none died with neurotoxicity grade 1-2. High pre-treatment LDH was frequently encountered in lymphoma patients with grade 3-4 neurotoxicity and correlated negatively with progression-free survival (p=0.048). We did not find evidence that steroid use ≥7 days altered the patient's outcome when compared to <7 days of steroids. Management of CAR T-cell-mediated neurotoxicity warrants evaluation in prospective clinical trials.

  • Submitted December 27, 2018.
  • Accepted February 10, 2019.