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

Blood. 2019 May 16;133(20):2212-2221. doi: 10.1182/blood-2018-12-893396. Epub 2019 Feb 26.

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 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.

MeSH terms

  • Adult
  • Aged
  • Biomarkers / analysis
  • Carcinoma, Hepatocellular / therapy
  • Cohort Studies
  • Disease Management
  • Female
  • Humans
  • Immunotherapy, Adoptive / adverse effects*
  • Immunotherapy, Adoptive / methods
  • Liver Neoplasms / therapy
  • Lymphoma, Non-Hodgkin / therapy
  • Male
  • Middle Aged
  • Neurotoxicity Syndromes / diagnosis*
  • Neurotoxicity Syndromes / etiology*
  • Neurotoxicity Syndromes / therapy
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / therapy
  • Treatment Outcome
  • Young Adult

Substances

  • Biomarkers