title: Cytokine Release Syndrome After Chimeric Antigen Receptor T Cell Therapy for Acute Lymphoblastic Leukemia.
abstract: OBJECTIVE
  Initial success with chimeric antigen receptor-modified T cell therapy for relapsed/refractory acute lymphoblastic leukemia is leading to expanded use through multicenter trials. Cytokine release syndrome, the most severe toxicity, presents a novel critical illness syndrome with limited data regarding diagnosis, prognosis, and therapy. We sought to characterize the timing, severity, and intensive care management of cytokine release syndrome after chimeric antigen receptor-modified T cell therapy.
  
  
  METHODS
  Retrospective cohort study.
  
  
  METHODS
  Academic children's hospital.
  
  
  METHODS
  Thirty-nine subjects with relapsed/refractory acute lymphoblastic leukemia treated with chimeric antigen receptor-modified T cell therapy on a phase I/IIa clinical trial (ClinicalTrials.gov number NCT01626495).
  
  
  METHODS
  All subjects received chimeric antigen receptor-modified T cell therapy. Thirteen subjects with cardiovascular dysfunction were treated with the interleukin-6 receptor antibody tocilizumab.
  
  
  RESULTS
  Eighteen subjects (46%) developed grade 3-4 cytokine release syndrome, with prolonged fever (median, 6.5 d), hyperferritinemia (median peak ferritin, 60,214 ng/mL), and organ dysfunction. Fourteen (36%) developed cardiovascular dysfunction treated with vasoactive infusions a median of 5 days after T cell therapy. Six (15%) developed acute respiratory failure treated with invasive mechanical ventilation a median of 6 days after T cell therapy; five met criteria for acute respiratory distress syndrome. Encephalopathy, hepatic, and renal dysfunction manifested later than cardiovascular and respiratory dysfunction. Subjects had a median of 15 organ dysfunction days (interquartile range, 8-20). Treatment with tocilizumab in 13 subjects resulted in rapid defervescence (median, 4 hr) and clinical improvement.
  
  
  CONCLUSIONS
  Grade 3-4 cytokine release syndrome occurred in 46% of patients following T cell therapy for relapsed/refractory acute lymphoblastic leukemia. Clinicians should be aware of expanding use of this breakthrough therapy and implications for critical care units in cancer centers.
authors.affiliation: 1Division of Critical Care Medicine, Department of Anesthesia and Critical Care, The Children's Hospital of Philadelphia and The University of Pennsylvania Perelman School of Medicine, Philadelphia, PA. 2Division of Oncology, Department of Pediatrics, The Children's Hospital of Philadelphia and The University of Pennsylvania Perelman School of Medicine, Philadelphia, PA. 3Center for Cellular Immunotherapies, Department of Pathology and Laboratory Medicine, The University of Pennsylvania Perelman School of Medicine, Philadelphia, PA. 4Department of Biostatistics and Epidemiology, The University of Pennsylvania Perelman School of Medicine, Philadelphia, PA. 5Division of Hematology-Oncology, Department of Medicine, Abramson Cancer Center, The University of Pennsylvania Perelman School of Medicine, Philadelphia, PA.
authors.forename: Julie C
authors.initials: JC
authors.lastname: Fitzgerald
authors.forename: Scott L
authors.initials: SL
authors.lastname: Weiss
authors.forename: Shannon L
authors.initials: SL
authors.lastname: Maude
authors.forename: David M
authors.initials: DM
authors.lastname: Barrett
authors.forename: Simon F
authors.initials: SF
authors.lastname: Lacey
authors.forename: J Joseph
authors.initials: JJ
authors.lastname: Melenhorst
authors.forename: Pamela
authors.initials: P
authors.lastname: Shaw
authors.forename: Robert A
authors.initials: RA
authors.lastname: Berg
authors.forename: Carl H
authors.initials: CH
authors.lastname: June
authors.forename: David L
authors.initials: DL
authors.lastname: Porter
authors.forename: Noelle V
authors.initials: NV
authors.lastname: Frey
authors.forename: Stephan A
authors.initials: SA
authors.lastname: Grupp
authors.forename: David T
authors.initials: DT
authors.lastname: Teachey
mesh_terms: D000293:Adolescent; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D016207:Cytokines / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000627:therapeutic use*; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use; D012008:Recurrence; D012189:Retrospective Studies; D013577:Syndrome; D018746:Systemic Inflammatory Response Syndrome / Q000139:chemically induced*; D055815:Young Adult
chemical_list: D061067:Antibodies, Monoclonal, Humanized; C000598123:CTL019 chimeric antigen receptor; D016207:Cytokines; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins; C502936:tocilizumab