title: Addition of interleukin-6 inhibition with tocilizumab to standard graft-versus-host disease prophylaxis after allogeneic stem-cell transplantation: a phase 1/2 trial.
abstract: BACKGROUND
  Interleukin 6 mediates graft-versus-host disease (GVHD) in experimental allogeneic stem-cell transplantation (allogeneic SCT) and represents an attractive therapeutic target. We aimed to assess whether the humanised anti-interleukin-6 receptor monoclonal antibody, tocilizumab, could attenuate the incidence of acute GVHD.
  
  
  METHODS
  We undertook a single-group, single-institution phase 1/2 study at the Royal Brisbane and Women's Hospital Bone Marrow Transplantation unit, QLD, Australia. Eligible patients were 18-65 years old and underwent T-replete HLA-matched allogeneic SCT with either total body irradiation-based myeloablative or reduced-intensity conditioning from unrelated or sibling donors. One intravenous dose of tocilizumab (8 mg/kg, capped at 800 mg, over 60 mins' infusion) was given the day before allogeneic SCT along with standard GVHD prophylaxis (cyclosporin [5 mg/kg per day on days -1 to +1, then 3 mg/kg per day to maintain therapeutic levels (trough levels of 140-300 ng/mL) for 100 days plus methotrexate [15 mg/m(2) on day 1, then 10 mg/m(2) on days 3, 6, and 11]). The primary endpoint was incidence of grade 2-4 acute GVHD at day 100, assessed and graded as per the Seattle criteria. Immunological profiles were compared with a non-randomised group of patients receiving allogeneic SCT, but not treated with tocilizumab. This trial is registered with the Australian and New Zealand Clinical Trials Registry, number ACTRN12612000726853.
  
  
  RESULTS
  Between Jan 19, 2012, and Aug 27, 2013, 48 eligible patients receiving cyclosporin and methotrexate as GVHD prophylaxis were enrolled into the study. The incidence of grade 2-4 acute GVHD in patients treated with tocilizumab at day 100 was 12% (95% CI 5-24), and the incidence of grade 3-4 acute GVHD was 4% (1-13). Grade 2-4 acute GVHD involving the skin developed in five (10%) patients of 48 treated with tocilizumab, involving the gastrointestinal tract in four (8%) patients; there were no reported cases involving the liver. Low incidences of grade 2-4 acute GVHD were noted in patients receiving both myeloablative total body irradiation-based conditioning (12% [95% CI 2-34) and fludarabine and melphalan reduced-intensity conditioning (12% [4-27]). Immune reconstitution was preserved in recipients of interleukin-6 receptor inhibition, but qualitatively modified with suppression of known pathogenic STAT3-dependent pathways.
  
  
  CONCLUSIONS
  Interleukin 6 is the main detectable and dysregulated cytokine secreted after allogeneic SCT and its inhibition is a potential new and simple strategy to protect from acute GVHD despite robust immune reconstitution; a randomised, controlled trial assessing tocilizumab in addition to standard GVHD prophylaxis in these patients is warranted.
  
  
  BACKGROUND
  National Health and Medical Research Council and Queensland Health.
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia; Department of Bone Marrow Transplantation, The Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia.
authors.forename: Glen A
authors.initials: GA
authors.lastname: Kennedy
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
authors.forename: Antiopi
authors.initials: A
authors.lastname: Varelias
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
authors.forename: Slavica
authors.initials: S
authors.lastname: Vuckovic
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
authors.forename: Laetitia
authors.initials: L
authors.lastname: Le Texier
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
authors.forename: Kate H
authors.initials: KH
authors.lastname: Gartlan
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
authors.forename: Ping
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Diamantina Institute, University of Queensland, Brisbane, QLD, Australia.
authors.forename: Gethin
authors.initials: G
authors.lastname: Thomas
authors.affiliation: Diamantina Institute, University of Queensland, Brisbane, QLD, Australia.
authors.forename: Lisa
authors.initials: L
authors.lastname: Anderson
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
authors.forename: Glen
authors.initials: G
authors.lastname: Boyle
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
authors.forename: Nicole
authors.initials: N
authors.lastname: Cloonan
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia; Department of Bone Marrow Transplantation, The Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia.
authors.forename: Justine
authors.initials: J
authors.lastname: Leach
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia; Department of Bone Marrow Transplantation, The Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia.
authors.forename: Elise
authors.initials: E
authors.lastname: Sturgeon
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia; Department of Bone Marrow Transplantation, The Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia.
authors.forename: Judy
authors.initials: J
authors.lastname: Avery
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
authors.forename: Stuart D
authors.initials: SD
authors.lastname: Olver
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
authors.forename: Mary
authors.initials: M
authors.lastname: Lor
authors.affiliation: Department of Bone Marrow Transplantation, The Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia.
authors.forename: Ashish K
authors.initials: AK
authors.lastname: Misra
authors.affiliation: Department of Bone Marrow Transplantation, The Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia.
authors.forename: Cheryl
authors.initials: C
authors.lastname: Hutchins
authors.affiliation: Department of Bone Marrow Transplantation, The Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia.
authors.forename: A James
authors.initials: AJ
authors.lastname: Morton
authors.affiliation: Department of Bone Marrow Transplantation, The Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia.
authors.forename: Simon Ts
authors.initials: ST
authors.lastname: Durrant
authors.affiliation: Department of Bone Marrow Transplantation, The Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia.
authors.forename: Elango
authors.initials: E
authors.lastname: Subramoniapillai
authors.affiliation: Department of Bone Marrow Transplantation, The Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia.
authors.forename: Jason P
authors.initials: JP
authors.lastname: Butler
authors.affiliation: Department of Bone Marrow Transplantation, The Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia.
authors.forename: Cameron I
authors.initials: CI
authors.lastname: Curley
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
authors.forename: Kelli P A
authors.initials: KPA
authors.lastname: MacDonald
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia; Department of Bone Marrow Transplantation, The Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia.
authors.forename: Siok-Keen
authors.initials: SK
authors.lastname: Tey
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia; Department of Bone Marrow Transplantation, The Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia. Electronic address: geoff.hill@qimrberghofer.edu.au.
authors.forename: Geoffrey R
authors.initials: GR
authors.lastname: Hill
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D005260:Female; D005500:Follow-Up Studies; D006086:Graft vs Host Disease / Q000188:drug therapy* / Q000209:etiology / Q000401:mortality; D019337:Hematologic Neoplasms / Q000150:complications* / Q000401:mortality / Q000628:therapy; D006801:Humans; D015850:Interleukin-6 / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011379:Prognosis; D011446:Prospective Studies; D033581:Stem Cell Transplantation / Q000009:adverse effects*; D015996:Survival Rate; D014184:Transplantation, Homologous; D055815:Young Adult; D000093242:Interleukin-6 Inhibitors
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D015850:Interleukin-6; D000093242:Interleukin-6 Inhibitors; C502936:tocilizumab