title: Etanercept plus topical corticosteroids as initial therapy for grade one acute graft-versus-host disease after allogeneic hematopoietic cell transplantation.
abstract: Clinical diagnosis of grade 1 acute graft-versus-host disease (GVHD) marks the beginning of a potentially progressive and fatal course of GVHD after hematopoietic stem cell transplantation (HSCT). However, interventional studies to treat early GVHD are lacking. We conducted a single-arm prospective phase II trial to test the hypothesis that treatment of newly diagnosed grade 1 acute GVHD with etanercept and topical corticosteroids would reduce progression to grade 2 to 4 within 28 days. Study patients (n = 34) had a median age of 51 years (range, 10 to 67 years) and had undergone unrelated (n = 22) or related (n = 12) donor HSCT. Study patients were treated with etanercept (.4 mg/kg, maximum 25 mg/dose) twice weekly for 4 to 8 weeks. Ten of 34 patients (29%) progressed to grade 2 to 4 acute GVHD within 28 days. The cumulative incidence of grade 2 to 4 and grade 3 to 4 acute GVHD at 1 year was 41% and 3%, respectively. Nonrelapse mortality was 19% and overall survival was 63% at 2 years. Among a contemporaneous control cohort of patients who were diagnosed with grade 1 acute GVHD and treated with topical corticosteroids but not etanercept during the study period, 12 of 28 patients (43%) progressed to grade 2 to 4 GVHD within 28 days, with a 1-year incidence of grade 2 to 4 GVHD and grade 3 to 4 GVHD of 61% (41% versus 61%, P = .08) and 18% (3% versus 18%, P = .05), respectively. Patients treated with etanercept also experienced less increase in GVHD plasma biomarkers suppression of tumorigenicity 2 (P = .06) and regenerating islet-derived 3-alpha (P = .01) 28 days after grade 1 acute GVHD diagnosis compared with contemporaneous control patients. This study was terminated early because of poor accrual. Future prospective studies are needed to identify patients with grade 1 acute GVHD at risk of swift progression to more severe GVHD and to establish consensus for the treatment of grade 1 acute GVHD. This trial is registered with ClinicalTrials.gov, number NCT00726375.
authors.affiliation: Blood and Marrow Transplantation Program, University of Michigan, Ann Arbor, Michigan; Department of Pediatrics, University of Michigan, Ann Arbor, Michigan.
authors.forename: Erin
authors.initials: E
authors.lastname: Gatza
authors.affiliation: Department of Biostatistics, University of Michigan, Ann Arbor, Michigan.
authors.forename: Thomas
authors.initials: T
authors.lastname: Braun
authors.affiliation: Blood and Marrow Transplantation Program, University of Michigan, Ann Arbor, Michigan; Department of Pediatrics, University of Michigan, Ann Arbor, Michigan.
authors.forename: John E
authors.initials: JE
authors.lastname: Levine
authors.affiliation: Blood and Marrow Transplantation Program, University of Michigan, Ann Arbor, Michigan; Department of Pediatrics, University of Michigan, Ann Arbor, Michigan.
authors.forename: James L M
authors.initials: JL
authors.lastname: Ferrara
authors.affiliation: Blood and Marrow Transplantation Program, University of Michigan, Ann Arbor, Michigan; Department of Pediatrics, University of Michigan, Ann Arbor, Michigan.
authors.forename: Shuang
authors.initials: S
authors.lastname: Zhao
authors.affiliation: Blood and Marrow Transplantation Program, University of Michigan, Ann Arbor, Michigan; Department of Pediatrics, University of Michigan, Ann Arbor, Michigan.
authors.forename: Tianyi
authors.initials: T
authors.lastname: Wang
authors.affiliation: Blood and Marrow Transplantation Program, University of Michigan, Ann Arbor, Michigan; Department of Pediatrics, University of Michigan, Ann Arbor, Michigan.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Chang
authors.affiliation: Blood and Marrow Transplantation Program, University of Michigan, Ann Arbor, Michigan; Department of Pediatrics, University of Michigan, Ann Arbor, Michigan.
authors.forename: Andrew
authors.initials: A
authors.lastname: Harris
authors.affiliation: Blood and Marrow Transplantation Program, University of Michigan, Ann Arbor, Michigan; Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
authors.forename: Attaphol
authors.initials: A
authors.lastname: Pawarode
authors.affiliation: Blood and Marrow Transplantation Program, University of Michigan, Ann Arbor, Michigan; Department of Pediatrics, University of Michigan, Ann Arbor, Michigan.
authors.forename: Carrie
authors.initials: C
authors.lastname: Kitko
authors.affiliation: Blood and Marrow Transplantation Program, University of Michigan, Ann Arbor, Michigan; Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
authors.forename: John M
authors.initials: JM
authors.lastname: Magenau
authors.affiliation: Blood and Marrow Transplantation Program, University of Michigan, Ann Arbor, Michigan; Department of Pediatrics, University of Michigan, Ann Arbor, Michigan.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Yanik
authors.affiliation: Blood and Marrow Transplantation Program, University of Michigan, Ann Arbor, Michigan; Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Couriel
authors.affiliation: Blood and Marrow Transplantation Program, University of Michigan, Ann Arbor, Michigan; Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
authors.forename: Steven
authors.initials: S
authors.lastname: Goldstein
authors.affiliation: Blood and Marrow Transplantation Program, University of Michigan, Ann Arbor, Michigan; Department of Pediatrics, University of Michigan, Ann Arbor, Michigan.
authors.forename: James
authors.initials: J
authors.lastname: Connelly
authors.affiliation: Blood and Marrow Transplantation Program, University of Michigan, Ann Arbor, Michigan; Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
authors.forename: Pavan
authors.initials: P
authors.lastname: Reddy
authors.affiliation: Department of Pediatrics, Indiana University, Indianapolis, Indiana.
authors.forename: Sophie
authors.initials: S
authors.lastname: Paczesny
authors.affiliation: Blood and Marrow Transplantation Program, University of Michigan, Ann Arbor, Michigan; Department of Pediatrics, University of Michigan, Ann Arbor, Michigan. Electronic address: sungchoi@med.umich.edu.
authors.forename: Sung Won
authors.initials: SW
authors.lastname: Choi
mesh_terms: D000208:Acute Disease; D015331:Cohort Studies; D000068800:Etanercept; D005260:Female; D005938:Glucocorticoids / Q000627:therapeutic use*; D006086:Graft vs Host Disease / Q000628:therapy*; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D006801:Humans; D007074:Immunoglobulin G / Q000008:administration & dosage / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D018124:Receptors, Tumor Necrosis Factor / Q000008:administration & dosage / Q000627:therapeutic use*; D019172:Transplantation Conditioning / Q000009:adverse effects*; D014184:Transplantation, Homologous / Q000009:adverse effects*
chemical_list: D005938:Glucocorticoids; D007074:Immunoglobulin G; D018124:Receptors, Tumor Necrosis Factor; D000068800:Etanercept
keywords: Clinical trial; Etanercept; Grade 1 acute; Graft-versus-host disease; Hematopoietic stem cell transplantation