title: A prognostic score for acute graft-versus-host disease based on biomarkers: a multicentre study.
abstract: BACKGROUND
  Graft-versus-host disease (GVHD) is the major cause of non-relapse mortality after allogeneic haemopoietic stem-cell transplantation (SCT). The severity of symptoms at the onset of GVHD does not accurately define risk, and thus most patients are treated alike with high dose systemic corticosteroids. We aimed to define clinically meaningful risk strata for patients with newly diagnosed acute GVHD using plasma biomarkers.
  
  
  METHODS
  Between April 13, 2000, and May 7, 2013, we prospectively collected plasma from 492 SCT patients with newly diagnosed acute GVHD and randomly assigned (2:1) using a random number generator, conditional on the final two datasets having the same median day of onset, into training (n=328) and test (n=164) sets. We used the concentrations of three recently validated biomarkers (TNFR1, ST2, and Reg3α) to create an algorithm that computed the probability of non-relapse mortality 6 months after GVHD onset for individual patients in the training set alone. We rank ordered the probabilities and identified thresholds that created three distinct non-relapse mortality scores. We evaluated the algorithm in the test set, and again in an independent validation set of an additional 300 patients who underwent stem cell transplant and were enrolled on multicentre clinical trials of primary therapy for acute GVHD.
  
  
  RESULTS
  In all three datasets (training, test, and validation), the cumulative incidence of 6-month non-relapse mortality significantly increased as the Ann Arbor GVHD score increased. In the multicentre validation set, scores were 8% (95% CI 3-16) for score 1, 27% (20-34) for score 2, and 46% (33-58) for score 3 (p<0·0001). Conversely, the response to primary GVHD treatment within 28 days decreased as the GVHD score increased 86% for score 1, 67% for score 2, and 46% for score 3 in the multicentre validation set, p<0·0001).
  
  
  CONCLUSIONS
  Biomarker-based scores can be used to guide risk-adapted therapy at the onset of acute GVHD. High risk patients with a score of 3 are candidates for intensive primary therapy, while low risk patients with a score of 1 are candidates for rapid tapers of systemic steroid therapy.
  
  
  BACKGROUND
  The National Cancer Institute, the National Heart, Lung, and Blood Institute, the National Institute of Allergy and Infectious Diseases, the Doris Duke Charitable Fund, the American Cancer Society, and the Judith Devries Fund.
authors.affiliation: Blood & Marrow Transplant Program, University of Michigan, Ann Arbor, MI, USA.
authors.forename: John E
authors.initials: JE
authors.lastname: Levine
authors.affiliation: School of Public Health, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Braun
authors.affiliation: Blood & Marrow Transplant Program, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Harris
authors.affiliation: Department of Hematology and Oncology, University of Regensburg, Regensburg, Germany.
authors.forename: Ernst
authors.initials: E
authors.lastname: Holler
authors.affiliation: Blood & Marrow Transplant Program, University of Michigan, Ann Arbor, MI, USA; The Tisch Cancer Institute, The Icahn School of Medicine at Mount Sinai Hospital, New York, NY, USA.
authors.forename: Austin
authors.initials: A
authors.lastname: Taylor
authors.affiliation: Blood & Marrow Transplant Program, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Holly
authors.initials: H
authors.lastname: Miller
authors.affiliation: Blood & Marrow Transplant Program, University of Michigan, Ann Arbor, MI, USA.
authors.forename: John
authors.initials: J
authors.lastname: Magenau
authors.affiliation: Blood & Marrow Transplant Program, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Weisdorf
authors.affiliation: Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA.
authors.forename: Vincent T
authors.initials: VT
authors.lastname: Ho
authors.affiliation: Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
authors.forename: Javier
authors.initials: J
authors.lastname: Bolaños-Meade
authors.affiliation: Department of Stem Cell Transplantation, MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Amin M
authors.initials: AM
authors.lastname: Alousi
authors.affiliation: Blood & Marrow Transplant Program, University of Michigan, Ann Arbor, MI, USA; The Tisch Cancer Institute, The Icahn School of Medicine at Mount Sinai Hospital, New York, NY, USA. Electronic address: james.ferrara@mssm.edu.
authors.forename: James L M
authors.initials: JL
authors.lastname: Ferrara
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000097:blood*; D002648:Child; D002675:Child, Preschool; D006086:Graft vs Host Disease / Q000175:diagnosis* / Q000188:drug therapy / Q000401:mortality; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008875:Middle Aged; D011379:Prognosis; D014184:Transplantation, Homologous / Q000009:adverse effects; D055815:Young Adult
chemical_list: D015415:Biomarkers