title: An early-biomarker algorithm predicts lethal graft-versus-host disease and survival.
abstract: BACKGROUND.No laboratory test can predict the risk of nonrelapse mortality (NRM) or severe graft-versus-host disease (GVHD) after hematopoietic cellular transplantation (HCT) prior to the onset of GVHD symptoms.METHODS.Patient blood samples on day 7 after HCT were obtained from a multicenter set of 1,287 patients, and 620 samples were assigned to a training set. We measured the concentrations of 4 GVHD biomarkers (ST2, REG3α, TNFR1, and IL-2Rα) and used them to model 6-month NRM using rigorous cross-validation strategies to identify the best algorithm that defined 2 distinct risk groups. We then applied the final algorithm in an independent test set (n= 309) and validation set (n= 358).RESULTS.A 2-biomarker model using ST2 and REG3α concentrations identified patients with a cumulative incidence of 6-month NRM of 28% in the high-risk group and 7% in the low-risk group (P< 0.001). The algorithm performed equally well in the test set (33% vs. 7%,P< 0.001) and the multicenter validation set (26% vs. 10%,P< 0.001). Sixteen percent, 17%, and 20% of patients were at high risk in the training, test, and validation sets, respectively. GVHD-related mortality was greater in high-risk patients (18% vs. 4%,P< 0.001), as was severe gastrointestinal GVHD (17% vs. 8%,P< 0.001). The same algorithm can be successfully adapted to define 3 distinct risk groups at GVHD onset.CONCLUSION.A biomarker algorithm based on a blood sample taken 7 days after HCT can consistently identify a group of patients at high risk for lethal GVHD and NRM.FUNDING.The National Cancer Institute, American Cancer Society, and the Doris Duke Charitable Foundation.
authors.affiliation: Tisch Cancer Institute, the Icahn School of Medicine at Mount Sinai.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Hartwell
authors.affiliation: Biostatistics Shared Resource Facility, TischCancer Institute, the Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Umut
authors.initials: U
authors.lastname: Özbek
authors.affiliation: Blood and Marrow Transplantation Program, University of Regensburg, Regensburg, Germany.
authors.forename: Ernst
authors.initials: E
authors.lastname: Holler
authors.affiliation: Tisch Cancer Institute, the Icahn School of Medicine at Mount Sinai.
authors.forename: Anne S
authors.initials: AS
authors.lastname: Renteria
authors.affiliation: Tisch Cancer Institute, the Icahn School of Medicine at Mount Sinai.
authors.forename: Hannah
authors.initials: H
authors.lastname: Major-Monfried
authors.affiliation: Blood and Marrow Transplantation Program, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Pavan
authors.initials: P
authors.lastname: Reddy
authors.affiliation: Tisch Cancer Institute, the Icahn School of Medicine at Mount Sinai.
authors.forename: Mina
authors.initials: M
authors.lastname: Aziz
authors.affiliation: Blood and Marrow Transplantation Program, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: William J
authors.initials: WJ
authors.lastname: Hogan
authors.affiliation: Department of Stem Cell Transplantation, University Medical Center, Hamburg-Eppendorf, Germany.
authors.forename: Francis
authors.initials: F
authors.lastname: Ayuk
authors.affiliation: Blood and Marrow Transplantation Program, Ohio State University, Columbus, Ohio, USA.
authors.forename: Yvonne A
authors.initials: YA
authors.lastname: Efebera
authors.affiliation: Blood and Marrow Transplantation Program, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Elizabeth O
authors.initials: EO
authors.lastname: Hexner
authors.affiliation: Blood and Marrow Transplantation Program, Chulalongkorn University, Bangkok, Thailand.
authors.forename: Udomsak
authors.initials: U
authors.lastname: Bunworasate
authors.affiliation: Pediatric Blood and Marrow Transplantation Program, Aflac Cancer and Blood Disorders Center, Emory University and Children's Healthcare of Atlanta, Atlanta, Georgia, USA.
authors.forename: Muna
authors.initials: M
authors.lastname: Qayed
authors.affiliation: Blood and Marrow Transplantation Program, University Hospital TU Dresden, Dresden, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Ordemann
authors.affiliation: Pediatric Blood and Marrow Transplantation Program, Children's Hospital.
authors.forename: Matthias
authors.initials: M
authors.lastname: Wölfl
authors.affiliation: Blood and Marrow Transplantation Program, University of Würzburg, Würzburg, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Mielke
authors.affiliation: Blood and Marrow Transplantation Program, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Attaphol
authors.initials: A
authors.lastname: Pawarode
authors.affiliation: Bone Marrow Transplantation Program, Massachusetts General Hospital, Boston, Massachusetts, USA.
authors.forename: Yi-Bin
authors.initials: YB
authors.lastname: Chen
authors.affiliation: Blood and Marrow Transplantation Program, Ohio State University, Columbus, Ohio, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Devine
authors.affiliation: Blood and Marrow Transplantation Program, University of Utah, Salt Lake City, Utah, USA.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Harris
authors.affiliation: Division of Hematology-Oncology.
authors.forename: Madan
authors.initials: M
authors.lastname: Jagasia
authors.affiliation: Pediatric Blood and Marrow Transplantation Program, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Carrie L
authors.initials: CL
authors.lastname: Kitko
authors.affiliation: Blood and Marrow Transplantation Program, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Litzow
authors.affiliation: Department of Stem Cell Transplantation, University Medical Center, Hamburg-Eppendorf, Germany.
authors.forename: Nicolaus
authors.initials: N
authors.lastname: Kröger
authors.affiliation: Pediatric Blood and Marrow Transplantation Program, Ospedale Pediatrico Bambino Gesu, Rome, Italy.
authors.forename: Franco
authors.initials: F
authors.lastname: Locatelli
authors.affiliation: Tisch Cancer Institute, the Icahn School of Medicine at Mount Sinai.
authors.forename: George
authors.initials: G
authors.lastname: Morales
authors.affiliation: Hematology and Hematopoietic Cell Transplantation, City of Hope Medical Center, Duarte, California, USA.
authors.forename: Ryotaro
authors.initials: R
authors.lastname: Nakamura
authors.affiliation: Blood and Marrow Transplantation Program, Columbia University Medical Center, New York, New York, USA.
authors.forename: Ran
authors.initials: R
authors.lastname: Reshef
authors.affiliation: Department of Internal Medicine 5, Hematology/Oncology, University Hospital Erlangen-Nuremburg, Erlangen, Germany.
authors.forename: Wolf
authors.initials: W
authors.lastname: Rösler
authors.affiliation: Blood and Marrow Transplantation Program, University of Regensburg, Regensburg, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Weber
authors.affiliation: Blood and Marrow Transplantation Program, Chulalongkorn University, Bangkok, Thailand.
authors.forename: Kitsada
authors.initials: K
authors.lastname: Wudhikarn
authors.affiliation: Blood and Marrow Transplantation Program, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Yanik
authors.affiliation: Tisch Cancer Institute, the Icahn School of Medicine at Mount Sinai.
authors.forename: John E
authors.initials: JE
authors.lastname: Levine
authors.affiliation: Tisch Cancer Institute, the Icahn School of Medicine at Mount Sinai.
authors.forename: James Lm
authors.initials: JL
authors.lastname: Ferrara
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000465:Algorithms; D015415:Biomarkers / Q000097:blood; D002648:Child; D002675:Child, Preschool; D005260:Female; D006086:Graft vs Host Disease / Q000097:blood / Q000401:mortality*; D018380:Hematopoietic Stem Cell Transplantation / Q000401:mortality*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D000072179:Interleukin-1 Receptor-Like 1 Protein / Q000097:blood*; D053645:Interleukin-2 Receptor alpha Subunit / Q000097:blood; D008297:Male; D008875:Middle Aged; D000073718:Pancreatitis-Associated Proteins / Q000097:blood*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000097:blood; D012307:Risk Factors; D055815:Young Adult
chemical_list: D015415:Biomarkers; C079241:IL1RL1 protein, human; C508017:IL2RA protein, human; D000072179:Interleukin-1 Receptor-Like 1 Protein; D053645:Interleukin-2 Receptor alpha Subunit; D000073718:Pancreatitis-Associated Proteins; C000612141:REG3A protein, human; D047888:Receptors, Tumor Necrosis Factor, Type I; C506235:TNFRSF1A protein, human