title: Plasma-derived proteomic biomarkers in human leukocyte antigen-haploidentical or human leukocyte antigen-matched bone marrow transplantation using post-transplantation cyclophosphamide.
abstract: Recent studies have suggested that plasma-derived proteins may be potential biomarkers relevant for graft-versus-host disease and/or non-relapse mortality occurring after allogeneic blood or marrow transplantation. However, none of these putative biomarkers have been assessed in patients treated either with human leukocyte antigen-haploidentical blood or marrow transplantation or with post-transplantation cyclophosphamide, which has been repeatedly associated with low rates of severe acute graft-versus-host disease, chronic graft-versus-host disease, and non-relapse mortality. We explored whether seven of these plasma-derived proteins, as measured by enzyme-linked immunosorbent assays, were predictive of clinical outcomes in post-transplantation cyclophosphamide-treated patients using plasma samples collected at serial predetermined timepoints from patients treated on prospective clinical studies of human leukocyte antigen-haploidentical (n=58;clinicaltrials.gov Identifier: 00796562) or human leukocyte antigen-matched-related or -unrelated (n=100;clinicaltrials.gov Identifiers: 00134017and00809276) T-cell-replete bone marrow transplantation. Day 30 levels of interleukin-2 receptor α, tumor necrosis factor receptor 1, serum STimulation-2 (IL1RL1 gene product), and regenerating islet-derived 3-α all had high areas under the curve of 0.74-0.97 for predicting non-relapse mortality occurrence by 3 months post-transplant in both the human leukocyte antigen-matched and human leukocyte antigen-haploidentical cohorts. In both cohorts, all four of these proteins were also predictive of subsequent non-relapse mortality occurring by 6, 9, or 12 months post-transplant and were significantly associated with non-relapse mortality in univariable analyses. Furthermore, day 30 elevations of interleukin-2 receptor α were associated with grade II-IV and III-IV acute graft-versus-host disease occurring after day 30 in both cohorts. These data confirm that plasma-derived proteins previously assessed in other transplantation platforms appear to retain prognostic and predictive utility in patients treated with post-transplantation cyclophosphamide.
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Kanakry
authors.affiliation: Department of Biostatistics, Indiana University School of Medicine, Indianapolis, IN.
authors.forename: Giorgos
authors.initials: G
authors.lastname: Bakoyannis
authors.affiliation: Department of Biostatistics, Indiana University School of Medicine, Indianapolis, IN.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Perkins
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Shannon R
authors.initials: SR
authors.lastname: McCurdy
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Ante
authors.initials: A
authors.lastname: Vulic
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA.
authors.forename: Edus H
authors.initials: EH
authors.lastname: Warren
authors.affiliation: Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN.|Department of Immunology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Etienne
authors.initials: E
authors.lastname: Daguindau
authors.affiliation: Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN.|Department of Immunology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Taylor
authors.initials: T
authors.lastname: Olmsted
authors.affiliation: Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN.|Department of Immunology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Christen
authors.initials: C
authors.lastname: Mumaw
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA.
authors.forename: Andrea M H
authors.initials: AMH
authors.lastname: Towlerton
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Cooke
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA.
authors.forename: Paul V
authors.initials: PV
authors.lastname: O'Donnell
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Heather J
authors.initials: HJ
authors.lastname: Symons
authors.affiliation: Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN luznile@jhmi.edu sophpacz@iu.edu.|Department of Immunology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Sophie
authors.initials: S
authors.lastname: Paczesny
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD luznile@jhmi.edu sophpacz@iu.edu.
authors.forename: Leo
authors.initials: L
authors.lastname: Luznik
mesh_terms: D000328:Adult; D000368:Aged; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use; D015415:Biomarkers / Q000097:blood*; D016026:Bone Marrow Transplantation / Q000379:methods*; D003520:Cyclophosphamide / Q000627:therapeutic use*; D005260:Female; D006086:Graft vs Host Disease / Q000175:diagnosis / Q000517:prevention & control; D006680:HLA Antigens / Q000032:analysis*; D019337:Hematologic Neoplasms / Q000401:mortality / Q000628:therapy*; D006650:Histocompatibility Testing; D006801:Humans; 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; D011446:Prospective Studies; D040901:Proteomics; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000097:blood; D015996:Survival Rate; D013997:Time Factors; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous
chemical_list: D018906:Antineoplastic Agents, Alkylating; D015415:Biomarkers; D006680:HLA Antigens; C079241:IL1RL1 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; D003520:Cyclophosphamide