title: Biomarker profiling of steroid-resistant acute GVHD in patients after infusion of mesenchymal stromal cells.
abstract: We performed a prospective phase II study to evaluate clinical safety and outcome in 48 patients with steroid-refractory grade II-IV acute graft-versus-host disease (aGVHD) treated with mesenchymal stromal cells (MSCs). Clinical outcomes were correlated to comprehensive analyses of soluble and cellular biomarkers. Complete resolution (CR) of aGVHD at day 28 (CR-28) occurred in 12 (25%) patients, CR lasting >1 month (CR-B) occurred in 24 (50%) patients. One-year overall survival was significantly improved in CR-28 (75 versus 33%, P=0.020) and CR-B (79 versus 8%, P<0.001) versus non-CR patients. A six soluble biomarker-panel was predictive for mortality (HR 2.924; CI 1.485-5.758) when measured before MSC-administration. Suppression of tumorigenicity 2 (ST2) was only predictive for mortality 2 weeks after but not before MSC-administration (HR 2.389; CI 1.144-4.989). In addition, an increase in immature myeloid dendritic cells associated with decreased mortality (HR 0.554, CI 0.389-0.790). Patients had persisting T-cell responses against defined virus- and leukemia-associated antigens. In conclusion, our data emphasize the need to carefully assess biomarkers in cohorts with homogeneous GVHD treatments. Biomarkers might become an additional valuable component of composite end points for the rapid and efficient testing of novel compounds to decrease lifecycle of clinical testing and improve the success rate of phase II/III trials.
authors.affiliation: Department of Haematology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: L C J
authors.initials: LC
authors.lastname: Te Boome
authors.affiliation: UMC Utrecht, Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: C
authors.initials: C
authors.lastname: Mansilla
authors.affiliation: Department of Haematology, University Medical Center Utrecht, Utrecht, The Netherlands.|UMC Utrecht, Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: L E
authors.initials: LE
authors.lastname: van der Wagen
authors.affiliation: UMC Utrecht, Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.|UMC Utrecht, Paediatrics - Blood and Marrow Transplantation Program, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: C A
authors.initials: CA
authors.lastname: Lindemans
authors.affiliation: Department of Haematology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: E J
authors.initials: EJ
authors.lastname: Petersen
authors.affiliation: UMC Utrecht, Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: E
authors.identifier: http://orcid.org/0000-0001-9441-1019
authors.initials: E
authors.lastname: Spierings
authors.affiliation: UMC Utrecht, Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: K A
authors.initials: KA
authors.lastname: Thus
authors.affiliation: Department of Clinical Pharmacy - Cell Therapy Facility, UMC Utrecht, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: K
authors.initials: K
authors.lastname: Westinga
authors.affiliation: UMC Utrecht, Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: Plantinga
authors.affiliation: UMC Utrecht, Paediatrics - Blood and Marrow Transplantation Program, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: Bierings
authors.affiliation: Department of Haematology, Erasmus MC Rotterdam, Rotterdam, The Netherlands.
authors.forename: A E C
authors.initials: AE
authors.lastname: Broers
authors.affiliation: Department of Haematology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: M L H
authors.initials: ML
authors.lastname: Cuijpers
authors.affiliation: Department of Haematology, UMC Groningen, Groningen, The Netherlands.
authors.forename: G W
authors.initials: GW
authors.lastname: van Imhoff
authors.affiliation: Department of Haematology, VU MC, Amsterdam, The Netherlands.
authors.forename: J J
authors.initials: JJ
authors.lastname: Janssen
authors.affiliation: Department of Haematology, AMC, Amsterdam, The Netherlands.
authors.forename: C
authors.initials: C
authors.lastname: Huisman
authors.affiliation: Department of Haematology, AMC, Amsterdam, The Netherlands.
authors.forename: S
authors.initials: S
authors.lastname: Zeerleder
authors.affiliation: Department of Haematology, Radboud UMC Nijmegen, Amsterdam, The Netherlands.
authors.forename: G
authors.initials: G
authors.lastname: Huls
authors.affiliation: UMC Utrecht, Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.|UMC Utrecht, Paediatrics - Blood and Marrow Transplantation Program, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: J J
authors.initials: JJ
authors.lastname: Boelens
authors.affiliation: UMC Utrecht, Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.|UMC Utrecht, Paediatrics - Blood and Marrow Transplantation Program, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: N M
authors.initials: NM
authors.lastname: Wulffraat
authors.affiliation: Department of Clinical Pharmacy - Cell Therapy Facility, UMC Utrecht, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: I C M
authors.initials: IC
authors.lastname: Slaper-Cortenbach
authors.affiliation: Department of Haematology, University Medical Center Utrecht, Utrecht, The Netherlands.|UMC Utrecht, Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Kuball
mesh_terms: D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000368:Aged; D000951:Antigens, Neoplasm / Q000276:immunology; D015415:Biomarkers / Q000097:blood / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D016572:Cyclosporine / Q000627:therapeutic use; D016207:Cytokines / Q000097:blood / Q000378:metabolism; D004351:Drug Resistance; D005260:Female; D006086:Graft vs Host Disease / Q000175:diagnosis / Q000209:etiology / Q000378:metabolism* / Q000401:mortality / Q000628:therapy*; D006801:Humans; D016130:Immunophenotyping; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007223:Infant; D008214:Lymphocytes / Q000276:immunology / Q000378:metabolism; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D008875:Middle Aged; D011241:Prednisone / Q000627:therapeutic use; D011379:Prognosis; D013256:Steroids / Q000627:therapeutic use; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000951:Antigens, Neoplasm; D015415:Biomarkers; D016207:Cytokines; D007166:Immunosuppressive Agents; D013256:Steroids; D016572:Cyclosporine; D011241:Prednisone
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