title: Heterogeneity in Studies of Mesenchymal Stromal Cells to Treat or Prevent Graft-versus-Host Disease: A Scoping Review of the Evidence.
abstract: Effective treatments are lacking for the treatment of steroid-refractory graft-versus-host disease (GVHD), a major cause of morbidity and mortality after allogeneic hematopoietic cell transplantation. Mesenchymal stromal cells (MSCs) have demonstrated promise but there is uncertainty regarding their clinical effectiveness. A systematic scoping review of the literature was performed to characterize the heterogeneity of published studies and identify opportunities for standardization. Thirty studies were identified, including 19 studies (507 patients) addressing the treatment of acute or chronic GVHD and 11 prevention studies (277 patients). Significant heterogeneity was observed in the age and diagnoses of study subjects, intensity and specifics of the conditioning regimens, degree of HLA matching, and source of hematopoietic cells. MSCs were derived from bone marrow (83% of studies), cord blood (13%), or adipose tissue (3%) and were cryopreserved from third-party allogeneic donors in the majority of studies (91% of prevention studies and 63% of treatment studies). Culture conditions and media supplements were highly variable and characterization of MSCs did not conform to all International Society for Cellular Therapy criteria in any study. MSCs were harvested from cell culture at passage 1 to 7 and the dosage of MSCs ranged from 0.3 to 10 × 10(6)/kg, using varying schedules of administration. Treatment response criteria were not standardized and effectiveness in controlled treatment studies (5 studies) was unconvincing. Details of actively recruiting trials suggest heterogeneity still persists with only 53% of registered trials describing the use of standard GVHD response criteria and few detailing methods of MSC manufacturing. Future studies will need to make substantial coordinated efforts to reduce study heterogeneity and clarify the role of MSCs in GVHD.
authors.affiliation: Blood and Marrow Transplantation, Department of Medicine, The Ottawa Hospital and University of Ottawa and Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
authors.forename: Mina
authors.initials: M
authors.lastname: Rizk
authors.affiliation: Blood and Marrow Transplantation, Department of Medicine, The Ottawa Hospital and University of Ottawa and Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
authors.forename: Madeline
authors.initials: M
authors.lastname: Monaghan
authors.affiliation: Blood and Marrow Transplantation, Department of Medicine, The Ottawa Hospital and University of Ottawa and Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
authors.forename: Risa
authors.initials: R
authors.lastname: Shorr
authors.affiliation: Blood and Marrow Transplantation, Department of Medicine, The Ottawa Hospital and University of Ottawa and Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
authors.forename: Natasha
authors.initials: N
authors.lastname: Kekre
authors.affiliation: Blood and Marrow Transplantation, Department of Medicine, The Ottawa Hospital and University of Ottawa and Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
authors.forename: Christopher N
authors.initials: CN
authors.lastname: Bredeson
authors.affiliation: Blood and Marrow Transplantation, Department of Medicine, The Ottawa Hospital and University of Ottawa and Ottawa Hospital Research Institute, Ottawa, Ontario, Canada. Electronic address: daallan@ohri.ca.
authors.forename: David S
authors.initials: DS
authors.lastname: Allan
mesh_terms: D002985:Clinical Protocols / Q000592:standards; D002986:Clinical Trials as Topic / Q000592:standards*; D006086:Graft vs Host Disease / Q000517:prevention & control / Q000628:therapy*; D006801:Humans; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods* / Q000592:standards; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D012015:Reference Standards
keywords: Graft-versus-host disease; Hematopoietic cell transplantation; Mesenchymal stromal cell; Prevention; Systematic review; Treatment