title: Cotransplantation of HLA-identical sibling culture-expanded mesenchymal stem cells and hematopoietic stem cells in hematologic malignancy patients.
abstract: Mesenchymal stem cells (MSCs) are found in a variety of tissues, including human bone marrow; secrete hematopoietic cytokines; support hematopoietic progenitors in vitro; and possess potent immunosuppressive properties. We hypothesized that cotransplantation of culture-expanded MSCs and hematopoietic stem cells (HSCs) from HLA-identical sibling donors after myeloablative therapy could facilitate engraftment and lessen graft-versus-host disease (GVHD); however, the safety and feasibility of this approach needed to be established. In an open-label, multicenter trial, we coadministered culture-expanded MSCs with HLA-identical sibling-matched HSCs in hematologic malignancy patients. Patients received either bone marrow or peripheral blood stem cells as the HSC source. Patients received 1 of 4 study-specified transplant conditioning regimens and methotrexate (days 1, 3, and 6) and cyclosporine as GVHD prophylaxis. On day 0, patients were given culture-expanded MSCs intravenously (1.0-5.0 x 10(6)/kg) 4 hours before infusion of either bone marrow or peripheral blood stem cells. Forty-six patients (median age, 44.5 years; range, 19-61 years) received MSCs and HLA-matched sibling allografts. MSC infusions were well tolerated, without any infusion-related adverse events. The median times to neutrophil (absolute neutrophil count > or = 0.500 x 10(9)/L) and platelet (platelet count > or = 20 x 10(9)/L) engraftment were 14.0 days (range, 11.0-26.0 days) and 20 days (range, 15.0-36.0 days), respectively. Grade II to IV acute GVHD was observed in 13 (28%) of 46 patients. Chronic GVHD was observed in 22 (61%) of 36 patients who survived at least 90 days; it was extensive in 8 patients. Eleven patients (24%) experienced relapse at a median time to progression of 213.5 days (range, 14-688 days). The probability of patients attaining disease- or progression-free survival at 2 years after MSC infusion was 53%. Cotransplantation of HLA-identical sibling culture-expanded MSCs with an HLA-identical sibling HSC transplant is feasible and seems to be safe, without immediate infusional or late MSC-associated toxicities. The optimal MSC dose and frequency of administration to prevent or treat GVHD during allogeneic HSC transplantation should be evaluated further in phase II clinical trials.
authors.affiliation: Department of Medicine, The University Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, USA. hillard.lazarus@case.edu
authors.forename: Hillard M
authors.initials: HM
authors.lastname: Lazarus
authors.forename: Omer N
authors.initials: ON
authors.lastname: Koc
authors.forename: Steven M
authors.initials: SM
authors.lastname: Devine
authors.forename: Peter
authors.initials: P
authors.lastname: Curtin
authors.forename: Richard T
authors.initials: RT
authors.lastname: Maziarz
authors.forename: H Kent
authors.initials: HK
authors.lastname: Holland
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Shpall
authors.forename: Philip
authors.initials: P
authors.lastname: McCarthy
authors.forename: Kerry
authors.initials: K
authors.lastname: Atkinson
authors.forename: Brenda W
authors.initials: BW
authors.lastname: Cooper
authors.forename: Stanton L
authors.initials: SL
authors.lastname: Gerson
authors.forename: Mary J
authors.initials: MJ
authors.lastname: Laughlin
authors.forename: Fausto R
authors.initials: FR
authors.lastname: Loberiza
authors.forename: Annemarie B
authors.initials: AB
authors.lastname: Moseley
authors.forename: Andrea
authors.initials: A
authors.lastname: Bacigalupo
mesh_terms: D000328:Adult; D049109:Cell Proliferation; D046508:Culture Techniques; D018572:Disease-Free Survival; D005260:Female; D006085:Graft Survival; D006086:Graft vs Host Disease; D019337:Hematologic Neoplasms / Q000628:therapy*; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D006650:Histocompatibility Testing; D006801:Humans; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D008875:Middle Aged; D035781:Siblings; D033581:Stem Cell Transplantation / Q000009:adverse effects / Q000379:methods*