Cotransplantation of HLA-identical sibling culture-expanded mesenchymal stem cells and hematopoietic stem cells in hematologic malignancy patients

Hillard M. Lazarus, Omer N. Koc, Steven M. Devine, Peter Curtin, Richard T. Maziarz, H. Kent Holland, Elizabeth J. Shpall, Philip McCarthy, Kerry Atkinson, Brenda W. Cooper, Stanton L. Gerson, Mary J. Laughlin, Fausto R. Loberiza, Annemarie B. Moseley, Andrea Bacigalupo

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671 Scopus citations

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 × 106/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 ≥0.500 × 109/L) and platelet (platelet count ≥20 × 109/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.

Original languageEnglish (US)
Pages (from-to)389-398
Number of pages10
JournalBiology of Blood and Marrow Transplantation
Volume11
Issue number5
DOIs
StatePublished - May 1 2005

Keywords

  • Allogeneic transplantation
  • Graft-versus-host disease
  • Hematopoietic progenitor cells
  • Human bone marrow
  • Mesenchymal stem cells
  • Stem cells
  • Stroma

ASJC Scopus subject areas

  • Hematology
  • Transplantation

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    Lazarus, H. M., Koc, O. N., Devine, S. M., Curtin, P., Maziarz, R. T., Holland, H. K., Shpall, E. J., McCarthy, P., Atkinson, K., Cooper, B. W., Gerson, S. L., Laughlin, M. J., Loberiza, F. R., Moseley, A. B., & Bacigalupo, A. (2005). Cotransplantation of HLA-identical sibling culture-expanded mesenchymal stem cells and hematopoietic stem cells in hematologic malignancy patients. Biology of Blood and Marrow Transplantation, 11(5), 389-398. https://doi.org/10.1016/j.bbmt.2005.02.001