Cotransplantation of Allogeneic Mesenchymal and Hematopoietic Stem Cells in Children With Aplastic Anemia

Abstract

We report here the preliminary results of allogeneic hematopoietic stem cell transplantation with mesenchymal stem cells (MSCs) for 6 cases of severe aplastic anemia. The patients ranged in age from 3 to 16 years, and the median time from diagnosis to transplantation was 32 months (range: 3-156 months). The conditioning regimens consisted of fludarabine, cyclophosphamide, and antithymocyte globulin with or without busulfan. Graft-versus-host disease (GvHD) was prevented by the administration of cyclosporine A, methotrexate, and mycophenolate mofetil, with or without anti-CD25 monoclonal antibody. The grafts were granulocyte colony-stimulating factor-mobilized bone marrow and peripheral blood from HLA antigen-haploidentical donors (3 cases) or peripheral blood only from unrelated HLA antigen-identical donors (3 cases). MSCs were intravenously injected at a median dose of 1.43 × 10(6)/kg (range: 0.85-2.5 × 10(6)/kg). The mean time for neutrophil and platelet recovery was 12.3 and 13.8 days, respectively. Acute GvHD grade I and II developed in 2 cases, and no chronic GvHD was documented. All patients were alive and transfusion independent at a median follow-up of 15 months (range: 6-29 months). Our report suggests that cotransplantation of allogeneic hematopoietic stem cells and MSCs might provide an opportunity for therapy for children with severe aplastic anemia.

Comparable Allogeneic Hematopoietic Cell Transplantation Outcome of a Haplo-Identical Family Donor with an Alternative Donor in Adult Aplastic Anemia

“…However, this resulted in increased graft failure, delayed immune reconstitution and more fatal infections [12,13,14]. Further efforts to improve the outcomes of HLA-mismatched FD HCT included the use of polyclonal [15,16] or monoclonal antibodies [17,18] against T cells as a part of the conditioning regimen (in vivo T cell depletion), the coinfusion of mesenchymal stem cells [19,20] and incorporating the concept of fetomaternal immune tolerance in the donor selection process among several available HLA-haplo-identical family members [21]. …”

Bone marrow mesenchymal stem cells from patients with aplastic anemia maintain functional and immune properties and do not contribute to the pathogenesis of the disease

“…1,36 On the one hand, the good responses to immunosuppressive treatments such as antithymocyte globulin and cyclosporine A support the belief that pathological T-cell-mediated autoimmune responses are a cause of the BM failure in AA. 1,34,36 On the other hand, several studies have shown that co-transplantation of allogeneic BM-or CB-derived MSC and HSC enhances hematopoietic engraftment and also improves stromal function in patients with AA, [37][38][39][40] suggesting a potential underlying role of the BM microenvironment in the pathogenesis of AA. In fact, AA patients have a hypocellular BM which is "physiologically" replaced by fatty BM, likely of mesenchymal origin, further supporting a potential contribution of the BM microenvironment to the pathogenesis of AA.…”

Allogeneic hematopoietic stem cell transplantation in children with aplastic anemia

“…Late graft failure (graft failures occurring 1 year or longer after transplantation) was observed in one patient, and only one patient developed Grade I acute GVHD that was limited to the skin. The presumed mechanism was that the G-CSF-primed mixture of PBSCs and bone marrow mesenchymal stem cells might not only increase the numbers of stem cells and mesenchymal stem cells but also change the function of T-cells and other cells, such as natural killer cells, which contribute to engraftment and cause a relatively low GVHD rate (WeberMzell et al, 2007;Sun et al, 2010;Wang et al, 2012). These studies indicated that the dual collection of stem cells was a safe and effective way to improve the number of nucleated cells.…”