Mesenchymal Stem Cells Co-transplantation in Alternative Donor Transplantation of Severe Aplastic Anemia.

The study is a phase II trial designed to evaluate the efficacy and safety of co-transplantation with bone marrow derived mesenchymal stem cells from related donors in alternative donor transplantation of severe aplastic anemia.

Aplastic anemia (AA) is an autoimmune hematologic stem cell disease mediated by activated T-lymphocytes that leads to bone marrow dysfunction. In the presence of an empty marrow, pancytopenia, and transfusion dependence, the severity of the disease is based on neutrophil (PMN) count: nonsevere AA (nSAA; PMN \> 0.5 × 109/L), severe AA (SAA;PMN 0.2- 0.5 × 109/L), and very severe AA (vSAA; PMN\< 0.2 × 109/L). Allogeneic BMT from an HLA-identical sibling donor or matched-alternative donor is the treatment of choice for patients with aplastic anaemia.Transplantation for patients with severe aplastic anaemia from an HLA identical sibling donor is now very successful with a 75-90% chance of long term cure and with overall survival of between 65% and 73% at 5 years for matched-alternative donor transplantation. However, these two approachs are limited by the availability of HLA-matched donors. Patients without HLA-identical sibling donor or matched-alternative donor can be offered immunosuppressive treatment (IST) involving injections of Anti-thymocyte globulin (ATG) in combination with cyclosporine (CsA). The treatment response with ATG is at best between 60-80%, 30%-40% patients relapse following an initial response to treatment. Moreover, a recent study has shown that on multivariate analysis of response at 6 months, only younger age, absolute reticulocyte count (ARC) and absolute lymphocyte count (ALC), correlate with response to ATG. Patients with SAA or vSAA, with much lower ARC and ALC, were poor response to IST and have high risks of dying of infection and bleeding. Nowadays, with advances in transplant technology, HLA-mismatched related donors and unrelated donors transplantation has achieved good clinical results. Data from the XJ Huang indicated that patients with HLA-mismatched related donors achieved 100% donor myeloid engraftment and have a survival rate of 64.6±12.4%. Retrospectively analyzed results for 154 patients with acquired SAA who received BMT from unrelated donors identified through the Japan Marrow Donor Program showed the probability of OS at 5 years was 56% (95% confidence interval, 34%-78%). Compared with malignant disease, mismatched related donor or unrelated donor HSCT for SAA involves distinct challenges mainly associated with high graft failure and high GVHD. So, if we can find a way to promote implantation meanwhile prevent or reduce GVHD , the efficacy of HLA-mismatched related donors transplantation can improve. Mesenchymal stem cells (MSCs) are multi-potent non-hematopoietic progenitors mainly found in BM, cord blood, and adipose tissue. MSCs are attractive because of the ease with which they can be isolated and expanded ex vivo, their ability to undergo multilineage differentiation, and their lack of immunogenicity. These cells were shown to provide support for the growth and differentiation of hematopoietic progenitor cells in BM micro-environments. In additon, preliminary studies have shown clinical effectiveness of allogeneic MSC in the treatment of refractory graft-versus-host disease and an improvement in or resolution of severe aGVHD when co-transplantation with MSCs. Due to these properties, MSCs have become an interesting candidate for use in cellular therapy and are considered "theoretically perfect cells" for potential clinical use against AA mismatched related donors transplantation.