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

 1. In line with the 2009 Edition (United Kingdom) aplastic anemia diagnostic criteria for
 SAA or VSAA;

 2. Age less than 50 years old,willing to transplant；

 3. No HLA-identical sibling donor；

 4. Have HLA-mismatched related donors or unrelated donors ( ≥5/10 HLA matched loci in
 related donors; ≥8/10 HLA matched loci in unrelated donors )

 5. No serious infection or acute hemorrhage;

 6. Cardiac ultrasound examination showed left ventricular ejection fraction is greater
 than 50%;

 7. Both transaminase and serum creatinine level are no more than twice times the upper
 limit of normal value (ULN);

 8. No acute infectious disease;

 9. Ability to understand and the willingness to sign a written informed consent document.

 10. ECOG score of 0-2 points.

 Exclusion Criteria:

 1. Patients with severe infection or active bleeding;

 2. With severe cardiac insufficiency, left ventricular ejection fraction <50%;

 3. With severe liver dysfunction, liver function (ALT and the TBIL) is higher than the
 ULN 3 times;

 4. With severe renal insufficiency, renal function (Cr) is twice higher than the ULN; or
 24-hour urine creatinine clearance rate (Ccr) lower than 50ml/min;

 5. Active tuberculosis, severe acute hepatitis and other infectious diseases in active
 period;

 6. ECOG score more than 3 points;

 7. Accompanied by malignant tumors and other clonal disease;

 8. Poor compliance and the researchers considered unsuitable for MSC infusion.