Mesenchymal Stem Cells Transplantation to Patients With Relapsed/Refractory Aplastic Anemia. (MSC)

• Hematologic response [ Time Frame: up to 1 year ] [ Designated as safety issue: No ]
• Relapse [ Time Frame: up to 1 year ] [ Designated as safety issue: No ]
• Clonal evolution to PNH, myelodysplasia or acute leukemia [ Time Frame: up to 1 year ] [ Designated as safety issue: No ]
• Survival [ Time Frame: up to 1 year ] [ Designated as safety issue: No ]

The study is a phase I/II trial designed to establish the safety and efficacy of intravenous administration of bone marrow derived mesenchymal stem cells from related donor to patients with relapsed/refractory 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). Patients with nSAA can be offered supportive care, anabolic steroids, and/or low-dose steroids or cyclosporine (CsA).Patients with SAA and vSAA can be offered immunosuppressive treatment involving injections of Anti-thymocyte globulin (ATG) in combination with cyclosporine (CsA). However, some nSAA patients remains dependent to transfusion, the treatment response with ATG for SAA is at best between 50-60%,30%-40% patients relapse following an initial response to treatment, they also do not have a HLA-matched donor for bone marrow transplantation. These patients have a high risk of dying without additional treatment. Since the prognosis of these refractory and relapsed AA patients remains poor, there is a need for more safe and effective therapy that can improve response rates and remission duration in refractory and relapsed AA.

Mesenchymal stem cells (MSCs) are part of the bone marrow stem cells repertoire. The main role of MSCs is to support hematopoiesis. Recently, significant interactions between MSCs and cells from the immune system have been demonstrated:MSCs were found to downregulate T and B lymphocytes, natural killer cells (NK) and antigen presenting cells through various mechanisms, including cell-to-cell interaction and soluble factor production. MSCs can fully suppress T cell function which involves some degree of MSC activation or 'licensing' thought to involve interferon (IFN)-γ in conjunction with IL-1α, IL-1β or tumour necrosis factor-a. Non-specific suppression of T cell proliferation is mediated by soluble factors such as transforming growth factor (TGF)-β, kynurenine, prostaglandin E2 (PGE2), nitric oxide, haem oxygenase products and insulin-like growth factor binding protein. Since the haematopoietic support and immunomodulatory effects, bone marrow-derived human MSCs transplantation maybe a safe novel therapeutic approach for patients with refractory and relapsed AA.

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Inclusion Criteria:

• Patients must fulfill definition of aplastic anaemia:

There must be at least two of the following:

haemoglobin < 100g/L; platelet count < 50 x 109/L; neutrophil count < 1.5 x 109/L, and a hypocellular bone marrow;

SAA as defined by a hypocellular bone marrow of <25% cellularity and two of the following:

neutrophil count < 0.5 x 109/L platelets < 20 x 109/L reticulocytes < 20 x 109/L nSAA as defined by a hypocellular bone marrow and cytopenia in at least two cell lines and neutrophil count > 0.5 x 109/L, and red cell and/or platelet transfusion dependence.

• Patients belong to acquired aplastic anaemia.
• Patients with a history SAA must have had an incomplete response at least 3 months following treatment with ATG/CsA, or they must have relapsed following an initial response to treatment, and they do not have a HLA-matched donor for bone marrow transplantation. Patients with a history nSAA must have red cell and/or platelet transfusion dependence.
• Peripheral blood counts at the time of enrollment must include at least one of the following: haemoglobin < 90 g/L or red blood cell (RBC) transfusion dependence, PMN < 1 x 109/L, or platelet count < 50 x 109/L.
• Patients must have organ function as defined below:

total bilirubin within normal institutional limits (NV: 0.0-20.5 umol/L) AST(SGOT)/ALT(SGPT) < 2.5 × institutional upper limit of normal AST (NV: 0-35 U/L); ALT (NV: 0-40 U/L) Creatinine within normal institutional limits (NV: 53-106 umol/L) or Creatinine clearance > 1.25 ml/s for patients with creatinine levels above institutional normal.

• Age minimum 16 years old with no upper age limit.
• Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

• Patients may not be receiving any other investigational agents within 4 weeks of study entry.
• History of allergic reactions attributed to compounds of similar biologic composition to mesenchymal stem cells.
• Current diagnosis of Fanconi's anemia, Dyskeratosis Congenita (DC) or other hereditary forms of AA.
• Psychiatric, addictive or any other disorder that compromises ability to give a truly informed consent.
• Age < 16 years old.
• ECOG performance status > 2.
• Malignancy within the last 5 years.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection (defined as invasive fungal infection and progressive CMV viremia), symptomatic congestive heart failure (NYH class III and IV), unstable angina pectoris, or cardiac arrhythmia.
• Pregnant or breastfeeding women.
• HIV-positive patients.

• Guangzhou Municipal Twelfth People's Hospital
• Guangdong Prevention and Treatment Center for Occupational Diseases