Brief Title
Safety and Efficacy of Patient's Own AD-MSC and AD-HSC Transplantation in Patients With Severe Aplastic Anemia
Official Title
A Multicenter, Randomized, Controlled Study of the Efficacy and Safety of the Combination of Adipose Tissue-derived Hematopoietic Stem Cells (AD-HSCs) and ATG in the Treatment of Severe Aplastic Anemia
Brief Summary
RATIONALE: It has been shown that about 30% of patients do not respond to immunosuppressive
therapy or experience recurrence, and graft rejection and graft-versus-host-disease (GVHD)
decrease event-free survival to 30% to 50% in the alternative donor (matched unrelated,
partially matched family member) transplantation. Although an overall and disease free
survival of 85% to 100%, can be obtained in allogeneic blood or bone marrow stem cell
transplantation using an human leukocyte antigen (HLA) matched sibling donor, only about 25%
of patients have such a donor.
PURPOSE: In an attempt to avoid GVHD, reduce earlier infection rate and decrease
regimen-related toxicity while maintaining better engraftment, this study is to evaluate the
effectiveness and safety of patient's own adipose-derived mesenchymal stem cell (AD-MSC) or
AD-MSC transdifferentiated HSC (AD-HSC) transplant after an immunosuppressive regimen in
treating patients who have severe aplastic anemia.
The patient will be in the study for one year for observation and active monitoring. After
treatment and active monitoring are over, the patient's medical condition will be followed
indefinitely. The principle measures of safety and efficacy will be :
1. Patient survival probability at 3 months, 6 months and 1 year.
2. Engraftment at 3 months, 6 months and 1 year
3. Incidence of graft versus host disease (GVHD), incidence of acute and chronic GVHD and
Incidence of earlier infection rate as well as other complications within 6 months and 1
years.
Detailed Description
Severe aplastic anemia is characterized by severe deficiencies in peripheral-blood platelets,
white cells, and red cells. These defects in mature cells occur because aplastic bone marrow
contains severely reduced numbers of hematopoietic stem cells. To date, Hematopoietic stem
cell (HSC) transplants are routinely used to treat patients with many different diseases,
including various cancers and blood disorders, such as aplastic anemia. The main sources of
HSCs are bone marrow, cord blood and peripheral blood. However, challenges include obtaining
enough functional HSCs to ensure optimal engraftment, and avoiding immune rejection and other
complications associated with allogeneic transplantations. Novel abundant sources of
clinical-grade HSCs are therefore being sought.
Our novel studies have demonstrated that adipose-derived mesenchymal stem cells (AD-MSCs) can
be converted rapidly (in 4 days) into AD-HSCs on a large scale (2X108-9 cluster of
differentiation 34（CD34）positive cells) by transfection of small RNAs to the the early region
1A (E1A)-like inhibitor of differentiation 1 (EID1) in the presence of specific cytokines. In
vitro, AD-HSCs expanded efficiently and resembled cord-blood HSCs in phenotype, genotype, and
colony-forming ability. In a mouse model, primary and secondary transplantation analysis and
repopulating assays showed that AD-HSCs homed to the bone marrow, differentiated into
functional blood cells, and showed a long-term ability to self-renew. we show that
adipose-derived mesenchymal stem cells (AD-MSCs) can be converted into AD-HSCs by
transfection of small RNAs to the E1A-like inhibitor of differentiation 1 (EID1) in the
presence of specific cytokines. In vitro, AD-HSCs expanded efficiently and resembled
cord-blood HSCs in phenotype, genotype, and colony-forming ability. In a mouse model, primary
and secondary transplantation analysis and repopulating assays showed that AD-HSCs homed to
the bone marrow, differentiated into functional blood cells, and showed a long-term ability
to self-renew. In the safety aspect, we saw no evidence of leukemia, teratoma and other
cancers in the blood, testes and subcutaneous tissues of transplanted mice. More importantly,
our preliminary data have shown that AD-HSCs can reconstitute hematopoietic function in five
patients with severe aplastic anemia. Based on these premilitary studies,, we have determined
to conduct a further clinical investigation in multiple medical centers. In this study we
plan to enroll up to 90 patients, to make a comprehensive assessment for this new treatment
regimen and to show it is equal or superior to the current immunosuppressive regimen.
Patients will be in the study for one years for treatment and active monitoring. All patients
will be followed until death.
Study Phase
Phase 1/Phase 2
Study Type
Interventional
Primary Outcome
Engraftment at 42 days post AD-HSC transplantation for patients with severe aplastic anemia.
Secondary Outcome
To estimate the overall survival (OS) at 1 year following AD-HSC transplantation for Patients with Severe Aplastic Anemia
Condition
Severe Aplastic Anemia
Intervention
Rabbit antithymoglobulin (ATG)
Study Arms / Comparison Groups
Rabbit antithymoglobulin （ATG）
Description: Patient in this arm will receive rabbit ATG at 3.5 mg/kg/dose IV from day -6 to -2 with the goals of ablating host repressive T cells.
Publications
* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.
Recruitment Information
Recruitment Status
Drug
Estimated Enrollment
90
Start Date
January 2015
Completion Date
July 2017
Primary Completion Date
January 2017
Eligibility Criteria
Inclusion Criteria:
Male or female recipients must have histopathologically confirmed diagnosis of SAA-I
without or with more than 6 months after less than one treatment with ATG. Diagnostic
Criteria for Server Aplastic Anemia will be based on the definitions set forth by the
international Aplastic Anemia Study Group.
At least two of the following:
Absolute neutrophil count ≤ 0.5 X 109/l, Platelet count ≤ 20 X 109 /l, Anemia with
corrected reticulocyte count ≤ 1%, and Bone marrow cellularity ≤ 25%, or bone marrow
cellularity ≤ 50% with fewer than 30% hematopoietic cell, Hepatic: alanine aminotransferase
(ALT)/ aspartate aminotransferase (AST) no greater than 4 times normal, Bilirubin: no
greater than 2 mg/dl, Renal: Creatinine clearance at least 50 ml/min, Cardiovascular:
Shortening fraction or ejection fraction at least 40% of normal for age by echocardiogram
or radionuclide scan.
No clinically significant comorbid illnesses (e.g., myocardial infarction or
cerebrovascular accident).
Exclusion Criteria:
Active and uncontrolled infection, Active bleeding, Severe allergic history of ATG, HIV-1
infection, Pregnancy or breastfeeding, Carbon monoxide lung diffusion capacity (DLCO) <40%
predicted, SAA-II, Patients with severe psychological disorders, Recipients of other
clinical trials.
Gender
All
Ages
14 Years - 70 Years
Accepts Healthy Volunteers
No
Contacts
james Q Yin, M.D.,Ph.D., 86-01-84008003, [email protected]
Location Countries
China
Location Countries
China
Administrative Informations
NCT ID
NCT02407470
Organization ID
Ginkgocell-ADHSC-AA-001
Responsible Party
Principal Investigator
Study Sponsor
Navy General Hospital, Beijing
Collaborators
Peking Union Medical College Hospital
Study Sponsor
james Q Yin, M.D.,Ph.D., Principal Investigator, The military general hospital of Beijing
Verification Date
March 2015