Stem Cell Transplant Using Peripheral and Cord Blood Stem Cells to Treat Severe Aplastic Anemia and Myelodysplastic Syndrome
Condition: Myelodysplastic Syndrome (MDS) With Refractory Anemia (RA); Severe Aplastic Anemia (SAA)
MeSH terms: Preleukemia; Anemia; Myelodysplastic Syndromes; Anemia, Aplastic; Anemia, Refractory; Syndrome
Intervention: Umbilical Cord Blood
Intervention description: unrelated umbilical cord blood will be co-infused with haploidentical CD34-selected cells from a related donor for treatment of severe aplastic anemia and myelodysplastic syndrome.
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 31.0
Sex: All
Minimum age: 4 Years
Maximum age: 75 Years
Healthy volunteers: No
Keywords: Nonmyeloablative; Haploidentical; Umbilical Cord Blood; SAA; Severe Aplastic Anemia; Myelodysplastic Syndrome; MDS

Summary:

      This study will evaluate the safety and effectiveness of treating patients with severe
      aplastic anemia (SAA) or myelodysplastic syndrome (MDS) with both peripheral blood stem cells
      from a family member and umbilical cord blood stem cells from an unrelated donor.

      Patients with SAA or MDS for whom other treatments have failed or are not available may be
      eligible for this study. Candidates may not have a tissue-matched sibling or matched
      unrelated donor and must have a family member who is a partial tissue type match.

      Participants undergo the following tests and procedures:

        -  Insertion of a central intravenous (IV) line (plastic tube) into a large vein. The tube
           is used for giving the donated stem cells and antibiotics and other medicines, for
           transfusions of red blood cells and platelets, and for collecting blood samples.

        -  Preparatory chemotherapy (fludarabine, cyclophosphamide and anti-thymocyte globulin) and
           total body irradiation to suppress immunity and prevent rejection of the donated cells.

        -  Infusion of the donated stem cells and umbilical cord cells.

        -  Immune suppression with the drugs tacrolimus, mycophenolate mofetil and prednisone to
           prevent rejection of the donated cells and to prevent graft-versus-host disease (GVHD),
           a complication of stem cell transplants in which the donors immune cells destroy the
           patients healthy tissues.

      The average hospital stay after stem cell transplantation is 3 to 4 weeks. Patients return
      for frequent follow-up visits for the first 2 to 4 months after transplantation. Once the
      patient returns home, his or her referring physician is asked to send results of any
      laboratory testing to the NIH researchers at least every 3 months for the first 3 years and
      annually thereafter. Patient follow-up visits are scheduled at NIH at 1, 2, 3, 4 and 5 years
      after transplantation to monitor for signs of disease or post-transplantation complications,
      such as infection or GVHD. After 5 years, participants are offered the opportunity to enroll
      in NHLBIs long-term evaluation and follow-up care protocol.
    

Eligibility criteria:

        -  INCLUSION CRITERIA - RECIPIENT:

          -  Diagnosed with severe aplastic anemia characterized by all of the following:

               1. Bone marrow cellularity less than 30 percent (excluding lymphocytes)

               2. Transfusion dependence for platelets and/or red blood cells (RBCs)

               3. Neutropenia (absolute neutrophil count less than 500 cells/microL) OR for
                  patients receiving granulocyte transfusions, absolute neutrophil count < 500
                  cells/microL before beginning granulocyte transfusions].)

        OR

          -  Diagnosed with myelodysplastic syndrome characterized by refractory anemia OR
             refractory anemia with ringed sideroblasts (RARS and at least one of the following:

               1. Neutropenia [(absolute neutrophil count < 500 cells/microL) OR for patients
                  receiving granulocyte transfusions, absolute neutrophil count < 500 cells/microL
                  before beginning granulocyte transfusions]) and history of 1 or more
                  opportunistic infections related to neutropenia. OR

               2. History of severe aplastic anemia transformed to MDS

          -  Intolerance of or failure to respond standard immunosuppressive therapy.

          -  Availability of at least one HLA-haploidentical (i.e. greater than or equal to 5/10
             and less than or equal to 8/10 HLA match) related donor (HLA-A, B, C, DR, and DO loci)
             who is available to donate CD34+ cells (4-75 years old).

          -  Availability of at least one 4/6 HLA-matched (HLA-A, B, and DR loci) cord blood unit
             from the National Marrow Donor Program (NMDP). The cord blood unit must contain a
             minimum total nucleated cells (TNC) (prior to thawing) of at least 1.5 x 10(7) cells
             per kilogram of recipient body weight with the following exception: if the minimum
             criterion of TNC is not met the cord unit must contain at least 1.7 x 10(5) CD34 plus
             cells/kg (prior to thawing).

          -  Ages 4-55 years inclusive.

          -  Ability to comprehend the investigational nature of the study and provide informed
             consent. The procedure will be explained to subjects aged 4-17 years with formal
             consent being obtained from parents or legal guardian.

               -  Telomere Length Testing

               -  In patients where a suspicion for a familial bone marrow failure syndromes (BMFS)
                  exists, TERC and TERT mutation testing will be performed on protocol 04-H-0012 or
                  performed elsewhere prior to enrolling on 04-H-0012.

        EXCLUSION CRITERIA - RECIPIENT:

          -  Availability of an HLA identical or 9/10 HLA matched(HLA A, B, C, DR, and DO
             loci-relative to serve as a stem cell donor.

          -  The patient is deemed to be a candidate for a 6/6 HLA matched unrelated stem cell
             transplant (availability of a donor and resources required for such a transplant).

          -  Eastern Cooperative Oncology Group (ECOG) performance status of 2 or more.

          -  Major anticipated illness or organ failure incompatible with survival from transplant

          -  Severe psychiatric illness. Mental deficiency sufficiently severe as to make
             compliance with the transplant treatment unlikely and making informed consent
             impossible.

          -  Positive pregnancy test for women of childbearing age.

          -  HIV positive

          -  Diagnosis of Fanconi anemia (by chromosome breakage study).

          -  Diffusion capacity of carbon monoxide (DLCO) less than 40 percent using DLCO corrected
             for Hgb or lung volumes (patients under the age of 10 may be excluded from this
             criterion if they have difficulty performing the test correctly and thus are unable to
             have their DLCO assessed) using DL Adj and DL/VA/Adj.

          -  Left ventricular ejection fraction less than 40 percent (evaluated by ECHO)

          -  Transaminases greater than 5x upper limit of normal (when transaminases are elevated,
             the subject may be excluded at the discretion of the PI).

          -  Serum bilirubin greater than 4 mg/dl

          -  Creatinine clearance less than 50 cc/min by 24 hr urine collection (adjusted for body
             surface area, i.e.50 ml/min/1.73m(2))

          -  Serum creatinine > 2.5 mg/dl

          -  Failure to collect an adequate number of CD34+ cells (i.e. greater than or equal 2 x
             10(6) CD34+ cells/kg) for transplantation from the subject s haploidentical relative.

          -  Presence of an active infection not adequately responding to appropriate therapy

          -  History of a malignant disease liable to relapse or progress within 5 years

        INCLUSION CRITERIA - RELATED HAPLOIDENTICAL DONOR DONATING PURIFIED CD34 PLUS CELLS:

          -  HLA mismatched family donor (greater than or equal to 5/10 and less than or equal to
             8/10 HLA matched (HLA-A, B, C, DR and DO loci) who is available to donate CD34+ cells.

          -  Ages 4-75 inclusive

          -  Weight greater than or equal to 15 kg.

          -  For adults: Ability to comprehend the investigational nature of the study and provide
             informed consent. For minors: Written informed consent from one parent or guardian who
             is not the recipient of the transplant and informed assent: The process will be
             explained to the minor on a level of complexity appropriate for their age and ability
             to comprehend.

          -  If there is a suspicion of familial BMFS in the recipient, then the donor must have
             undergone genetic testing for genes associated with BMFS - performed at a
             CLIA-certified laboratory, prior to enrolling in this protocol.

        EXCLUSION CRITERIA RELATED DONOR (ANY OF THE FOLLOWING):

          -  Pregnant or breastfeeding.

          -  A suitable adult haplo identical donor is available.

          -  Unfit to receive filgrastim (G-CSF) and undergo apheresis (history of stroke, MI,
             unstable angina, uncontrolled hypertension, severe heart disease or palpable spleen).

          -  HIV positive (Donors who are positive for HBV, HCV or HTLV I/II, T. cruzi [Chagas] may
             be used at the discretion of the investigator following counseling and approval from
             the recipient).

          -  Sickling hemoglobinopathies including HbSS, HbAS, HbSC. Donors with HbAS are
             acceptable.

          -  Severe psychiatric illness. Mental deficiency sufficiently severe as to make
             compliance with the BMT treatment unlikely and making informed consent impossible.

          -  Screening test positive for Chagas disease (Trypanosoma cruzi /T.
             cruzi/trypanosomiasis) confirmed by the Center for Disease Control (CDC).