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
Study type: Interventional
Phase: Phase 2

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.
    

Detailed description: 
      Severe aplastic anemia (SAA) and myelodysplastic syndrome (MDS) are life-threatening bone
      marrow disorders. For SAA patients, long term survival can be achieved with immunosuppressive
      treatment. However, of those patients treated with immunosuppressive therapy, one quarter to
      one third will not respond, and about 50 percent of responders will relapse.

      Allogeneic bone marrow transplantation from either HLA-matched sibling or matched unrelated
      donor cures about 70 percent of patients with SAA and 30-60 percent of patients with MDS.
      Unfortunately, most patients with these disorders are not suitable candidates for
      hematopoietic stem cell transplantation (HSCT) due to advanced age or lack of a
      histocompatible donor. For such patients, transplantation using unrelated cord blood (UCB)
      has been shown to be a reasonable alternative transplant strategy. The advantage to UCB
      transplant is the ease and rapidity of availability, requirement of less than perfect HLA
      match, and lower rates of graft versus host disease compared to mismatched bone marrow or
      peripheral blood stem cell transplants. The major disadvantage of UCB transplantation in
      adults is the limited number of nucleated cells contained within the cord unit resulting in
      prolonged neutropenia and failure of engraftment which contributes to infection and
      transplant related mortality (TRM). In order to harness the advantage of UCB availability and
      to overcome the disadvantage of delayed neutrophil recovery, we propose to test whether
      co-administration of unrelated umbilical cord blood and a relatively low number of highly
      purified haploidentical peripheral blood CD34+ cells from a related donor might promote rapid
      engraftment and reduce TRM secondary to prolonged neutropenia associated with conventional
      umbilical cord blood transplant (UCBT).

      This research protocol is therefore designed to evaluate the safety and effectiveness of
      co-infusion of unrelated umbilical cord blood and haploidentical CD34 plus cells from a
      related donor following nonmyeloablative conditioning for neutropenic patients with SAA or
      MDS with refractory anemia (RA) that has proven to be refractory to medical therapy. Subjects
      will receive a novel non-myeloablative immunosuppressive conditioning regimen of
      cyclophosphamide, fludarabine, horse ATG (antithymocyte globulin) and one dose of total body
      irradiation (200cGy) followed by an infusion of the allografts. The haploidentical stem cell
      product will be T-cell depleted and enriched for CD34 plus cells using the Miltenyi CliniMacs
      system. To reduce TRM secondary to prolonged neutropenia associated with conventional UCB
      transplantation, haploidentical CD34+ stem cells will be co-infused with a single UCB unit
      (serologically matched at greater than or equal to 4/6 HLA loci).

      The primary endpoint is donor engraftment by day 42 (defined as an ANC of greater than 500
      from either the haplo donor, the cord, or both combined). Secondary endpoints will include
      standard transplant outcome variables such as non-hematological toxicities, incidence and
      severity of acute and chronic GVHD, and relapse of disease. We will also evaluate ANC
      recovery (ANC greater than 500 cells/microl) at day 22, and 100 day and 200 day treatment
      related mortality (TRM) of this novel transplant approach. Health related quality of life
      will also be assessed pre-transplant 30 and 100 days post-transplant, and every 6 months
      until 5 years post transplant.
    

Intervention name(s): Umbilical Cord Blood
Intervention type(s): Biological
Intervention description(s): 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.
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Nonmyeloablative; Haploidentical; Umbilical Cord Blood; SAA; Severe Aplastic Anemia; Myelodysplastic Syndrome; MDS