Donor Stem Cell Transplant in Treating Young Patients With Myelodysplastic Syndrome, Leukemia, Bone Marrow Failure Syndrome, or Severe Immunodeficiency Disease
Condition: Congenital Amegakaryocytic Thrombocytopenia; Leukemia; Myelodysplastic Syndromes; Severe Congenital Neutropenia
MeSH terms: Leukemia; Preleukemia; Myelodysplastic Syndromes; Thrombocytopenia; Neutropenia; Immunologic Deficiency Syndromes; Syndrome
Study type: Interventional
Phase: Phase 1

Summary: 
      RATIONALE: Giving chemotherapy and total body irradiation before a donor bone marrow
      transplant or peripheral blood stem cell transplant helps stop the growth of cancer cells. It
      also helps stop the patient's immune system from rejecting the donor's stem cells. When the
      healthy stem cells from a donor are infused into the patient they may help the patient's bone
      marrow make stem cells, red blood cells, white blood cells, and platelets. Sometimes the
      transplanted cells from a donor can make an immune response against the body's normal cells.
      Giving antithymocyte globulin and removing the T cells from the donor cells before transplant
      may stop this from happening.

      PURPOSE: This phase I trial is studying the side effects and best dose of donor T cells and
      antithymocyte globulin when given together with chemotherapy and total-body irradiation in
      treating young patients who are undergoing T-cell depleted donor stem cell transplant for
      myelodysplastic syndrome, leukemia, bone marrow failure syndrome, or severe immunodeficiency
      disease.
    

Detailed description: 
      OBJECTIVES:

        -  Determine the efficacy and toxicity of stem cell-enriched, T-cell-depleted,
           haplocompatible allogeneic hematopoietic stem cell transplantation in children with
           high-risk myelodysplastic syndromes, high-risk leukemia, severe acquired or congenital
           cytopenias, or primary immunodeficiency diseases.

        -  Determine the toxicity of a fludarabine and thiotepa-containing regimen in combination
           with lower doses of antithymocyte globulin in these patients.

        -  Determine the engraftment rate in patients treated with this regimen.

        -  Define T-cell reconstitution in these patients.

        -  Determine the toxicity and effects of administering stem cell and T-cell boosts after
           transplantation on hematopoiesis and immune reconstitution in these patients.

      OUTLINE: This is a dose-escalation study of donor CD3+ cells and antithymocyte globulin
      (ATG).

        -  Cytoreductive regimen: Patients undergo total body irradiation twice daily on days -9 to
           -7. Patients also receive fludarabine IV on days -6 to -2, thiotepa IV every 12 hours on
           day -6, and ATG IV on days -5 to -2.

        -  Transplantation: Patients undergo CD34-enriched, T-cell-depleted, haplocompatible
           allogeneic peripheral blood stem cell or bone marrow transplantation on day 0.

        -  Donor T-cell infusion:Patients with no active graft-vs-host disease and evidence of
           engraftment but low absolute CD34+ lymphocyte count at 12 weeks post transplant may
           receive donor CD3+ cells at 4-week intervals.

        -  Donor stem cell boost: Patients with engraftment but either cytokine or transfusion
           dependent at 12 weeks post transplant may receive a boost of donor CD34+ cells.

      Cohorts of 3-6 patients receive escalating doses of donor CD3+ cells and ATG until the
      optimum is determined. The optimum dose is defined as the dose at which both engraftment and
      T-cell recovery occur, without dose-limiting toxicity, in ≥ 5 of 6 patients.

      After the completion of study treatment, patients are followed periodically for 5 years and
      then every 5 years thereafter.

      PROJECTED ACCRUAL: A total of 21 patients will be accrued for this study.
    

Intervention name(s): anti-thymocyte globulin; therapeutic allogeneic lymphocytes; fludarabine phosphate; thiotepa; allogeneic bone marrow transplantation; allogeneic hematopoietic stem cell transplantation; in vitro-treated peripheral blood stem cell transplantation; total-body irradiation
Intervention type(s): Biological; Biological; Drug; Drug; Procedure; Procedure; Procedure; Radiation
Intervention MeSH terms: Fludarabine; Fludarabine phosphate; Thiotepa; Antilymphocyte Serum
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: childhood acute lymphoblastic leukemia in remission; childhood acute myeloid leukemia in remission; de novo myelodysplastic syndromes; previously treated myelodysplastic syndromes; secondary myelodysplastic syndromes; secondary acute myeloid leukemia; juvenile myelomonocytic leukemia; chronic phase chronic myelogenous leukemia; refractory anemia with excess blasts in transformation; refractory anemia with excess blasts; severe congenital neutropenia; congenital amegakaryocytic thrombocytopenia; childhood chronic myelogenous leukemia; childhood myelodysplastic syndromes