A Pilot Study of HSCT for Patients With High-risk Hemoglobinopathy Using a Nonmyeloablative Preparative Regimen
Condition: Sickle Cell Disease; Thalassemia; Hemoglobinopathies
MeSH terms: Anemia, Sickle Cell; Thalassemia; Hemoglobinopathies
Study type: Interventional

Summary: 
      Hypothesis 1: A novel nonmyeloablative condition regimen will be safe and efficacious in
      producing stable donor chimerism and cure of severe hemoglobinopathy.

      Hypothesis 2: Stable donor chimerism will result in amelioration of cerebral vasculopathy,
      improved cerebral perfusion and neurocognitive function.

      Specific Aim 1: Study the safety and efficacy of a novel non-toxic conditioning regimen for
      HSCT for patients with severe hemoglobinopathies and the kinetics of lineage specific
      chimerism after HSCT

      We will test our hypothesis that a novel nonmyeloablative condition regimen will be safe and
      efficacious in producing stable donor chimerism and cure of severe hemoglobinopathy:

      Specific Aim 2: Optimize the immunosuppressive regimen for HSCT patients through a thorough
      understanding of the pharmacokinetics of Busulfan (BU) and mycophenolate mofetil (MMF) in the
      patient population. This will involve:

        1. Determine the pharmacokinetics of intravenously and orally administered MMF and
           intravenous BU in patients receiving HSCT.

        2. Determine the relationship of Area under the curve (AUC) of BU and mean trough
           concentrations of mycophenolic acid (MPA) to engraftment and graft versus host disease
           (GVHD).

        3. Determine the relationship of Area under the curve (AUC) and steady state concentration
           of BU to engraftment at day 30 and 1 year post HSCT.

      Specific Aim 3: Study the effect of complete or partial donor chimerism on silent and overt
      cerebral vasculopathy, and neurocognitive functioning in patients with SCD undergoing HSCT.
      We will test our hypothesis that stable donor chimerism will result in improvement in
      cerebral vasculopathy and neurocognitive function. This will include.

        1. Determine effect of transplantation silent and overt cerebral vasculopathy by comparison
           MRA and TCD 1 year after HSCT to pre-HSCT studies.

        2. Determine effect on HSCT on neurocognitive function. Specific Aim 4: To determine the
           rate of T cell immune reconstitution in children with sickle cell disease following
           myeloablative compared to nonmyeloablative stem cell transplantation, using
           immunophenotyping assays, CDR3 spectratyping TREC analysis, and measurement of T cell
           specific donor engraftment.
    

Detailed description: 
      Severe hemoglobinopathies such as sickle cell disease (SCD) and Thalassemia are associated
      with considerable morbidity, organ damage and premature mortality. Allogeneic hematopoietic
      stem cell transplantation (HSCT) is the only therapy that can cure a hemoglobinopathy. The
      applicability of HSCT for hemoglobinopathies is limited by the paucity of suitable donors,
      and risk of early regimen-related toxicity and the late effects. Reduction of the dose of
      myelotoxic drugs in preparative regimens prior to HSCT has the potential to increase the
      applicability of this curative option for patients with hemoglobinopathies. We hypothesize
      that a preparative regimen that maximizes host immunosuppression without myeloablation will
      be well tolerated and sufficient for engraftment of donor hematopoietic stem cells in
      patients with severe hemoglobinopathies. The long term objective of this research is to
      develop novel, less toxic approaches to HSCT for patients with severe hemoglobinopathies.
      Specific aims: 1. To evaluate the safety and efficacy of a novel nontoxic nonmyeloablative
      approach to hematopoietic stem cell transplantation for hemoglobinopathies. 2. To optimize
      the immunosuppressive regimen for HSCT patients through a thorough understanding of the
      pharmacokinetics of Busulfan (BU) and Mycophenolic acid (MPA) 3. To determine the effect of
      partial or complete donor chimerism on cerebral vasculopathy in patients with SCD. 4. To
      determine the rate of T cell immune reconstitution in children with sickle cell disease
      following myeloablative compared to nonmyeloablative stem cell transplantation, using
      immunophenotyping assays, CDR3 spectratyping TREC analysis, and measurement of T cell
      specific donor engraftment. Subjects meeting eligibility criteria in whom an human leukocyte
      antigen matched, partially mismatched related or unrelated donor of bone marrow or umbilical
      cord blood will receive a HSCT after a nonmyeloablative preparative regimen consisting of BU,
      Fludarabine (FLU), total lymphoid radiation and Anti-Thymocyte globulin followed by
      prophylaxis against graft versus host disease with cyclosporine A and MMF. Patients will be
      studied for survival, cure of hemoglobinopathy, absence of severe regimen related toxicity
      and graft versus host disease. The relationship of engraftment, survival and Graft versus
      host disease to kinetics of lineage specific donor chimerism and area under the curve for
      Mycophenolic acid and Busulfan will be studied.
    

Intervention name(s): Busulfan; Fludarabine; cyclosporine A and MMF
Intervention type(s): Other
Intervention description(s): Hematopoietic stem cell transplantation from a matched sibling or unrelated donor following a reduced intensity conditioning regimen
Other intervention name(s): Busulfex, Fludara, Gengraf, CellCept
Intervention MeSH terms: Cyclosporine; Fludarabine; Busulfan; Cyclosporins
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Sickle Cell Disease; Thalassemia; Hemoglobinopathies