A Pilot Study of HSCT for Patients With High-risk Hemoglobinopathy Using a Nonmyeloablative Preparative Regimen

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.