A Pilot Study of HSCT for Patients With High-Risk Hemoglobinopathy Using a Nonmyeloablative Preparative Regimen
Recruitment status was Recruiting
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:
- Determine the pharmacokinetics of intravenously and orally administered MMF and intravenous BU in patients receiving HSCT.
- 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).
- 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.
- Determine effect of transplantation silent and overt cerebral vasculopathy by comparison MRA and TCD 1 year after HSCT to pre-HSCT studies.
- 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.
Sickle Cell Disease
Drug: Busulfan; Fludarabine; cyclosporine A and MMF
|Study Design:||Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||A Pilot Study of Allogeneic Hematopoietic Stem Cell Transplantation for Patients With High Risk Hemoglobinopathy Using a Non-Myeloablative Preparative Regimen to Achieve Stable Mixed Chimerism|
- GVHD at 100 days, 6 months and 1 year will be tabulated by grade. [ Time Frame: 100 days, 6 months and 1 year ] [ Designated as safety issue: Yes ]
- The incidence of ≥5% chimerism at 100 days, 6 months and 1 year will be estimated, and reported with 95% confidence bounds. [ Time Frame: 100 days, 6 months and 1 year ] [ Designated as safety issue: No ]
- The association between % donor chimerism of lymphocytes and erythroid precursors at day 30 to % donor chimerism in the bone marrow at 1 year will be assessed via the Spearman correlation coefficient. [ Time Frame: day 30 and 1 year ] [ Designated as safety issue: No ]
- In addition, the Wilcoxon test will be used to assess association of the % chimerism on day 30 to successful transplantation, which is defined as ≥ 5% donor chimerism in the bone marrow at 1 year. [ Time Frame: Day 30, 1 year ] [ Designated as safety issue: No ]
|Study Start Date:||June 2002|
|Estimated Study Completion Date:||December 2012|
|Estimated Primary Completion Date:||June 2012 (Final data collection date for primary outcome measure)|
Drug: Busulfan; Fludarabine; cyclosporine A and MMF
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.
|Contact: Lakshmanan Krishnamurti, MDemail@example.com|
|United States, Pennsylvania|
|Children's Hospital of Pittsburgh||Recruiting|
|Pittsburgh, Pennsylvania, United States, 15213|
|Principal Investigator:||Lakshmanan Krishnamurti, MD||Children's Hospital Medical Center, Cincinnati|