A Pilot Study of HSCT for Patients With High-risk Hemoglobinopathy Using a Nonmyeloablative Preparative Regimen
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 Thalassemia Hemoglobinopathies||Other: Busulfan; Fludarabine; cyclosporine A and MMF|
|Study Design:||Intervention Model: Single Group Assignment
Masking: None (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|
- Development of GVHD Within 1 Year of BMT [ Time Frame: 1 year ]GVHD is assessed by physical exam, bloodwork and biopsy.
- Engraftment at 1 Year Post BMT. [ Time Frame: 1 year ]Measurement of total PBMC chimerism
- Incidence of Grade 2-4 Acute GVHD. [ Time Frame: 100 days ]
|Study Start Date:||June 2002|
|Study Completion Date:||May 2014|
|Primary Completion Date:||May 2014 (Final data collection date for primary outcome measure)|
AHCT in High Risk SCD
Intervention: Busulfan; Fludarabine; cyclosporine A and MMF
Other: Busulfan; Fludarabine; cyclosporine A and MMF
Hematopoietic stem cell transplantation from a matched sibling or unrelated donor following a reduced intensity conditioning regimen
Other Name: Busulfex, Fludara, Gengraf, CellCept
Please refer to this study by its ClinicalTrials.gov identifier: NCT00427661
|United States, Pennsylvania|
|Children's Hospital of Pittsburgh|
|Pittsburgh, Pennsylvania, United States, 15213|
|Principal Investigator:||Lakshmanan Krishnamurti, MD||Children's Hospital Medical Center, Cincinnati|