A Pilot Study of HSCT for Patients With High-risk Hemoglobinopathy Using a Nonmyeloablative Preparative Regimen
|The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.|
|ClinicalTrials.gov Identifier: NCT00427661|
Recruitment Status : Completed
First Posted : January 29, 2007
Results First Posted : August 18, 2016
Last Update Posted : August 18, 2016
- Study Details
- Tabular View
- Study Results
- How to Read a Study Record
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.
|Condition or disease||Intervention/treatment||Phase|
|Sickle Cell Disease Thalassemia Hemoglobinopathies||Other: Busulfan; Fludarabine; cyclosporine A and MMF||Not Applicable|
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||8 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|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|
|Study Start Date :||June 2002|
|Actual Primary Completion Date :||May 2014|
|Actual Study Completion Date :||May 2014|
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
- 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 ]
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.
|Ages Eligible for Study:||3 Years to 35 Years (Child, Adult)|
|Sexes Eligible for Study:||All|
|Accepts Healthy Volunteers:||No|
Patients with SCD 0-35 years of age with an HLA-identical or 1 HLA antigen mismatched bone marrow or up to 2 HLA antigen mismatched umbilical cord blood (UCB) donor with one or more of the following:
- Stroke, CNS hemorrhage or a neurologic event lasting longer than 24 hours, or abnormal cerebral MRI or cerebral arteriogram or MRI angiographic study and impaired neuropsychological testing,
- Acute chest syndrome with a history of recurrent hospitalizations or exchange transfusions,
- Recurrent vaso-occlusive pain 3 or more episodes per year for 3 years or more years or recurrent priapism,
- Impaired neuropsychological function and abnormal cerebral MRI scan,
- Stage I or II sickle lung disease,
- Sickle nephropathy (moderate or severe proteinuria or a glomerular filtration rate [GFR] 30-50% of the predicted normal value),
- Bilateral proliferative retinopathy and major visual impairment in at least one eye,
- Osteonecrosis of multiple joints with documented destructive changes,
- Requirement for chronic transfusions but with RBC alloimmunization >2 antibodies during long term transfusion therapy.
- Patients with transfusion dependent Thalassemia 0-35 years of age with an HLA-identical or 1 HLA antigen mismatched bone marrow or up to 2 HLA antigen mismatched UCB donor.
- Patients with sickle cell disease or Thalassemia who have failed to engraft or have autologous recovery are eligible for this protocol.
- Patients must meet above criteria.
- If first transplant was a non-myeloablative regimen, the second transplant can occur at any time.
- If the first transplant was a myeloablative regimen, then the second transplant must be > 6 months from the first transplant.
Patients with one or more of the following:
- Karnofsky or Lansky performance score <70,
- Acute hepatitis or evidence of moderate or severe portal fibrosis or cirrhosis on biopsy,
- Stage III-IV lung disease,
- GFR<30% predicted normal values.
- Pregnant or lactating females.
- Active serious infection whereby patient has been on intravenous antibiotics for one week prior to study entry. Any patient with AIDS or ARC or HIV seropositivity. Any patient with invasive aspergillums infection within one year of study entry.
- Psychologically incapable of undergoing BMT with associated strict isolation or documented history of medical non-compliance.
- Patients not able to receive TLI due to prior radiation therapy.
Donor Inclusion Criteria
- Donor must be in good health based on review of systems and results of physical examination.
- Donor must have a normal hemoglobin, white count, platelet count and PTT.
- Female donors of childbearing potential must have a negative pregnancy test.
Donor Exclusion Criteria
- Donor has active infection (including HIV, hepatitis).
- Donor is a lactating female.
In the case where more than one donor meets the eligibility criteria, donor selection will be guided by the following considerations:
- HLA A, B, DRB1 identical sibling donor is preferable to an unrelated donor
- Homozygous normal donor is preferable to heterozygote (carrier)
- ABO-compatible donor is preferable to ABO-incompatible donor
- Younger donor is preferable to older
- Cytomegalovirus seronegative donor is preferable to CMV seropositive donor, if the patient is CMV negative
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): 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|
|Responsible Party:||Lakshmanan Krishnamurti, MD, University of Pittsburgh|
|Other Study ID Numbers:||
|First Posted:||January 29, 2007 Key Record Dates|
|Results First Posted:||August 18, 2016|
|Last Update Posted:||August 18, 2016|
|Last Verified:||July 2016|
Sickle Cell Disease
Anemia, Sickle Cell
Anemia, Hemolytic, Congenital
Genetic Diseases, Inborn
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Antineoplastic Agents, Alkylating