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

NCT00427661 | Completed Results DMC

• 1 other identifier: IRB #0504048
• Study Type: interventional
• Target: 8
• Locations: 1 country
• Sites: 1

Brief 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. 1.Determine the pharmacokinetics of intravenously and orally administered MMF and intravenous BU in patients receiving HSCT.
2. 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. 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.
4. 4.Determine effect of transplantation silent and overt cerebral vasculopathy by comparison MRA and TCD 1 year after HSCT to pre-HSCT studies.
5. 5.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.

Conditions

Sickle Cell Disease; Thalassemia; Hemoglobinopathies

Keywords

Sickle Cell Disease; Thalassemia; Hemoglobinopathies

Outcome Measures

Primary Outcomes (2)

• Development of GVHD Within 1 Year of BMT

  GVHD is assessed by physical exam, bloodwork and biopsy.

  1 year

• Engraftment at 1 Year Post BMT.

  Measurement of total PBMC chimerism

  1 year

Secondary Outcomes (1)

• Incidence of Grade 2-4 Acute GVHD.

  100 days

Study Arms (1)

AHCT in High Risk SCD

OTHER

Intervention: Busulfan; Fludarabine; cyclosporine A and MMF

Other: Busulfan; Fludarabine; cyclosporine A and MMF

Interventions

Busulfan; Fludarabine; cyclosporine A and MMF OTHER

Hematopoietic stem cell transplantation from a matched sibling or unrelated donor following a reduced intensity conditioning regimen

Also known as: Busulfex, Fludara, Gengraf, CellCept

AHCT in High Risk SCD

Eligibility Criteria

• Age: 3 Years - 35 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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.
• Second Transplants
• 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.

You may not qualify if:

• 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 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 has active infection (including HIV, hepatitis).
• Donor is a lactating female.
• Donor Selection

Sponsors & Collaborators

• University of Pittsburgh: lead

Study Sites (1)

Children's Hospital of Pittsburgh

Pittsburgh, Pennsylvania, 15213, United States

Location

MeSH Terms

Conditions

Anemia, Sickle Cell; Thalassemia; Hemoglobinopathies

Interventions

Busulfan; fludarabine; Cyclosporine; fludarabine phosphate; Cyclosporins; Mycophenolic Acid

Condition Hierarchy (Ancestors)

Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Anemia; Hematologic Diseases; Hemic and Lymphatic Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Butylene Glycols; Glycols; Alcohols; Organic Chemicals; Mesylates; Alkanesulfonates; Alkanesulfonic Acids; Alkanes; Hydrocarbons, Acyclic; Hydrocarbons; Sulfonic Acids; Sulfur Acids; Sulfur Compounds; Peptides, Cyclic; Macrocyclic Compounds; Polycyclic Compounds; Peptides; Amino Acids, Peptides, and Proteins; Caproates; Acids, Acyclic; Carboxylic Acids; Fatty Acids; Lipids

Results Point of Contact

• Title: Nancy Harter-Administrative Director of Research
• Organization: University of Pittsburgh-Department of Pediatrics

harterne@upmc.edu

412-692-7487

Study Officials

• Lakshmanan Krishnamurti, MD

  Children's Hospital Medical Center, Cincinnati

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: MD

Study Record Dates

• First Submitted: January 18, 2007
• First Posted: January 29, 2007
• Study Start: June 1, 2002
• Primary Completion: May 1, 2014
• Study Completion: May 1, 2014
• Last Updated: August 18, 2016
• Results First Posted: August 18, 2016

Record last verified: 2016-07

Locations

US (1)