Stem Cell Transplant for Hemoglobinopathy

• Determine the incidence of chimerism at 100 days, 6 months and 1 year. [ Time Frame: 100 days, 6 months and 1 year ] [ Designated as safety issue: No ]
• Determine the incidence of grade 2-4 and 3-4 acute GVHD at 100 days. [ Time Frame: 100 days ] [ Designated as safety issue: Yes ]
• Determine the incidence of chronic GVHD at 6 months and 1 year. [ Time Frame: 6 months and 1 year. ] [ Designated as safety issue: Yes ]
• Compare the quality of life (QOL) at 1, 2 and 5 years with the pre-transplant assessment. [ Time Frame: 1, 2 and 5 years ] [ Designated as safety issue: No ]
• Determine overall and disease free survival at 100 days and 1 year. [ Time Frame: 100 days and 1 year ] [ Designated as safety issue: No ]
• Determine physical characteristics and biologic effects of mixed populations of donor and host red blood cells [ Time Frame: During study ] [ Designated as safety issue: No ]
• Determine the concentration of Campath in the serum [ Time Frame: Day 0 ] [ Designated as safety issue: No ]

• Determine the incidence of chimerism at 100 days, 6 months and 1 year.
• Determine the incidence of grade 2-4 and 3-4 acute GVHD at 100 days.
• Determine the incidence of chronic GVHD at 6 months and 1 year.
• Determine the physical characteristics and biologic effects of mixed populations of donor and host red blood cells (RBCs).
• Compare the quality of life (QOL) at 1, 2 and 5 years with the pre-transplant assessment.
• Determine overall and disease free survival at 100 days and 1 year.

This study tests the clinical outcomes of one of two preparative regimens (determined by available donor source) in patients with non-malignant hemoglobinopathies. The researchers hypothesize that these regimens will have a positive effect on post transplant engraftment and the incidence of graft-versus-host-disease.

Regimen A2 has replaced Regimen A in this study. Two patients were treated on Regimen A but did not have evidence of initial engraftment thus triggering the stopping rule for that arm of this study.

Prior to transplantation, subjects will receive either:

Cyclophosphamide, Fludarabine, Campath, Total body irradiation (TBI)

Or

Busulfan, Cyclophosphamide, antithymocyte globulin (ATG), granulocyte colony-stimulating factor (GSCF)

These drugs (and the radiation) are being given to help the new stem cells take and grow. On the day of transplantation, subjects will receive stem cells transfused via intravenous (IV) catheter.

After stem cell transplantation, subjects will be given cyclosporine-A and mycophenolate (MMF)/or Methylprednisone/or Methotrexate to reduce the risk of graft-versus-host disease, the complication that occurs when the donor's stem cells react against the patient.

• Sickle Cell Disease
• Thalassemia
• Severe Congenital Neutropenia
• Diamond-Blackfan Anemia
• Shwachman-Diamond Syndrome

• Drug: Busulfan, Fludarabine, ATG, TLI
  Busulfan 0.8 mg/kg/dose intravenous (IV) Days -8 and -7 Fludarabine 35 mg/m2 IV Days -6 through -2 Antithymocyte globulin (ATG) 30 mg/kg IV Days -2 and -1 Total lymphoid radiation 300 cGy
  Other Names:

  • Busulfex
  • Fludara
  • ATG
  • Total lymphoid Irradiation
• Drug: Busulfan, Cyclophosphamide, ATG, GCSF
  Busulfan 0.8 mg/kg/dose intravenous (IV) Days -9 through -6 Cyclophosphamide 50 mg/kg IV Days -5 through -2 ATG 30 mg/kg IV Day -1 GCSF 5 mcg/kg/day IV until ANC >2500 x 2 days.
  Other Names:

  • Busulfex
  • Cytoxan
  • antithymocyte globulin
  • granulocyte colony-stimulating factor
• Drug: Campath, Fludarabine, Cyclophosphamide
  Receives Campath-1H 0.2 mg/kg Days -10 through -6, Fludarabine 35 mg/m2 intravenous (IV) Days -6 through -2, total body irradiation (TBI) 300 cGy Day -1.
  Other Names:

  • Fludara
  • alemtuzumab
  • Cytoxan
• Radiation: Total Body Irradiation
  300 cGY Day -1
  Other Name: TBI
• Procedure: Stem cell infusion
  Given Day 0
  Other Name: bone marrow transplant

• Regimen A - Full Prep (Discontinued)
  Full Preparative Regimen for subjects with matched donors. Busulfan 0.8 mg/kg/dose intravenous (IV) Days -8 and -7, Fludarabine 35 mg/m2 IV Days -6 through -2, antithymocyte globulin (ATG) 30 mg/kg IV Days -2 through -1, total lymphoid radiation (TLI) Day -1, stem cell infusion on Day 0.
  Intervention: Drug: Busulfan, Fludarabine, ATG, TLI
• Experimental: Regimen B - Myeloablative
  Myeloablative Preparative Regimen for subjects with HLA identical sibling donors. Receives Busulfan 0.8 mg/kg/dose intravenous (IV) Days -9 through -6, Cyclophosphamide 50 mg/kg IV Days -5 through -2, ATG 30 mg/kg IV Day -1, stem cell infusion on Day 0 and G-CSF 5mcg/kg/day IV until ANC >2500 x 2 days.
  Interventions:

  • Drug: Busulfan, Cyclophosphamide, ATG, GCSF
  • Radiation: Total Body Irradiation
  • Procedure: Stem cell infusion
• Experimental: Regimen A2 - Non-myeloablative

  Receives Campath-1H 0.2 mg/kg Days -10 through -6, Cyclophosphamide 50 mg/kg I Day -7, Fludarabine 35 mg/m2 intravenous (IV) Days -6 through -2, total body irradiation (TBI) 300 cGy Day -1, stem cell infusion on Day 0.

  Regimen A2 will be utilized for patients with sickle cell disease or thalassemia who do not have an HLA-identical sibling donor or for any patient who has pre-existing organ dysfunction making them ineligible for a myeloablative preparative regimen.

  Interventions:

  • Drug: Campath, Fludarabine, Cyclophosphamide
  • Radiation: Total Body Irradiation
  • Procedure: Stem cell infusion

Inclusion Criteria:

• Patients with Sickle Cell Disease/Thalassemia (SCD/THAL) 0-50 years of age with an acceptable stem cell donor and disease characteristic defined by the following:

  • Stroke, central nervous system (CNS) hemorrhage or a neurologic event lasting longer than 24 hours, or abnormal cerebral magnetic resonance imaging (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 red blood cell (RBC) alloimmunization >2 antibodies during long term transfusion therapy
• Patients with transfusion dependent alpha- or beta-thalassemia 0-35 years of age with an acceptable stem cell donor as defined in the criteria in section above.
• Patients with other non-malignant hematologic disorders that are transfusion-dependent or involve other potentially life-threatening cytopenias (including but not limited to Severe Congenital Neutropenia, Diamond-Blackfan Anemia and Shwachman-Diamond Syndrome) who are 0-35 years of age with an acceptable stem cell donor

• Second Transplants

  • Patients with sickle cell disease or thalassemia who have failed to engraft or have autologous recovery after a myeloablative SCT regimen or non-myeloablative regimen are eligible for this protocol.
  • Regimen A2 will be utilized for patients with sickle cell disease or thalassemia who do not have an HLA-identical sibling donor or for any patient who has pre-existing organ dysfunction making them ineligible for a myeloablative preparative regimen.
  • Regimen B will be utilized for patients with sickle cell disease or thalassemia who have an HLA-identical sibling donor.
  • Patients must meet above criteria.
  • If the patient has received prior radiation therapy, eligibility to receive additional radiation therapy must be determined by Dr. Dusenbery
  • 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

Exclusion Criteria:

• 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
• 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
• Psychologically incapable of undergoing bone marrow transplant (BMT) with associated strict isolation or documented history of medical non-compliance
• Patients not able to receive total lymphocytic irradiation (TLI) due to prior radiation therapy