Stem Cell Transplant for Hemoglobinopathy

University of Minnesota (UMN)

Status and phase: Completed; Phase 3; Phase 2

Conditions: Thalassemia; Shwachman-Diamond Syndrome; Diamond-Blackfan Anemia; Sickle Cell Disease; Severe Congenital Neutropenia

Treatments: Drug: Busulfan, Cyclophosphamide, ATG, GCSF; Drug: Campath, Fludarabine, Cyclophosphamide; Procedure: Stem cell infusion; Drug: Busulfan, Fludarabine, ATG, TLI; Radiation: Total Body Irradiation

Study type: Interventional

Funder types: Other

Identifiers

NCT00176852

MT2002-07

0206M26241 (Other Identifier)

Details and patient eligibility

About

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.

Full description

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.

Enrollment: 22 patients

Sex: All

Ages: Under 50 years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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22 participants in 3 patient groups

RIC Bu/Flu (A) (discontinued)

Other group

Description:

Full Preparative Regimen for subjects with matched donors using Busulfan on Day -8 and -7, Fludarabine on Day -6 through -2, antithymocyte globulin (ATG) on Day -2 through -1, total lymphoid radiation (TLI) on Day -1, stem cell infusion on Day 0.

Treatment:

Drug: Busulfan, Fludarabine, ATG, TLI

MA Bu/Cy (B)

Experimental group

Description:

Myeloablative Preparative Regimen for subjects with HLA identical sibling donors consists of Busulfan on day -9 through -6, Cyclophosphamide on day -5 through -2, ATG on day -3 through -1, stem cell infusion on Day 0 and Granulocyte Colony Stimulating Factor on day -3 until ANC \>2500 x 2 days.

Treatment:

Radiation: Total Body Irradiation

Drug: Busulfan, Cyclophosphamide, ATG, GCSF

Procedure: Stem cell infusion

RIC Cy/Flu/TBI (A2)

Experimental group

Description:

Patients with sickle cell disease or thalassemia who do not have an HLA-identical sibling donor or who has pre-existing organ dysfunction making myeloablative condition ineligible will receive Campath on day -10 through -6, Cyclophosphamide on day -7, Fludarabine on day -6 through -2, total body irradiation (TBI) on day -1, stem cell infusion on Day 0.

Treatment:

Radiation: Total Body Irradiation

Procedure: Stem cell infusion

Drug: Campath, Fludarabine, Cyclophosphamide