Stem Cell Transplant for Hemoglobinopathy

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Allogeneic Hematopoietic Stem Cell Transplant for Patients With High Risk Hemoglobinopathy Using a Preparative Regimen to Achieve Stable Mixed Chimerism

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

Intervention / Treatment
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* Drug: Busulfan, Fludarabine, ATG, TLI
* Drug: Busulfan, Cyclophosphamide, ATG, GCSF
* Drug: Campath, Fludarabine, Cyclophosphamide
* Radiation: Total Body Irradiation
* Procedure: Stem cell infusion


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: RIC Bu/Flu (A) (discontinued)<br>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. | Drug: Busulfan, Fludarabine, ATG, TLI<br>* 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<br>* Other names: Total lymphoid Irradiation;|
| Experimental: MA Bu/Cy (B)<br>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. | Drug: Busulfan, Cyclophosphamide, ATG, GCSF<br>* 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.<br>* Other names: granulocyte colony-stimulating factor;Radiation: Total Body Irradiation<br>* 300 cGY Day -1<br>* Other names: TBI;Procedure: Stem cell infusion<br>* Given Day 0<br>* Other names: bone marrow transplant;|
| Experimental: RIC Cy/Flu/TBI (A2)<br>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. | Drug: Campath, Fludarabine, Cyclophosphamide<br>* 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.<br>* Other names: Cytoxan;Radiation: Total Body Irradiation<br>* 300 cGY Day -1<br>* Other names: TBI;Procedure: Stem cell infusion<br>* Given Day 0<br>* Other names: bone marrow transplant;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients Who Experienced Grade 3-5 Treatment Related Toxicity | In general, grade 3 equates to moderate, grade 4 to severe and grade 5 to death. | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Incidence of Chimerism at 100 Days | The number of patients whose blood and/or bone marrow contains > 10% donor cells. | 100 days | 
| The Incidence of Chimerism at 6 Months | The number of patients whose blood and/or bone marrow contains > 10% donor cells. | 6 months | 
| The Incidence of Chimerism at 1 Year | The number of patients whose blood and/or bone marrow contains > 10% donor cells. | 1 year | 
| The Incidence of Grade 2-4 Acute Graft Versus Host Disease (Acute GVHD) | The number of patients who experienced grades 2-4 Acute GVHD. Acute GVHD is when the donated bone marrow or peripheral blood stem cells view the recipient's body as foreign, and the donated cells/bone marrow attack the body. Grades 2-4 equate to mild to severe disease. Symptoms typically appear within weeks after transplant. | 100 days | 
| The Incidence of Grade 3-4 Acute Graft Versus Host Disease (Acute GVHD) | The number of patients who experienced grades 3-4 Acute GVHD. Acute GVHD is when the donated bone marrow or peripheral blood stem cells view the recipient's body as foreign, and the donated cells/bone marrow attack the body. IGrades 3-4 equate to moderate to severe disease. Symptoms typically appear within weeks after transplant. | 100 days | 
| The Incidence of Chronic Graft Versus Host Disease (Chronic GVHD) | The number of patients who experienced Chronic GVHD. Chronic GVHD is when the donated bone marrow or peripheral blood stem cells view the recipient's body as foreign, and the donated cells/bone marrow attack the body. Chronic GVHD can appear at any time after allogeneic transplant or several years after transplant. | 6 months | 
| The Incidence of Chronic Graft Versus Host Disease (Chronic GVHD) | The number of patients who experienced Chronic GVHD. Chronic GVHD is when the donated bone marrow or peripheral blood stem cells view the recipient's body as foreign, and the donated cells/bone marrow attack the body. Chronic GVHD can appear at any time after allogeneic transplant or several years after transplant. | 1 year | 
| Change in the Patient's Quality of Life as Compared to the Pre-Transplant Assessment | The measure for quality of life used in this study is the Karnofsky Performance Score. The Karnofsky Performance Score runs from 100 to 0, where 100 is perfect health and 0 is death. | pre-transplant | 
| Change in the Patient's Quality of Life as Compared to the Pre-Transplant Assessment | The measure for quality of life used in this study is the Karnofsky Performance Score. The Karnofsky Performance Score runs from 100 to 0, where 100 is perfect health and 0 is death. | 1 year | 
| Change in the Patient's Quality of Life as Compared to the Pre-Transplant Assessment | The measure for quality of life used in this study is the Karnofsky Performance Score. The Karnofsky Performance Score runs from 100 to 0, where 100 is perfect health and 0 is death. | 2 years | 
| Determine Physical Characteristics and Biologic Effects of Mixed Populations of Donor and Host Red Blood Cells |  | During study | 
| Determine the Concentration of Campath in the Serum |  | Day 0 | 
| Overall Survival | Number of patients alive 100 days after transplant. | 100 days | 
| Overall Survival | Number of patients alive 1 year after transplant. | 1 year | 
| Disease Free Survival | Number of patients alive without disease 100 days after transplant. | 100 days | 
| Disease Free Survival | Number of patients alive without disease 1 year after transplant. | 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stem cell transplant, high risk hemoglobinopathy, donor lymphocyte infusion, transfusion dependent, stem cell donor, cord blood, marrow, transfusion dependent non-malignant hematologic disorders