Non-Myeloablative Bone Marrow Transplant for Patients With Sickle Cell Anemia and Other Blood Disorders

Study Overview
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Brief Summary
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RATIONALE: Giving low doses of chemotherapy, such as fludarabine and cyclophosphamide, and total-body irradiation before a donor bone marrow transplant helps stop the growth of abnormal cells. It also helps stop the patient's immune system from rejecting the donor's stem cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Giving sirolimus and mycophenolate mofetil after transplant may stop this from happening. PURPOSE: This phase II trial is studying how well giving fludarabine and cyclophosphamide together with total-body irradiation followed by a donor bone marrow transplant works in treating patients with sickle cell anemia and other blood disorders.

Detailed Description
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OBJECTIVES: Determine the transplant-related mortality and progression-free survival of patients with severe hemoglobinopathies receiving nonmyeloablative conditioning comprising fludarabine phosphate, cyclophosphamide, and total-body irradiation followed by partially HLA-mismatched bone marrow transplantation from first-degree relatives or HLA-matched donors. Characterize donor hematopoietic chimerism at 30, 60, and 180 days after transplantation in these patients. Determine the hematologic and non-hematologic toxicity of this regimen in these patients. OUTLINE: Preparative regimen: Patients receive fludarabine phosphate IV over 30 minutes on days -6 to -2 and cyclophosphamide IV over 1-2 hours on days -6 and -5. Patients also undergo total-body irradiation on day -1. Bone marrow transplantation: Patients undergo allogeneic bone marrow transplantation on day 0. Patients then receive cyclophosphamide IV over 1-2 hours on days 3 and 4. Graft-versus-host disease prophylaxis: Patients receive sirolimus orally daily on days 5-365 and oral mycophenolate mofetil 3 times a day on days 5-35. After completion of study treatment, patients are followed periodically. PROJECTED ACCRUAL: A total of 50 patients will be accrued for this study.

Official Title
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A Phase II Trial of Non-Myeloablative Conditioning and Transplantation of Partially HLA-Mismatched and HLA-Matched Bone Marrow for Patients With Sickle Cell Anemia and Other Hemoglobinopathies

Conditions
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Sickle Cell Disease

Intervention / Treatment
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* Drug: Cyclophosphamide
* Drug: Fludarabine
* Drug: Mycophenolate mofetil
* Drug: Sirolimus
* Procedure: Allogeneic bone marrow transplant
* Radiation: Total body irradiation - 200
* Drug: Levetiracetam
* Biological: Anti-thymocyte globulin
* Radiation: Total body irradiation - 400


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Diagnosis of 1 of the following sickle cell anemias (Hb SS): Hb S/β° thalassemia Hb S/β+ thalassemia Hb SC disease Hb SE disease Hb SD disease Hemoglobin SO-Arab disease Hb S/hereditary persistence of fetal hemoglobin Meets 1 of the following criteria: History of invasive pneumococcal disease Stroke or CNS event lasting > 24 hours MRI changes indicative of brain parenchymal damage Evidence of cerebrovascular disease by magnetic resonance angiography Acute chest syndrome requiring exchange transfusion or hospitalization Recurrent vaso-occlusive pain crisis (> 2 per year for the last 2 years) Stage I or II sickle lung disease Sickle retinopathy Osteonecrosis Red cell alloimmunization (> 2 antibodies) during long-term transfusion Constellation of dactylitis in the first year of life AND a baseline hemoglobin < 7 g/dL and leukocytosis (WBC > 13.4/mm^3) in the absence of infection during the second year of life Pitted RBC count > 3.5% during the first year of life Ineligible for or refused bone marrow transplantation from an HLA-matched sibling donor Partially mismatched (at least haploidentical) first-degree relative donor available No minor (donor anti-recipient) ABO incompatibility if an ABO compatible donor is available PATIENT CHARACTERISTICS: ECOG performance status (PS) 0-1 OR Karnofsky or Lansky PS 70-100% LVEF ≥ 35% FEV_1 and forced vital capacity ≥ 40% predicted Direct bilirubin < 3.1 mg/dL No moderate to severe pulmonary hypertension by ECHO No debilitating medical or psychiatric illness that would preclude study participation No HIV positivity Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception PRIOR CONCURRENT THERAPY: No prior transfusions from donor No immunosuppressive agents, including steroids as antiemetics, within 24 hours after the last dose of post-transplantation cyclophosphamide

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

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: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Transplant - 200 cGy<br>Conditioning regimen with anti-thymocyte globulin, fludarabine, cyclophosphamide, and total body irradiation - 200. Seizure prophylaxis with levetiracetam. Allogeneic bone marrow transplant infusion on Day 0. Graft-vs-host-disease (GVHD) prophylaxis with cyclophosphamide, mycophenolate mofetil, and sirolimus. | Drug: Cyclophosphamide<br>* Cyclophosphamide (Cy) 14.5 mg/kg/day intravenously (IV) on Days -6 and -5 and 50 mg/kg/day IV on Days +3 and +4.<br>* Other names: CTX;Drug: Fludarabine<br>* Fludarabine 30 mg/m^2/day IV on Days -6, -5, -4, -3, and -2.<br>* Other names: Fludara;Drug: Mycophenolate mofetil<br>* Mycophenolate mofetil 15 mg/kg by mouth (PO) three times a day from Day +5 to Day +35.<br>* Other names: CellCept;Drug: Sirolimus<br>* The first dose of Sirolimus is 6 mg PO on Day +5. Further dosing is adjusted according to drug levels. Sirolimus is continued through Day +365.<br>* Other names: Rapamune;Procedure: Allogeneic bone marrow transplant<br>* An allogeneic bone marrow transplant is a procedure that involves taking bone marrow from a donor and giving it to a recipient.<br>* Other names: Allo BMT;Radiation: Total body irradiation - 200<br>* 200 centigray (cGy) in one fraction on Day -1.<br>* Other names: TBI;Drug: Levetiracetam<br>* Given at 500 mg PO twice daily from Day -6 to Day +365.<br>* Other names: Keppra;Biological: Anti-thymocyte globulin<br>* Test dose of 0.5 mg/kg IV given on Day -9, then 2 mg/kg/day IV on Day -8 and -7.<br>* Other names: Thymoglobulin;|
| Experimental: Transplant - 400 cGy<br>Conditioning regimen with anti-thymocyte globulin, fludarabine, cyclophosphamide, and total body irradiation - 400. Seizure prophylaxis with levetiracetam. Allogeneic bone marrow transplant infusion on Day 0. Graft-vs-host-disease (GVHD) prophylaxis with cyclophosphamide, mycophenolate mofetil, and sirolimus. | Drug: Cyclophosphamide<br>* Cyclophosphamide (Cy) 14.5 mg/kg/day intravenously (IV) on Days -6 and -5 and 50 mg/kg/day IV on Days +3 and +4.<br>* Other names: CTX;Drug: Fludarabine<br>* Fludarabine 30 mg/m^2/day IV on Days -6, -5, -4, -3, and -2.<br>* Other names: Fludara;Drug: Mycophenolate mofetil<br>* Mycophenolate mofetil 15 mg/kg by mouth (PO) three times a day from Day +5 to Day +35.<br>* Other names: CellCept;Drug: Sirolimus<br>* The first dose of Sirolimus is 6 mg PO on Day +5. Further dosing is adjusted according to drug levels. Sirolimus is continued through Day +365.<br>* Other names: Rapamune;Procedure: Allogeneic bone marrow transplant<br>* An allogeneic bone marrow transplant is a procedure that involves taking bone marrow from a donor and giving it to a recipient.<br>* Other names: Allo BMT;Drug: Levetiracetam<br>* Given at 500 mg PO twice daily from Day -6 to Day +365.<br>* Other names: Keppra;Biological: Anti-thymocyte globulin<br>* Test dose of 0.5 mg/kg IV given on Day -9, then 2 mg/kg/day IV on Day -8 and -7.<br>* Other names: Thymoglobulin;Radiation: Total body irradiation - 400<br>* 400 centigray (cGy) in one fraction on Day -1.<br>* Other names: TBI;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Transplant-related Mortality | Number of participants who died for reasons related to bone marrow transplant. | Up to one year | 
| Progression-free Survival | Percentage of participants who are alive without relapse. | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Donor Chimerism at 30 Days | Number of participants with full (95-100%), mixed (5-94%), and no (0-4%) donor cells. Chimerism is reported for unsorted whole blood and T cells. | 30 days | 
| Donor Chimerism at 1 Year | Number of participants with full (95-100%), mixed (5-94%), and no (0-4%) donor cells. Chimerism is reported for unsorted whole blood and T cells. | 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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sickle cell disease