Stem Cell Transplantation After Reduced-Dose Chemotherapy for Patients With Sickle Cell Disease or Thalassemia

Study Overview
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Brief Summary
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The purpose of this study is to find out if using a lower dose of chemotherapy before stem cell transplantation can cure patients of sickle cell anemia or thalassemia while causing fewer severe side effects than conventional high dose chemotherapy with transplantation.

Detailed Description
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Hemoglobinopathies, such as sickle cell disease and thalassemia major, are genetic diseases associated with significant morbidity and premature death. Allogeneic bone marrow transplantation (BMT) is the only potential cure for severe hemoglobinopathies. Typical regimens have used high doses of chemotherapy or chemo-radiotherapy to ablate recipient hematopoiesis and to prevent graft rejection. The widespread use of this treatment has been limited by toxicity, risk of end-organ damage, and donor availability. This study will use a nonmyeloablative regimen of fludarabine and busulfan to attempt to generate consistent engraftment with donor hematopoietic stem cells in patients with severe hemoglobinopathy. G-CSF mobilization of the donor's peripheral blood white blood cells will precede donor apheresis. A nonmyeloablative conditioning regimen of fludarabine and busulfan will be administered to patients prior to allogeneic peripheral blood stem cell infusions. FK506 and prednisone will be administered for graft versus host disease (GVHD) prophylaxis. Patients will be evaluated for engraftment, donor: host hematopoietic chimerism, toxicity, and hemoglobinopathy.

Official Title
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Allogeneic Stem Cell Transplantation Following Nonmyeloablative Chemotherapy in Patients With Hemoglobinopathies

Conditions
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Hemoglobinopathies, Anemia, Sickle Cell, Hemoglobin SC Disease, Thalassemia, Thalassemia Major

Intervention / Treatment
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* Drug: Busulfan
* Drug: Fludarabine
* Drug: FK506
* Drug: Prednisone


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: All patients must: Have related donors who are identical at 6 human leukocyte antigens (HLA) loci (A, B and DR) by molecular typing Have a performance status from 0-2 Give written informed consent Patients with sickle cell disease should have 1 or more of the following: Acute chest syndrome requiring recurrent hospitalization or exchange transfusion Nonhemorrhagic stroke or central nervous system event lasting longer than 24 hours Recurrent vaso-occlusive pain (2 episodes or more per year) or recurrent priapism Sickle nephropathy (moderate or severe proteinuria or a glomerular filtration rate 30-50 percent of normal predicted value) Bilateral proliferative retinopathy and major visual impairment in at least 1 eye Osteonecrosis of multiple joints Patients with thalassemia should have 1 or more of the following: Transfusion dependence, defined as a transfusion requirement of greater than or equal to 6 units of packed red blood cells over the past 12 months Iron overload, defined as serum ferritin greater than 500 mcg/L in the absence of infection or biopsy-proven iron overload Presence of 2 or more alloantibodies against red cell antigens Exclusion criteria: Pregnancy Acute hepatitis (transaminases greater than 3 times the normal value) Cardiac ejection fraction less than 30 percent Severe renal impairment (glomerular filtration rate less than 30 percent of predicted normal value) Severe residual functional neurologic impairment (other than hemiplegia alone) Seropositivity for the human immunodeficiency virus (HIV)

Ages Eligible for Study
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Minimum Age: 18 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Allogeneic stem cell transplantation<br>Participants will receive a nonmyeloablative conditioning regimen of fludarabine and busulfan prior to allogeneic peripheral blood stem cell (CD34+) infusions. FK506 and prednisone will be administered for graft versus host disease (GVHD) prophylaxis. | Drug: Busulfan<br>* 0.8 mg/kg/d administered as a single intravenous infusion over 3 hours for 4 days. All infusions are anticipated to be given in the outpatient clinic.<br>* Other names: Busulfex;Drug: Fludarabine<br>* 30 mg/m^2/d administered as a bolus infusion over 30 minutes for 4 days. All infusions are anticipated to be given in the outpatient clinic.<br>* Other names: Oforta;Drug: FK506<br>* 0.15 mg/kg taken orally daily for 12 to 14 weeks<br>* Other names: Tacromilus;Drug: Prednisone<br>* 0.5 mg/kg taken orally four times daily on Day 7 and increase to 1 mg/kg taken orally four times daily on Day 14. Participants will continue regimen until Day 30 before a 20-25% taper per week.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evidence of engraftment of donor hematopoietic cells following administration of low doses of busulfan and fludarabine |  | Throughout study | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Solid organ toxicity related to the conditioning regimen |  | Throughout study | 
| Incidence of grade II, III, or IV acute graft versus host disease (GVHD) |  | Throughout study | 
| Level of disease response |  | Throughout study |