Hemoglobinopathies, Anemia, Sickle Cell, Hemoglobin SC Disease, Thalassemia, Thalassemia Major
Conditions
Brief summary
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
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.
Interventions
DRUGBusulfan
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.
DRUGFludarabine
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.
DRUGFK506
0.15 mg/kg taken orally daily for 12 to 14 weeks
DRUGPrednisone
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.
Sponsors
National Institute of Allergy and Infectious Diseases (NIAID)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Evidence of engraftment of donor hematopoietic cells following administration of low doses of busulfan and fludarabine | Throughout study |
Secondary
| Measure | 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 |
Countries
United States
Outcome results
None listed