Sickle Cell Anemia Clinical Trial
Official title:
Reduced Intensity Allogeneic Hematopoietic Stem Cell Transplantation for Sickle Cell Anemia From HLA Matched or Partially-Matched Related Donors
This is a clinical research trial in which a novel preparatory regimen was developed for
bone marrow transplant (BMT) which eliminates the primary obstacle to transplant, the lack
of a matched sibling donor. It is believed this regimen is sufficiently efficacious and
sufficiently gentle to apply to patients with sickle cell anemia and related disorders. It
is proposed to characterize the efficacy and toxicity of this regimen in high risk patients
with sickle cell anemia using criteria for patient selection that have been accepted in
prior BMT trials in patients with sickle cell disease, specifically only the subset of
patients whose prior clinical behavior indicates that they are at high risk for serious
morbidity and early mortality. In addition, it is proposed to characterize the
pathophysiology of a consistent febrile response seen in the haploidentical BMT regimen the
investigators have developed at Thomas Jefferson University (TJU).
The primary goal of this study is to determine the response rate to a reduced intensity
conditioning regimen which consists of fludarabine, cytarabine, low dose total body
irradiation and cyclophosphamide in patients with severe sickle cell anemia.
Hemoglobinopathies, such as sickle cell disease and thalassemia major, constitute a group of
genetic diseases associated with significant morbidity and premature death. In the 1970s,
the mean survival of patients with sickle cell disease was 14.3 years. With improvements in
medical practice, this has improved such that estimates are now into the third decade of
life.
In patients with sickle cell disease, a single amino acid substitution in beta-hemoglobin
causes erythrocytes to sickle in response to oxidative stress. The sequelae of this defect
are vaso-occlusive crises, resulting in episodes of bony pain and infarction, acute chest
syndrome, and strokes. Life long need for transfusion leads to complications including
alloimmunization and iron overload. The latter condition is frequently associated with
significant end-organ damage.
In recent years, new strategies in supportive care, such as the use of hydroxyurea to
stimulate fetal hemoglobin production in patients with sickle cell anemia, have resulted in
the amelioration of some of the devastating manifestations of this disease. However, this
therapy does not benefit all patients, and there have been concerns about the possible risk
of latent transformation to leukemia with prolonged use of this drug. Clearly, better
treatment strategies are needed for this devastating group of diseases.
Patients with sickle cell anemia will be offered enrollment on a clinical trial of reduced
intensity stem cell transplant. The transplant donors will be either HLA matched siblings or
family members who are 50% matched for HLA. Patients will receive therapy in 2 steps.
For patients who are allo-immunized against the donor (patients who have made an immune
response already against the donor's HLA type), there will be a desensitization process.
This will be outpatient therapy and will include therapy with bortezomib on the 1st, 4th,
8th and 11th day of a 21 day cycle. This will be repeated for a second cycle, for a total of
8 doses of bortezomib over a 6 week period. In addition, they will receive rituximab on the
1st and 8th day of each cycle. These therapies are designed to decrease the subject's chance
of rejecting the transplant, as it is known that patients with sickle cell anemia are likely
to be heavily immunized against donors. For patients who have high levels of antibodies
against the donors, a plasmapheresis procedure will be performed prior to admission as well.
All patients will undergo red cell exchange prior to admission.
During the transplant admission, subjects will receive a "Two Step" chemotherapy and
transplant regimen. The chemotherapy "first step" will be with fludarabine and cytarabine
and a low dose of total body irradiation. This will be followed by the "first step" of the
transplant graft - the donor lymphocytes. The "second step" of the chemotherapy will be two
doses of cyclophosphamide. This will then be followed by the "second step" of the transplant
graft - the stem cells.
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Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
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