Treatment of Sickle Cell Anemia With Stem Cell Transplant
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.
|Sickle Cell Anemia Sickle Cell-hemoglobin C Disease Sickle Cell-β0-thalassemia||Drug: Fludarabine Drug: Cytarabine Device: Cellular Infusions Radiation: Total Body Irradiation Drug: Cyclophosphamide Drug: Bortezomib Drug: Rituximab Procedure: Plasmapheresis|
|Study Design:||Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Reduced Intensity Allogeneic Hematopoietic Stem Cell Transplantation for Sickle Cell Anemia From HLA Matched or Partially-Matched Related Donors|
- Stable Engraftment [ Time Frame: 180 days post-infusion ]To determine if the reduced intensity preparative regimen of fludarabine, cytarabine, cyclophosphamide and low-dose total body irradiation will generate stable engraftment with donor hematopoietic stem cells in at least 80% of patients with severe sickle cell anemia.
- Organ Toxicity [ Time Frame: 30 days post infusion ]To assess organ toxicity related to fludarabine, cytarabine, cyclophosphamide and low-dose total body irradiation in a population with severe sickle cell anemia.
- Overall Survival [ Time Frame: 6 months post infusion ]To determine the overall survival at 6 months post-transplant in patients receiving a matched or partially-matched related donor transplant after reduced-intensity conditioning.
- Acute Graft Versus Host Disease [ Time Frame: 100 days post infusion ]To describe the incidence and severity of acute and chronic GVHD following this reduced intensity transplant from partially matched related donors using a combination of cyclophosphamide, tacrolimus and mycophenolate mofetil (MMF) as GVHD prophylaxis.
- Correction of Hemoglobinopathy [ Time Frame: 100 days post infusion through 5 years post infusion ]To evaluate the extent of correction of hemoglobinopathy following this reduced intensity transplant.
- Immune Recovery [ Time Frame: 100 days post infusion through 5 years post infusion ]To assess the pace of lymphoid recovery and associated risk for opportunistic infections and relapse (return to recipient erythropoiesis) in this patient population.
- Quality of Life [ Time Frame: Through 5 years post infusion ]To describe the quality of life and functional status following transplantation.
- Cytokine Profile [ Time Frame: Through 5 years after infusion ]To characterize the profiles of cytokines released following administration of the lymphoid portion of the transplant (donor lymphocyte infusion [DLI]).
|Study Start Date:||September 2009|
|Study Completion Date:||August 2011|
|Primary Completion Date:||August 2011 (Final data collection date for primary outcome measure)|
Subjects receive the preparative regimen in 2 steps. The "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.
Only subjects with prior alloimmunization against donor will receive desensitization. Subjects who demonstrate alloimmunization against the HLA of the donor will receive bortezomib and rituximab in combination with plasmapheresis prior to the admission for transplant.
Subjects will receive fludarabine at a dose of 30 mg/m2 daily for 4 days as part of the preparative regimen
Other Name: FludaraDrug: Cytarabine
Subjects will receive cytarabine at a dose of 2 g/m2 daily for 4 days, approximately 4 hours after the fludarabine
Other Names:Device: Cellular Infusions
Subjects will receive the cellular product in 2 steps. The first is a lymphocyte infusion of 2 X 10e8 lymphocytes/kg on the day they receive total body irradiation. The second is a CD34 enriched stem cell product approximately 48 hours after the cyclophosphamide.
The CliniMACS® Plus Instrument will be used for the selection of human CD34+ hematopoietic stem and progenitor cells in human allogeneic hematopoietic stem cell transplantation.
Other Names:Radiation: Total Body Irradiation
All subjects will receive 200cGy TBI in a single fraction on the AM they receive the lymphocyte infusion
Other Name: TBIDrug: Cyclophosphamide
All subjects will receive cyclophosphamide at a dose of 60 mg/kg at approximately 72 and 96 hours after the lymphocyte infusion
Other Name: CytoxanDrug: Bortezomib
Subjects will receive bortezomib 1.3 mg/kg on Day 1,4,8, and 11 of a 21 day cycle. This will be repeated for 2 cycles.
Other Name: VelcadeDrug: Rituximab
Subjects will receive rituximab 375 mg/m2 on day 1 and day 8 of a 21 day cycle, on days they will also be receiving rituximab. This will be repeated for 2 cycles.
Other Name: RituxanProcedure: Plasmapheresis
Subjects who continue to have detectable anti-donor antibody will receive plasmapheresis to reduce the antibody further
Other Name: Plasma exchange
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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01350232
|United States, Pennsylvania|
|Thomas Jefferson University|
|Philadelphia, Pennsylvania, United States, 19107|
|Principal Investigator:||Joanne Filicko-O'Hara, MD||Thomas Jefferson University|