Sickle Cell Disease
Conditions
Brief summary
Related donor stem cell transplantation using the alemtuzumab/ TBI platform has been shown to be a safe strategy to cure severe sickle cell disease. However, due to a lack of suitable donors, many patients cannot benefit from this strategy. Alternative donor sources are desperately needed to fill this gap. Nearly all patients will have a haploidentical family member who would be able to donate. The use of post transplantation cyclophosphamide has greatly improved the outcome of haploidentical stem cell transplantation. The investigators propose to combine this with alemtuzumab/TBI conditioning.
Detailed description
Sickle cell anemia is an inherited form of anemia, a condition in which there aren't enough healthy red blood cells to carry adequate oxygen throughout the body. These patients are at increased risk of death, stroke, frequent pain crises, acute chest syndrome as well as chronic conditions including: lung damage, retinopathy, kidney damage, leg ulcers, and pulmonary hypertension. There's no cure for most people with sickle cell anemia. However, treatments can relieve pain and help prevent co-morbid conditions associated with sickle cell anemia. Hydroxyurea is the only FDA approved drug to help alleviate symptoms associated with sickle cell disease. The mortality rate is still high in patients using hydroxyurea and a significant percentage of patients still have aggressive disease despite the hydroxyurea treatment. Hydroxyurea therapy also does not seem to prevent the development of many of the complications of sickle cell disease such as pulmonary hypertension. Historically, stem cell transplantation in sickle cell disease was mainly done in the pediatric population. The options were more limited for adults with sickle cell disease with aggressive disease despite hydroxyurea. Most rely on chronic red blood cell transfusions which carry significant risks of infection, iron overload, and alloimmunization. Alloimmunization refers to the production of antibodies which occurs in up to 50% of patients with sickle cell disease who are on chronic transfusion therapy making further transfusions difficult with a high potential for hemolytic transfusion reactions. Recently the use of a non-myeloablative stem cell transplantation regimen (relying on immunotherapy instead of chemotherapy) for sickle cell disease in adults showed 88% engraftment rates (30 out of 34 patients) with no GVHD and 0% mortality. However, these transplants used only fully HLA-matched siblings, which are unavailable to all but approximately 14-28% of patients who could benefit from such a transplant at UIC. A recent study at Johns Hopkins carried out a similar haploidentical (half matched) transplant with 14 sickle cell patients who lacked fully HLA-matched donors. Approximately two years following transplant, 57% of patients successfully engrafted (8 or 14 patients). There were no deaths and only one episode of acute GVHD of the skin which resolved without therapy. The investigators plan to offer stem cell transplantation to sickle cell patients with aggressive disease who only have a partially matched HLA sibling donor. Haploidentical transplants are considered only for patients with no other standard options available who would normally be treated with supportive (palliative) care or given the option to participate in a clinical trial. Donors who are HLA-haploidentical will be the source of hematopoietic stem cells. Potential donors can include any relative (e.g. parents, offspring, siblings, cousins, aunts/uncles, grandparents). The related donor stem cell transplantation using the alemtuzumab/TBI platform has been shown to be a safe strategy to cure severe sickle cell disease. However, due to a lack of suitable donors, many patients cannot benefit from this strategy. Alternative donor sources are desperately needed to fill this gap. Nearly all patients will have a haploidentical family member who would be able to donate. The use of post transplantation cyclophosphamide has greatly improved the outcome of haploidentical stem cell transplantation. The investigators propose to combine this with alemtuzumab/TBI conditioning. The investigational component of this study is the combination of the Alemtuzumab (immunotherapy) and Total Body Irradiation conditioning regimen and the HLA Haploidentical Transplant with post-transplant Cyclophosphamide. Investigators plan to study the engraftment rates (transplant success rates) at Day 60 in sickle cell patients undergoing an HLA haploidentical stem cell transplant with post transplant high dose cyclophosphamide.
Interventions
PROCEDUREHaploidentical Transplant
All subjects will undergo pre-conditioning treatment with alemtuzumab (0.3 mg/kg Day -5, Day -4, Day -3) and total body irradiation (300cGy), followed by stem cell transplant, and post-transplant treatment with cyclophosphamide (50mg/kg/day) and sirolimus (target trough level of 10-15ng/mL).
DRUGAlemtuzumab
On Day -7, the first test dose of alemtuzumab (0.03 mg/kg) will be administered and on Day -6, the second test dose of alemtuzumab (0.1 mg/kg) will be administered. Alemtuzumab (0.3 mg/kg) will be infused daily on Day -5, -4, and -3.
RADIATIONTotal Body Irradiation
A 300cGy dose of TBI will be administered in a single fraction on Day -2.
DRUGCyclophosphamide
Cyclophosphamide (50 mg/kg IBW) IV, over approximately 1-2 hours, is given on Day 3 post-transplantation (ideally between 60 and 72 hours after marrow infusion) and on Day 4 (approximately 24 hours after Day 3 cyclophosphamide).
DRUGSirolimus
Sirolimus will be started on Day +5 (at least 24 hours after the completion of the cyclophosphamide infusion). The starting dose will be 12mg followed by 4mg PO daily. Doses will be adjusted to achieve a whole blood trough level of 4 - 12ng/mL.
Sponsors
Damiano Rondelli, MD
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
16 Years to 60 Years
Healthy volunteers
No
Inclusion criteria
Patient Eligibility: * Patients with sickle cell disease are eligible if they have any of the following complications: * Stroke or central nervous system event lasting longer than 24 hours * Frequent vaso-occlusive pain episodes, defined as ≥ 3 per year requiring emergency room, acute care center, or hospital admissions. * Recurrent episodes of priapism, defined as ≥ 2 per year requiring emergency room visits * Acute chest syndrome with recurrent hospitalizations, defined as ≥ 2 lifetime events * Red-cell alloimmunization (≥ 2 antibodies) during long-term transfusion therapy * Bilateral proliferative retinopathy with major visual impairment in at least one eye * Osteonecrosis of 2 or more joints * Sickle cell nephropathy, defined by a GFR \< 90mL/min/1.73m2 or the presence of macroalbuminuria (urine albumin \> 300 mg/g creatinine) * Pulmonary hypertension, defined by a mean pulmonary artery pressure \> 25mmHg * Age 16-60 years * Karnofsky performance status of 60 or higher * Adequate cardiac function, defined as left ventricular ejection fraction ≥ 40% * Adequate pulmonary function, defined as diffusion lung capacity of carbon monoxide ≥ 50% predicted (after adjustment for hemoglobin concentration) * Estimated GFR ≥ 50mL/min as calculated by the modified MDRD equation * ALT ≤ 3x upper limit of normal * HIV-negative * Patient is pregnant * Patient is able and willing to sign informed consent * Patient has an HLA-haploidentical relative
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Engraftment Rate | Up to Day 60 post-transplant. | To determine the engraftment at Day +60 following HLA-haploidentical hematopoietic stem cell transplant protocol using immunosuppressive agents and low-dose total body irradiation (TBI) for conditioning and post-transplant cyclophosphamide in patients with sickle cell disease. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Acute & Chronic Complications | Up to one year post-transplant | To assess the frequency of acute and chronic complications of sickle cell disease during and after HLA-haploidentical hematopoietic stem cell transplantation with this protocol. The acute complications include vaso-occlusive pain episodes, acute chest syndrome, stroke, and priapism. The chronic complications include nephropathy, retinopathy, osteonecrosis, pulmonary artery pressures, cardiomyopathy, and chronic lung disease. |
| Overall & Disease-Free Survival | Up to one year post-transplant. | To determine the overall and disease-free survival of patients with sickle cell disease receiving HLA-haploidentical hematopoietic stem cell transplantation with this protocol. |
| Morbidity & Mortality | Up to one year post-transplant. | To determine the incidence of acute and chronic graft-versus-host disease, the incidence of infectious complications, and the transplant related mortality in sickle cell disease patients after HLA-haploidentical hematopoietic stem cell transplantation with this protocol. |
Countries
United States
Participant flow
Recruitment details
Subjects are referred by their primary care physicians to the UIC Sickle Cell clinic for specialty care. Subjects are evaluated to see if they are eligible for studies and if they are, the subject is presented with the option of enrolling into a research study or participating in alternative therapies that have also been presented to the subject.
Participants by arm
| Arm | Count |
|---|---|
| Haploidentical Transplant All subjects will undergo pre-conditioning treatment with alemtuzumab (0.3 mg/kg Day -5, Day -4, Day -3) and total body irradiation (300cGy), followed by stem cell transplant, and post-transplant treatment with cyclophosphamide (50mg/kg/day) and sirolimus (target trough level of 10-15ng/mL). | 2 |
| Total | 2 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Did not engraft | 1 |
Baseline characteristics
| Characteristic | Haploidentical Transplant |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants |
| Age, Continuous | 38 Years STANDARD_DEVIATION 1 |
| Race/Ethnicity, Customized | 2 Participants |
| Region of Enrollment United States | 2 Participants |
| Sex: Female, Male Female | 1 Participants |
| Sex: Female, Male Male | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 2 |
| other Total, other adverse events | 0 / 2 |
| serious Total, serious adverse events | 0 / 2 |
Outcome results
Primary
Engraftment Rate
To determine the engraftment at Day +60 following HLA-haploidentical hematopoietic stem cell transplant protocol using immunosuppressive agents and low-dose total body irradiation (TBI) for conditioning and post-transplant cyclophosphamide in patients with sickle cell disease.
Time frame: Up to Day 60 post-transplant.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Haploidentical Transplant | Engraftment Rate | 0 Participants |
Secondary
Acute & Chronic Complications
To assess the frequency of acute and chronic complications of sickle cell disease during and after HLA-haploidentical hematopoietic stem cell transplantation with this protocol. The acute complications include vaso-occlusive pain episodes, acute chest syndrome, stroke, and priapism. The chronic complications include nephropathy, retinopathy, osteonecrosis, pulmonary artery pressures, cardiomyopathy, and chronic lung disease.
Time frame: Up to one year post-transplant
Population: No subjects engrafted
Secondary
Morbidity & Mortality
To determine the incidence of acute and chronic graft-versus-host disease, the incidence of infectious complications, and the transplant related mortality in sickle cell disease patients after HLA-haploidentical hematopoietic stem cell transplantation with this protocol.
Time frame: Up to one year post-transplant.
Population: 0 subjects engrafted
Secondary
Overall & Disease-Free Survival
To determine the overall and disease-free survival of patients with sickle cell disease receiving HLA-haploidentical hematopoietic stem cell transplantation with this protocol.
Time frame: Up to one year post-transplant.
Population: No subjects engrafted