Nonmyeloablative Haploidentical Peripheral Blood Mobilized Hematopoietic Precursor Cell Transplantation for Sickle Cell Disease
- Conditions
- Sickle Cell Disease
- Interventions
- Procedure: haploidentical stem cell transplant
- Registration Number
- NCT03077542
- Brief Summary
Background:
Peripheral blood stem cell transplantation procedures are used for people with sickle cell disease. Researchers want to improve the success and reduce the complications for these procedures. This might allow more people to have a transplant.
Objective:
To see if a new transplant regime is effective, safe and well tolerated in people with sickle cell disease.
Eligibility:
Adults at least 18 years old with sickle cell disease and certain complications.
A relative who is a half tissue match.
Design:
Participants will be screened with medical history, physical exam, and blood tests. Recipients will also have:
* Heart, lung, and mental health tests
* Chest x-rays
* Bone marrow taken from the pelvic bone
* Eyes and teeth checked
Recipients will have a large central line inserted into a vein for up to 6 months.
Donors will have their veins tested and have an IV inserted for 1 day or on rare occasions 2 days.
Donors will get a drug to activate bone marrow. It will be injected for about 6 days.
Donors will have at least 1 five-hour procedure where bone marrow stem cells will be collected. Blood will be taken from a vein in one arm or in rare cases from a groin vein and put through a machine. Some blood will be saved and the rest will be returned. Stem cells will be taken from the saved blood in a lab and frozen until ready to give to the recipient.
Recipients will have:
* Stems cells collected and frozen
* Hygiene lessons
* Bone density scans
* Low-dose radiation
* Drugs for their immune system
* Donor cells infused through their central line
* Transfusions
After about 30 days, recipients will leave the hospital. They must stay near NIH for 3 months after the transplant and have frequent visits. After returning home, they will have 8 visits over 5 years, then be contacted yearly.
- Detailed Description
Nonmyeloablative allogeneic peripheral blood stem cell (PBSC) transplants are currently being investigated in phase I/II trials assessing engraftment, efficacy, and toxicity at a number of transplant centers. Our ongoing protocol for patients with severe congenital anemias, particularly sickle cell disease (SCD), and an HLA-matched sibling donor has had excellent preliminary results. None of the patients who engrafted had sickle-related events or any evidence of graft versus host disease (GVHD). There was no significant toxicity associated with the conditioning regimen. An additional protocol is ongoing for patients with high risk of graft rejection which employs pentostatin and oral cyclophosphamide (PC) pre-transplant to further deplete recipient lymphocytes in an attempt to decrease the rate of graft rejection. Four of 4 patients transplanted remain free of SCD.
Our main limitation has been a lack of HLA-matched sibling donors in the majority of patients. We performed a study in which patients with severe SCD who lacked a suitable donor underwent a search for a matched unrelated donor or umbilical cord donor. The vast majority of patients were not found to have an appropriate alternative donor. We therefore seek to develop a safe nonmyeloablative regimen to be applied to the haploidentical setting so that family members can serve as donors and greatly expand the donor pool.
We developed a nonmyeloablative haploidentical PBSC transplant protocol which included 3 cohorts, with stopping rules built in for regimen failure, defined as graft rejection or severe GVHD. All included 400 cGy total body irradiation (TBI) in divided doses 1 and 2 days prior to transplant, alemtuzumab, and sirolimus. The first cohort included no cyclophosphamide. The 2nd included one dose of cyclophosphamide given at 50mg/kg on day 3 post-transplant, and the 3rd included 100mg/kg cyclophosphamide given in divided doses on days 3 and 4 post-transplant. The engraftment rate and percentage of patients who remained free of SCD improved with each successive cohort. However, the graft rejection rate in the 3rd cohort remained high at 50%. To attempt to reduce the rate of graft rejection in the haploidentical setting, this protocol will add PC to the conditioning regimen.
In this protocol, we propose PBSC transplantation in patients with SCD considered at high risk for complications from or ineligible for standard bone marrow transplantation, with allogeneic peripheral blood stem cells from a haploidentical donor using a novel immunosuppressive regimen without myeloablation in an attempt to further decrease the transplant-related morbidity/mortality. The low intensity nonmyeloablative conditioning regimen will consist of a relatively low radiation dose for therapeutic radiation, Alemtuzumab (Campath ), Sirolimus (Rapamune ), Cyclophosphamide (Cytoxan ), and pentostatin (Nipent ) as a strategy to provide adequate immunosuppression to allow sufficient engraftment for clinical remission with a lower risk of GVHD development. T-cell replete, donor-derived, granulocyte colony-stimulating factor (G-CSF)- mobilized PBSC will be used to establish hematopoietic and lymphoid reconstitution.
The primary endpoint of this study is the percentage of patients at 100 days post-transplant who have not rejected their grafts, and who are without severe GVHD (defined as grade 3 and higher acute GVHD and moderate to severe chronic GVHD). Other endpoints include degree of donor-host chimerism necessary for long-term graft survival and disease amelioration, incidence of acute and chronic GVHD, incidence of graft rejection, transplant-related morbidity, as well as disease-free and overall survival.
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 57
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Participants with Sickle Cell Disease with Nonmyeloablative Haplo Transplants haploidentical stem cell transplant Participants will receive pentostatin on days -21, -17, -13, and -9 and oral cyclophosphamide from days -21 to -8. Alemtuzumab to be infused on days -7 to -3, followed by 400 cGy TBI on day -1. Donor-derived peripheral blood stem cells will be given on Day 0 then cyclophosphamide will be given at 50 mg/kg on day +3. Sirolimus loading dose of 5mg PO q4h x three doses at one day after the completion of cyclophosphamide (on day +4) and continued the following day at 5mg PO q24h to maintain trough levels between 5-15 ng/ml. Participants with Sickle Cell Disease with Nonmyeloablative Haplo Transplants Sirolimus Participants will receive pentostatin on days -21, -17, -13, and -9 and oral cyclophosphamide from days -21 to -8. Alemtuzumab to be infused on days -7 to -3, followed by 400 cGy TBI on day -1. Donor-derived peripheral blood stem cells will be given on Day 0 then cyclophosphamide will be given at 50 mg/kg on day +3. Sirolimus loading dose of 5mg PO q4h x three doses at one day after the completion of cyclophosphamide (on day +4) and continued the following day at 5mg PO q24h to maintain trough levels between 5-15 ng/ml. Participants with Sickle Cell Disease with Nonmyeloablative Haplo Transplants Pentostatin Participants will receive pentostatin on days -21, -17, -13, and -9 and oral cyclophosphamide from days -21 to -8. Alemtuzumab to be infused on days -7 to -3, followed by 400 cGy TBI on day -1. Donor-derived peripheral blood stem cells will be given on Day 0 then cyclophosphamide will be given at 50 mg/kg on day +3. Sirolimus loading dose of 5mg PO q4h x three doses at one day after the completion of cyclophosphamide (on day +4) and continued the following day at 5mg PO q24h to maintain trough levels between 5-15 ng/ml. Participants with Sickle Cell Disease with Nonmyeloablative Haplo Transplants Cyclophosphamide Participants will receive pentostatin on days -21, -17, -13, and -9 and oral cyclophosphamide from days -21 to -8. Alemtuzumab to be infused on days -7 to -3, followed by 400 cGy TBI on day -1. Donor-derived peripheral blood stem cells will be given on Day 0 then cyclophosphamide will be given at 50 mg/kg on day +3. Sirolimus loading dose of 5mg PO q4h x three doses at one day after the completion of cyclophosphamide (on day +4) and continued the following day at 5mg PO q24h to maintain trough levels between 5-15 ng/ml. Participants with Sickle Cell Disease with Nonmyeloablative Haplo Transplants Alemtuzumab Participants will receive pentostatin on days -21, -17, -13, and -9 and oral cyclophosphamide from days -21 to -8. Alemtuzumab to be infused on days -7 to -3, followed by 400 cGy TBI on day -1. Donor-derived peripheral blood stem cells will be given on Day 0 then cyclophosphamide will be given at 50 mg/kg on day +3. Sirolimus loading dose of 5mg PO q4h x three doses at one day after the completion of cyclophosphamide (on day +4) and continued the following day at 5mg PO q24h to maintain trough levels between 5-15 ng/ml. Participants with Sickle Cell Disease with Nonmyeloablative Haplo Transplants Hydroxyurea Participants will receive pentostatin on days -21, -17, -13, and -9 and oral cyclophosphamide from days -21 to -8. Alemtuzumab to be infused on days -7 to -3, followed by 400 cGy TBI on day -1. Donor-derived peripheral blood stem cells will be given on Day 0 then cyclophosphamide will be given at 50 mg/kg on day +3. Sirolimus loading dose of 5mg PO q4h x three doses at one day after the completion of cyclophosphamide (on day +4) and continued the following day at 5mg PO q24h to maintain trough levels between 5-15 ng/ml. Human Leukocyte Antigens (HLA) Haploidentical Related Stem Cell Donor Filgrastim A haploidentical relative donor will receive filgrastim (G-CSF) 10 to 16 µg/kg/d subcutaneously or intravenously for up to 6 days with apheresis collections of peripheral blood hematopoietic progenitor cells (PBPC) after the 5th day (and after the 6th day if required).
- Primary Outcome Measures
Name Time Method Percentage of Participants Who Have Not Rejected Their Stem Cell Graft and Who Are Without Severe Graft-versus-host Disease Following Stem Cell Transplant 100 days post transplant The percentage of sickle cell participants at 100 days post-transplant who have not rejected their grafts and who are without severe graft-versus-host disease (GVHD). Severe GVHD is defined as grade 3 or higher for acute GVHD and moderate to severe for chronic GVHD according to NIH Consensus Criteria.
Stem cell graft rejection is defined as
- Secondary Outcome Measures
Name Time Method Chimeric Value That is Required to Maintain Graft Survival and Hematologic Normalcy. Up to Year 5 The level of chimerism required to maintain both graft survival as well as hematologic normalcy. Hematologic normalcy may be defined as: being free from acute complications of sickle cell disease.
The chimeric status of patients will be measured on days +14 (or when subject starts to engraft), +30, +60 and +100, and periodically after day +100, by microsatellite analysis of the peripheral blood.
Engraftment of donor cells was assessed with the use of methods that detect informative polymorphisms in regions known to contain short tandem repeats. Peripheral-blood CD3+ T cells and CD14+CD15+ myeloid cells were selected for analysis with the use of immunomagnetic beads (Dynal).Incidence of Donor Type Hemoglobin Post-transplant in SCD Patients Who Have Not Been Transfused in the Previous 3 Months. 1 year Incidence of donor type hemoglobin at 1 year post-transplant in SCD patients who have not been transfused in the previous 3 months.
Number of Participants Who Developed Acute GVHD Grades I, II, III, IV Day 100 Number of participants who developed Acute Graft vs Host Disease (GVHD) Grades I, II, III, IV as defined by CIMBTR criteria for Organ Stages of Acute GVHD.
Grades are defined as:
Grade I: Skin = Maculopapular rash\< 25% of body surface area (BSA); Liver = Total Bilirubin 2-3 mg/dL; Lower GI = stool output/day is 500-999 mL/day.
Grade II: Skin = rash on 25-50 percent body surface area; Liver = Total Bilirubin 3.1-6.0 mg/dL; Lower GI = Diarrhea 1001-1500 mL/day.
Grade III: Skin = Rash on \>50% of body surface; Liver = Total Bilirubin 6.1 - 15.0 mg/dL; Lower GI = Diarrhea \> 1500 mL/day.
Grade IV: Skin = Generalized erythroderma plus bullous formation; Liver = Total Bilirubin \>15 mg/dL; Lower GI = Severe abdominal pain with or without ileus.
Grade I GVHD is characterized as mild disease, grade II GVHD as moderate, grade III as severe, and grade IV life-threatening.Participant Graft Rejection Rate Following Stem Cell Transplant Up to 5 years Participant graft rejection rate following stem cell transplant. Graft rejection is defined as donor myeloid chimerism and donor lymphoid chimerism \<5%.
Number of Participants Who Developed Moderate or Severe Chronic Graft vs Host Disease (GVHD) Up to Year 5 Number of Participants Who Developed Moderate or Severe Chronic Graft vs Host Disease (GVHD) up to 5 years.
Moderate chronic GVHD involves EITHER 3 organs/sites with no clinically significant functional impairment OR a less than or equal to 1 organ/site with clinically significant functional impairment, but no major disability. Severe GVHD is associated with a major disability caused by chronic GVHD.Percentage of Participant Overall Survival Following Stem Cell Transplant Up to Year 5 Percentage of Participant Overall Survival up to year 5 following stem cell transplant. Overall survival is defined as being alive following stem cell transplant.
Number of Participants That Experienced Transplant-related Mortality 1 year Number of participants that experienced transplant-related mortality. Transplant-related mortality is defined as death that is at least possibly related to the transplant (GVHD, toxicity, infection, other causes).
Number of Participants That Experienced Regimen Failure by Type of Haploidentical Donor Up to Year 5 Determine whether the type of haploidentical donor impacts the incidence of regimen failure. Number of participants that experienced regimen failure and type of haploidentical donor. Determine whether specific haploidentical donors (i.e. parent versus sibling versus child) will decrease the incidence of regimen failure. Haploidentical donor analyses include mother versus father, parent versus sibling, and parent versus child.
Percentage of Participant That Are Disease-free Survival Following Stem Cell Transplant Up to Year 5 Percentage of participant that are disease-free survival following stem cell transplant. Disease-free survival is defined as alive and free acute complications related to sickle cell disease.
Incidence of Graft Failure Following Stem Cell Transplant Up to 5 Years Incidence of graft failure following stem cell transplant. Graft failure is defined as the absence of or insufficient donor chimerism associated with the return of acute complications of sickle cell disease.
Trial Locations
- Locations (1)
National Institutes of Health Clinical Center
🇺🇸Bethesda, Maryland, United States