Background:
Allogeneic blood or marrow transplant is when stem cells are taken from one person s blood or bone marrow and given to another person. Researchers think this may help people with immune system problems.
Objective:
To see if allogeneic blood or bone marrow transplant is safe and effective in treating people with primary immunodeficiencies.
Eligibility:
Donors: Healthy people ages 4 or older
Recipients: People ages 4-75 with a primary immunodeficiency that may be treated with allogeneic blood or marrow transplant
Design:
Participants will be screened with medical history, physical exam, and blood tests.
Participants will have urine tests, EKG, and chest x-ray.
Donors will have:
Bone marrow harvest: With anesthesia, marrow is taken by a needle in the hipbone.
OR
Blood collection: They will have several drug injections over 5-7 days. Blood is taken by IV in one arm, circulates through a machine to remove stem cells, and returned by IV in the other arm.
Possible vein assessment or pre-anesthesia evaluation
Recipients will have:
Lung test, heart tests, radiology scans, CT scans, and dental exam
Possible tissue biopsies or lumbar puncture
Bone marrow and a small piece of bone removed by needle in the hipbone.
Chemotherapy 1-2 weeks before transplant day
Donor stem cell donation through a catheter put into a vein in the chest or neck
Several-week hospital stay. They will take medications and may need blood transfusions and additional procedures.
After discharge, recipients will:
Remain near the clinic for about 3 months. They will have weekly visits and may require hospital readmission.
Have multiple follow-up visits to the clinic in the first 6 months, and less frequently for at least 5 years.
Patients age >= 4 through 75 years
PID as defined by identified genetic defect or, in the absence of a PID-associated genetic mutation, patients with an immune defect potentially amenable to allo BMT who meet the clinical history criteria below may be eligible upon discussion with the PI
Mutations should be confirmed in a CLIA-certified laboratory, if such testing is available.
Patients without a mutation must be deemed eligible and appropriate for allo BMT by the PI. Some patients may meet the clinical history criteria listed below, but will not be eligible if it is thought that their clinical history is due to a condition apart from an immune defect. In addition, patients with a PID of mild severity, such as those with selective IgA deficiency, may meet at least two of the clinical history criteria, but may be deemed inappropriate for allo BMT by the PI if it is felt that the risks of the procedure outweigh the severity of the disease.
Patients who are receiving any other investigational agents, with the exception of virus-specific cytotoxic T-cells for the treatment of viral infection/reactivation prior to allo BMT.
History of allergic reactions attributed to compounds of similar chemical or biologic composition to agents (cyclophosphamide, busulfan, pentostatin, sirolimus, MMF, filgrastim or filgrastim biosimilar) used in the study
Active psychiatric disorder which may compromise compliance with the transplant protocol, or which does not allow for appropriate informed consent
Active central nervous system (CNS) involvement by malignancy, except in cases of virus-associated malignancies with CNS involvement in which case the patient may benefit from the transplant to control the malignancy.
Parallel
Immunosuppression Only Conditioning -Closed with amendment L
DrugPentostatin 4 mg/m2/day IV on days -9 and -5, cyclophosphamide 5 mg/kg orally daily on days -9 through -2 (Closed with amendment L)
Reduced Intensity Conditioning
Drugpentostatin 4 mg/m2/day IV on days -11 and -7, cyclophosphamide 3 mg/kg orally daily on days -11 through -4; busulfan IV, pharmokinetically dosed, on days -3 and -2.
Myeloablative Conditioning-Closed with amendment L
DrugPentostatin 4 mg/m2/day IV on days -13 and -9, low-dose cyclophosphamide orally daily on days -13 through -6; busulfan IV, pharmokinetically dosed, on days -5, -4, -3, and -2. (Closed with amendment L)
GVHD Prophylaxis
DrugHigh-dose, post-transplantation cyclophosphamide (PTCy) 25-50 mg/kg on days +3 and +4, sirolimus 6 mg on days +5 through +90, and mycophenolate mofetil (MMF) on days +5 through 0, +18, +25, or +35 depending on treatment arm and cohort.
Allo BMT
Procedure/SurgeryAllogeneic blood or marrow transplantation
6
Treatment groupsSee each treatment group below.
For the RIC-SHORT arm: To estimate the aGVHD-free, graft failure-free survival
Proportion of participants without GVHD
For the RIC : To estimate the aGVHD-free, graft failure-free survival
Proportion of participants without GVHD
For the RIC-MMF arm: To determine the shortest duration of MMF that can be safely administered without excessive rates of graft failure or acute grade 3-4 GVHD
Shortest duration of MMF
Transplant-related mortality
Cumulative incidence of transplant-related mortality at 180 days and 1 year post transplant.
Secondary graft failure
Cumulative incidence of secondary graft failure at 1 year post transplant.
Overall survival
Time from transplant to death of any cause.
Kinetics and durability of lineage-specific donor chimerism
Median amount of patient who has early chimerism
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