Background:
During a transplant, blood stem cells from one person are given to someone else. The cells grow into the different cells that make up the immune system. This can cure people with certain immunodeficiencies. But transplant has many risks and complications.
Objective:
To see if stem cell transplant can be successfully performed in people with primary immunodeficiency disease and cure them.
Eligibility:
People ages 4-69 for whom a primary immunodeficiency (PID) or Primary Immune Regulatory Disorder (PIRD), has caused significant health problems and either standard management has not worked or there are no standard management options, along with their donors
Design:
Donors will be screened under protocol 01-C-0129. They will donate blood or bone marrow.
Participants will be screened with:
Medical history
Physical exam
Blood, urine, and heart tests
CT or PET scans
Before transplant, participants will have dental and eye exams. They will have a bone marrow biopsy. For this, a needle will be inserted through the skin into the pelvis to remove marrow.
Participants will be hospitalized before their transplant. They will have a central catheter put into a vein in their chest or neck. They will get medications through the catheter to prevent complications. Participants will get stem cells through the catheter. They will stay in the hospital for at least 4 weeks. They will give blood, urine, bone marrow, and stool samples. They may need blood transfusions. They may need more scans. They will take more medications.
Participants will have visits on days 30, 60, 100, 180, and 360, and 24 months after the transplant. Then they will have visits once a year for about 5 years
Age >= 4 years and <=69 yo with Weight >=12 kilograms
Mutation in a known monogenic (IEI) gene performed by a CLIA certified laboratory, who have failed standard medical management, or when no standard medical management is available.
Availability of an 8/8, 7/8, or 6/8 HLA-matched related or unrelated donor (if the mismatch is at DQ this will be considered an 8/8 matched donor), or a haploidentical related donor. Karnofsky or Lansky performance status of >= 40%
Creatinine: Adult patients: <= 2.0 mg/dl and creatinine clearance >= 30 ml/min; Pediatric patients (<18 years old): creatinine < 1.5 mg/dL and a creatinine clearance, using the Schwartz Formula > 30 mL/min/1.73m².
Patients who are receiving any other investigational agents (with the exception of virus-specific therapy e.g. cytotoxic T-cells for the treatment of viral infection/reactivation prior to allo HCT).
Patients with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.
HIV-positive patients are ineligible because these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated.
History of allergic reactions attributed to compounds of similar chemical or biologic composition to agents (steroids, cyclophosphamide, busulfan, tacrolimus, sirolimus, MMF, G-CSF, alemtuzumab) used in the study
Parallel
Busulfan test dose
Drug0.8 mg/kg IV infusion over 2 hours
Fludarabine
Drug40 mg/m2 IV infusion over 30 min once daily for 4 days
Busulfan
DrugAUC Targeted Dose based on busulfan test dose PKs, IV infusion over 3 hours once daily (3.2 mg/kg IV per day will be the default dose) per the below time frame: For 10/10 Matched Related and Unrelated Donor Recipients For the High Intensity Arm, the busulfan dose will be given for 4 days (-6, -5, -4, and -3). For Intermediate Intensity Arm, the busulfan dose will be given for 3 days (-6,-5, and -4). For Low Intensity Arm, the busulfan dose will be given for 2 days on days (-6 and -5). 9/10 HLA Matched Related or Unrelated Donor Recipients For the High Intensity Arm, the busulfan dose will be given for 3 days (-6, -5, and -4). For the the Intermediate Intensity Arm, the busulfan dose will be given for 2 days (-6 and -5). For the Low Intensity Arm, the busulfan dose will be given for 1 day on day (-6).
Alemtuzumab
DrugAlemtuzumab will be given if there is evidence of immune dysregulation 10 mg/m2 SC divided over three days (-14, -13, and -12)
Total body Irradiation
Radiation200 cGy Transplant Day -1 (Only for 9/10 HLA Matched Related or Unrelated Donor Recipients )
Allogeneic HSCT
Procedure/SurgeryStem cell transplant
Tacrolimus (Tacro)
DrugTacrolimus 0.02 mg/kg IV continuous infusion over 24 hours starting on day +5
Mycophenolate mofetil (MMF)
DrugMycophenolate mofetil 15 mg/kg IV over 2 hours three times a day starting on day +5 will continue until Approximately+35 (+/- two days)
Cyclophosphamide (Cytoxan)
DrugCyclophosphamide: 50 mg/kg IV once daily over 2 hours on days +3 and +4, dosed according to ideal body weight
Sustained donor engraftment
neutrophil recovery with ANC \>/= 500/mm\^3 for 3 consecutive days with \>50% or \>75% T-cell and myeloid donor chimerism
Reversal of the immunological abnormalities
Cumulative correction of disease-specific immunological abnormalities by 1-5 years post transplant
Reversal of the clinical phenotype
Cumulative improvement of clinical phenotype consistent with the replacement of hematopoietic cells at 1 -5 years post transplant
regimen-related mortality
Cumulative incidence of transplant-related mortality at 180 days and 1 year post transplant
Overall survival
Time from transplant to death of any cause
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