Allogeneic Hematopoietic Stem Cell Transplant for Patients With Inborn Errors of Immunity
- Conditions
- Autoimmune LymphoproliferativeCommon Variable ImmunodeficiencyImmune System DiseasesPrimary T-cell Immunodeficiency DisordersLymphoproliferative Disorders
- Interventions
- Radiation: Total body IrradiationProcedure: Allogeneic HSCT
- Registration Number
- NCT04339777
- Lead Sponsor
- National Cancer Institute (NCI)
- Brief Summary
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
- Detailed Description
Background:
* With the availability of whole exome sequencing (WES) and whole genome sequencing (WGS) for patients with suspected inborn errors of immunity (IEI), the number of recognized IEI has increased in recent years to over 400 distinct immune defects.
* Allogeneic hematopoietic stem cell transplantation (HSCT) represents a potentially curative therapy for many hematologic diseases.
* Hematopoietic stem cell transplant is now an accepted standard or an appropriate experimental approach for treatment of an increasing number of IEI
* We propose to evaluate the efficacy and safety of allogeneic hematopoietic stem cell transplantation using selected conditioning regimens and selected donor sources in reconstituting normal hematopoiesis and immune function and reversing the disease phenotype in patients with IEI.
Objectives:
-To determine whether allogeneic HSCT in patients with IEI results in sustained donor engraftment defined as neutrophil recovery with ANC \>= 500/mm\^3 for 3 consecutive days associated with \> 50% donor T-cell and myeloid cell donor chimerism by day 100 for diseases characterized by loss of function, and \>75% donor T-cell and myeloid cell chimerism for diseases characterized by gain-of-function mutations.
Eligibility:
* Participants ages 4-69 years old with a known IEI, or with clinical evidence of an IEI with a history of recurrent infections requiring prolonged courses of therapy, or evidence of immune dysregulation manifested by autoimmune/autoinflammatory disease, atopy, hemophagocytic lymphohistiocytosis, hypogammaglobulinemia, or impaired response to vaccination. A virally-driven malignancy alone will also constitute a basis for inclusion.
* Have an 8/8, 7/8, or 6/8 HLA-matched related or unrelated donor (HLA -A, -B, -C, DRB1, by high resolution typing) or a haploidentical related donor; unrelated donors are identified through the National Marrow Donor Program.
Design:
For Recipients with Fully Matched Donors
* Patients with IEI receiving a high intensity transplant conditioning regimen will receive a regimen consisting of fludarabine 40 mg/m\^2 IV once daily for 4 days on days -6, -5, -4, and -3, busulfan IV once daily for 4 days on days -6, -5, -4, -3 (busulfan dose will be based on pharmacokinetic levels from the test dose or real time pharmacokinetics (PKs) and will be targeted to a daily AUC of 3200-4400 micro Mol min/L (total busulfan exposure of 52-72 mg h/L) (3.2 mg/kg IV per day will be the default dose), and HSCT on day 0.
* Patients with IEI receiving an intermediate intensity transplant conditioning regimen will receive a regimen consisting of fludarabine 40 mg/m2 IV once daily for 4 days on days -6, -5, -4, and -3, busulfan IV once daily for 3 days on days -6, -5, -and -4 (busulfan dose will be based on pharmacokinetic levels from the test dose or real time PKs and will be targeted
to a daily AUC of 3200-4400 micro Mol min/L (total busulfan exposure of 39-54 mg h/L) (3.2 mg/kg IV per day will be the default dose), and HSCT on day 0.
-Patients with IEI receiving a low intensity transplant conditioning regimen will receive a regimen consisting of fludarabine 40 mg/m\^2 IV once daily for 4 days on days -6, -5, -4, and -3, busulfan IV once daily for 2 days on days -6, and -5 (busulfan dose will be based on pharmacokinetic levels from the test dose or real time PKs and will be targeted to a daily AUC of 3200-4400 micro Mol min/L (total busulfan exposure of 26-36 mg h/L) (3.2 mg/kg IV per day will be the default dose), and HSCT on day 0.
In all cohorts, alemtuzumab will be given per PI discretion to patients with clinical evidence of immune dysregulation, at the dose of 10 mg/m\^2 subcutaneously divided over 3 days, on days -14, -13 and -12.
For Recipients with 7/8 or 6/8 Matched Related or Unrelated Donors and Haploidentical Related Donors
* Patients with IEI receiving a high intensity transplant conditioning regimen will receive a regimen consisting of fludarabine 40 mg/m\^2 IV once daily for 4 days on days -6, -5, -4, and -3, busulfan IV once daily for 4 days on days -6, -5, -4, and -3 (busulfan dose will be based on pharmacokinetic levels from the test dose or real time PKs and will be targeted to a daily AUC of 3200-4400 micro Mol min/L (52-72 mg h/L) (3.2 mg/kg IV per day will be the default dose), 200 cGy TBI on day -1, and HSCT on day 0.
* Patients with IEI receiving an intermediate intensity transplant conditioning regimen will receive a regimen consisting of fludarabine 40 mg/m2 IV once daily for 4 days on days - 6, -5, -4, -and 3, busulfan IV once daily for 3 days on days -6, -5, and -4 (busulfan dose will be based on pharmacokinetic levels from the test dose or real time PKs and will be targeted to a daily AUC of 3200-4400 micro Mol min/L (39-54 mg h/L) (3.2 mg/kg IV per day will be the default dose), 200 cGy TBI on day -1, and HSCT on day 0.
* Patients with IEI receiving a low intensity transplant conditioning regimen will receive a regimen consisting of fludarabine 40 mg/m2 IV once daily for 4 days on days -6, -5, -4, and -3, busulfan IV once daily for 2 days on day -6 and -5 (busulfan dose will be based on pharmacokinetic levels from the test dose or real time PKs and will be targeted to a daily AUC of 3200-4400 micro Mol min/L (26-36 mg h/L) (3.2 mg/kg IV per day will be the default dose), 200 cGy TBI on day -1, and HSCT on day 0.
In all cohorts, alemtuzumab will be given per PI discretion to patients with clinical evidence of immune dysregulation, at the dose of 10 mg/m2 subcutaneously divided over 3 days, on days -14, -13 and -12.
For Post-Transplant GVHD Prophylaxis
-Post-transplant GVHD prophylaxis in all groups will consist of cyclophosphamide 50 mg/kg IV once daily for 2 days on days +3 and +4, along with mycophenolate mofetil from day +5 to approximately day +35 and tacrolimus from day +5 to approximately day +180.
If there is no evidence of GVHD, tacrolimus will be stopped or tapered at approximately day +180.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 66
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Arm B Fludarabine Intermediate Intensity Conditioning with or without Alemtuzumab Arm B Busulfan test dose Intermediate Intensity Conditioning with or without Alemtuzumab Arm B Total body Irradiation Intermediate Intensity Conditioning with or without Alemtuzumab Arm B Allogeneic HSCT Intermediate Intensity Conditioning with or without Alemtuzumab Arm B Mycophenolate mofetil (MMF) Intermediate Intensity Conditioning with or without Alemtuzumab Arm B Cyclophosphamide (Cytoxan) Intermediate Intensity Conditioning with or without Alemtuzumab Arm B Tacrolimus (Tacro) Intermediate Intensity Conditioning with or without Alemtuzumab Arm A Busulfan test dose Low Intensity, Intermediate Intensity and High Intensity Conditioning with or without alemtuzumab Arm A Fludarabine Low Intensity, Intermediate Intensity and High Intensity Conditioning with or without alemtuzumab Arm A Alemtuzumab Low Intensity, Intermediate Intensity and High Intensity Conditioning with or without alemtuzumab Arm A Allogeneic HSCT Low Intensity, Intermediate Intensity and High Intensity Conditioning with or without alemtuzumab Arm A Tacrolimus (Tacro) Low Intensity, Intermediate Intensity and High Intensity Conditioning with or without alemtuzumab Arm A Mycophenolate mofetil (MMF) Low Intensity, Intermediate Intensity and High Intensity Conditioning with or without alemtuzumab Arm A Cyclophosphamide (Cytoxan) Low Intensity, Intermediate Intensity and High Intensity Conditioning with or without alemtuzumab Arm A Busulfan Low Intensity, Intermediate Intensity and High Intensity Conditioning with or without alemtuzumab Arm B Busulfan Intermediate Intensity Conditioning with or without Alemtuzumab Arm B Alemtuzumab Intermediate Intensity Conditioning with or without Alemtuzumab
- Primary Outcome Measures
Name Time Method Sustained donor engraftment baseline to day +100 neutrophil recovery with ANC \>/= 500/mm\^3 for 3 consecutive days with \>50% or \>75% T-cell and myeloid donor chimerism
- Secondary Outcome Measures
Name Time Method Reversal of the immunological abnormalities 1 through 5 years post transplant Cumulative correction of disease-specific immunological abnormalities by 1-5 years post transplant
Reversal of the clinical phenotype 1 and 2 years post transplant Cumulative improvement of clinical phenotype consistent with the replacement of hematopoietic cells at 1 -5 years post transplant
regimen-related mortality +180 and 1 year post transplant Cumulative incidence of transplant-related mortality at 180 days and 1 year post transplant
Overall survival 1 through 5 years post transplant Time from transplant to death of any cause
infection and viral reactivation +180 and 1 year post transplant Cumulative incidence of transplant-related mortality at 180 days and 1 year post transplant
Incidence of Chronic Graft-versus-host disease 1 and 2 years post transplant Cumulative incidence of chronic graft versus host disease at 1 and 2 years post transplant
Incidence of Acute Graft-versus-host disease 100 days post transplant Cumulative incidence of acute graft versus host disease at day 100 post transplant
Event free survival 1 through 5 years post transplant Time from transplant to death of any cause, primary or secondary graft failure, or second transplant
Trial Locations
- Locations (1)
National Institutes of Health Clinical Center
🇺🇸Bethesda, Maryland, United States