Pilot Trial of Allogeneic Blood or Marrow Transplantation for Primary Immunodeficiencies
- Conditions
- Common Variable ImmunodeficiencyPrimary T-cell Immunodeficiency DisordersImmune System DiseasesAutoimmune LymphoproliferativeLymphoproliferative Disorders
- Interventions
- Drug: Reduced Intensity ConditioningDrug: Myeloablative Conditioning-Closed with amendment LDrug: Immunosuppression Only Conditioning -Closed with amendment LDrug: GVHD ProphylaxisProcedure: Allo BMT
- Registration Number
- NCT02579967
- Lead Sponsor
- National Cancer Institute (NCI)
- Brief Summary
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.
- Detailed Description
Background:
* Primary immunodeficiency diseases (PIDs) are conditions associated with major quantitative or qualitative immunologic abnormalities that are, in most cases, due to defects in cells of hematopoietic origin
* Participants with PID can have life-threatening complications including malignancy, recurrent infection, and autoimmunity/immune dysregulation
* Allogeneic blood or marrow transplantation (allo BMT) has the potential to cure the immune defect in PID and thereby reduce the morbidity and mortality associated with these diseases
Objectives:
-To estimate the acute graft-versus-host disease (aGVHD)-free, graft failure-free survival at day +180 after allo BMT, analyzed separately by conditioning arm/cohort
Eligibility:
* Patients age greater than or equal to 4 through 75 years
* PID deemed to be of sufficient past severity to warrant allo BMT, by meeting the two criteria below:
* PID as defined by identified genetic defect or, in the absence of a mutation, patients with an immune defect potentially amenable to allo BMT who meet the clinical history criteria below may be eligible
* Clinical history of at least two of the following:
* Life-threatening, organ-threatening, or severely disfiguring infection
* Protracted or recurrent infections
* Infection with an opportunistic organism
* Chronic elevation in the blood of a latent virus
* Evidence of immune dysregulation
* Hypogammaglobulinemia/dysglobulinemia
* Hematologic malignancy or lymphoproliferative disorder
* Virus-associated solid tumor malignancy or pre-cancerous lesion
* At least one 7-8/8 (9-10/10) HLA-matched related or unrelated donor, or an HLA-haploidentical related donor
* Adequate end-organ function
* Consensus opinion by the investigative team that the patient has the potential to benefit from transplant despite existing, non-hematopoietic organ dysfunction
* Not pregnant or breastfeeding
* HIV negative
* Disease status: patients with malignancy should be referred in remission for evaluation, except in the case of virus-associated malignancy who may be referred at any time
Design:
* The study will have two arms that vary in mycophenolate mofetil (MMF) duration.
* RIC and RIC-MMF arms: pentostatin 4 mg/m2/day IV on days -11 and -7, low-dose cyclophosphamide orally daily on days -11 through -4; busulfan IV, pharmacokinetically dosed, on days -3 and -2.
* RIC-SHORT arm: pentostatin 4 mg/m2/day IV on days -9 and -5, low-dose cyclophosphamide orally daily on days -9 through -2; busulfan IV, pharmacokinetically dosed, on days -3 and -2.
* Bone marrow is the preferred graft source. Peripheral blood stem cells are permitted on RIC-MMF arm but not on RIC-SHORT arm.
* GVHD prophylaxis:
* High-dose, post-transplantation cyclophosphamide (PTCy) on days +3 and +4, sirolimus on days +5 through +90, and mycophenolate mofetil (MMF) on days +5 through +35 for all arms except the RIC-MMF and RIC-SHORT arm. The RICMMF arm will receive MMF of varying durations based on a duration de-escalation schema.
* RIC-SHORT: Reduced-dose, post-transplantation cyclophosphamide (PTCy) on days +3 and +4, sirolimus on days +5 through +90, and mycophenolate mofetil (MMF) on days +5 through +18 for all arms.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 254
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description 1/ IOC Arm-Closed with amendment L (07/05/2019) GVHD Prophylaxis Immunosuppression Only Conditioning Arm 2/ RIC Arm - Closed with Amendment L (07/05/2019) GVHD Prophylaxis Reduced Intensity Conditioning Arm 2/ RIC Arm - Closed with Amendment L (07/05/2019) Allo BMT Reduced Intensity Conditioning Arm 4/ RIC-MMF Arm Reduced Intensity Conditioning Reduced Intensity Conditioning with MMF duration de-escalation design 4/ RIC-MMF Arm Allo BMT Reduced Intensity Conditioning with MMF duration de-escalation design 3/ MAC Arm-Closed with amendment L (07/05/2019) Myeloablative Conditioning-Closed with amendment L Myeloablative Conditioning Arm 2/ RIC Arm - Closed with Amendment L (07/05/2019) Reduced Intensity Conditioning Reduced Intensity Conditioning Arm 6/ RIC-SHORT Arm Allo BMT Reduced Intensity Conditioning with shortened duration and dose-reduced PTCy 1/ IOC Arm-Closed with amendment L (07/05/2019) Immunosuppression Only Conditioning -Closed with amendment L Immunosuppression Only Conditioning Arm 1/ IOC Arm-Closed with amendment L (07/05/2019) Allo BMT Immunosuppression Only Conditioning Arm 3/ MAC Arm-Closed with amendment L (07/05/2019) GVHD Prophylaxis Myeloablative Conditioning Arm 3/ MAC Arm-Closed with amendment L (07/05/2019) Allo BMT Myeloablative Conditioning Arm 4/ RIC-MMF Arm GVHD Prophylaxis Reduced Intensity Conditioning with MMF duration de-escalation design 6/ RIC-SHORT Arm Reduced Intensity Conditioning Reduced Intensity Conditioning with shortened duration and dose-reduced PTCy 6/ RIC-SHORT Arm GVHD Prophylaxis Reduced Intensity Conditioning with shortened duration and dose-reduced PTCy
- Primary Outcome Measures
Name Time Method For the RIC : To estimate the aGVHD-free, graft failure-free survival +180 after allo BMT Proportion of participants without GVHD
For the RIC-SHORT arm: To estimate the aGVHD-free, graft failure-free survival +180 after allo BMT 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 Duration de-escalation design Shortest duration of MMF
- Secondary Outcome Measures
Name Time Method Secondary graft failure 1 year post transplant Cumulative incidence of secondary graft failure at 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.
Overall survival 1 year post transplant Time from transplant to death of any cause.
Transplant-related mortality +180 and 1 year post transplant Cumulative incidence of transplant-related mortality at 180 days and 1 year post transplant.
Kinetics and durability of lineage-specific donor chimerism days +28 and +42 Median amount of patient who has early chimerism
Event-free survival 1 year post transplant Time from transplant to death of any cause or other event, including disease relapse, graft failure, grade 3-4 acute GVHD, chronic GVHD requiring systemic therapy, or receipt of post-transplant donor cell infusion.
Disease free survival 1 year post-transplant Time from transplant to death of any cause or disease relapse.
Kinetics and durability of engraftment days +28, +42, +60, +100, +180, and 1 year after allo BMT The percentage of donor T-, B-, NK-, and myeloid cell populations at days +28, +42, +60, +100, +180, and 1 year post transplant.
Incidence of Acute Graft-versus-host disease 1 year post transplant Cumulative incidence of acute graft versus host disease at 1 year post transplant
Trial Locations
- Locations (2)
National Marrow Donor Program
🇺🇸Minneapolis, Minnesota, United States
National Institutes of Health Clinical Center
🇺🇸Bethesda, Maryland, United States