Pilot Trial of Allogeneic Blood or Marrow Transplantation for Primary Immunodeficiencies

简要总结

详细描述

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 \>= 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.

主要结局

次要结局

• Secondary graft failure(1 year post transplant)
• Incidence of Chronic Graft-versus-host disease(1 and 2 years post transplant)
• Overall survival(1 year post transplant)
• Transplant-related mortality(+180 and 1 year post transplant)
• Kinetics and durability of lineage-specific donor chimerism(days +28 and +42)
• Event-free survival(1 year post transplant)
• Disease free survival(1 year post-transplant)
• Kinetics and durability of engraftment(days +28, +42, +60, +100, +180, and 1 year after allo BMT)
• Incidence of Acute Graft-versus-host disease(1 year post transplant)