Pilot Trial of Allogeneic Blood or Marrow Transplantation for Primary Immunodeficiencies

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.