Fludarabine Phosphate, Cyclophosphamide, and Total-Body Irradiation Followed by Donor Bone Marrow Transplant and Cyclophosphamide, Mycophenolate Mofetil, Tacrolimus, and Sirolimus in Treating Patients With Primary Immunodeficiency Disorders or Noncancerous Inherited Disorders
Condition: Immunodeficiency Syndrome; Severe Aplastic Anemia; Genetic Disorder
MeSH terms: Anemia, Aplastic; Primary Immunodeficiency Diseases; Genetic Diseases, Inborn; Immunologic Deficiency Syndromes
Intervention: Allogeneic Bone Marrow Transplantation; Cyclophosphamide; Fludarabine Phosphate; Laboratory Biomarker Analysis; Mycophenolate Mofetil; Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation; Sirolimus; Tacrolimus; Total-Body Irradiation
Intervention description: Undergo allogeneic bone marrow transplantation; Given IV; Given IV; Correlative studies; Given PO; Undergo allogeneic bone marrow transplantation; Given PO; Given IV or PO; Undergo total-body irradiation
Intervention MeSH terms: Mycophenolic Acid; Sirolimus; Cyclophosphamide; Fludarabine; Fludarabine phosphate; Tacrolimus
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 14.0
Sex: All
Maximum age: 55 Years
Healthy volunteers: No

Summary:

      This phase I/II trial studies the side effects of fludarabine phosphate, cyclophosphamide and
      total-body irradiation followed by donor bone marrow transplant and cyclophosphamide,
      mycophenolate mofetil, tacrolimus, and sirolimus in treating patients with primary
      immunodeficiency disorders or noncancerous inherited disorders. Giving low doses of
      chemotherapy and total-body irradiation before a bone marrow transplant helps prepare the
      patient's body to accept the incoming donor's bone marrow and decrease the risk that the
      patient's immune system will reject the donor's stem cells. When the healthy stem cells from
      a donor are infused into the patient they may help the patient's bone marrow make stem cells,
      red blood cells, white blood cells, and platelets. Sometimes the transplanted cells from a
      donor can make an immune response against the body's normal cells called graft versus host
      disease. Giving cyclophosphamide, mycophenolate mofetil, tacrolimus, and sirolimus after the
      transplant may help decrease this from happening.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Primary immunodeficiency disorder or other nonmalignant inherited disease (except
             Fanconi anemia) treatable by allogeneic HCT

          -  Patients with pre-existing medical conditions or other factors that renders them at
             high risk for regimen related toxicity or ineligible for conventional myeloablative
             HCT and who do not have HLA-matched related or unrelated donors

          -  Patients with a related donor who is identical for one HLA haplotype

          -  Acquired aplastic anemia: severe aplastic anemia (SAA) is defined as follows:

               -  Bone marrow cellularity < 25%, or marrow cellularity < 50% but with < 30%
                  residual hematopoietic cells

               -  Two out of three of the following (in peripheral blood): neutrophils < 0.5 x
                  10^9/L; platelets < 20 x 10^9/L; reticulocytes < 20 x 10^9/L

               -  SAA diagnostic criteria may be applied to assessment at initial diagnosis or
                  follow-up assessments

          -  DONOR: Related donors who are identical for one HLA haplotype

          -  DONOR: Bone marrow will be the only allowed stem cell source

        Exclusion Criteria:

          -  Fanconi anemia

          -  Suitably HLA-matched related or unrelated donors

          -  Patients with metabolic storage diseases who have severe central nervous system (CNS)
             involvement of disease, defined as intelligence quotient (IQ) score < 70

          -  Cardiac ejection fraction < 30% (or, if unable to obtain ejection fraction, shortening
             fraction < 26%) on multiple-gated acquisition (MUGA) scan or cardiac echocardiogram
             (echo), symptomatic coronary artery disease, or other cardiac failure requiring
             therapy; patients with a history of, or current cardiac disease should be evaluated
             with appropriate cardiac studies and/or cardiology consult; patients with a shortening
             fraction of < 26% must be seen by cardiology for approval

          -  Poorly controlled hypertension despite anti-hypertensive medications

          -  Patients with clinical or laboratory evidence of liver disease will need to be
             evaluated for the cause of the liver disease, its clinical severity in terms of liver
             function and the degree of portal hypertension; patients will be excluded if they are
             found to have fulminant liver failure, cirrhosis of the liver with evidence of portal
             hypertension, bridging fibrosis, alcoholic hepatitis, esophageal varices, a history of
             bleeding esophageal varices, hepatic encephalopathy, uncorrectable hepatic synthetic
             dysfunction evidenced by prolongation of the prothrombin time, ascites related to
             portal hypertension, bacterial or fungal liver abscess, biliary obstruction, chronic
             viral hepatitis with total serum bilirubin > 3 mg/dl, or symptomatic biliary disease

          -  Positive for human immunodeficiency virus (HIV)

          -  Females who are pregnant (beta-human chorionic gonadotropin positive [beta-HCG+]) or
             breast-feeding

          -  Fertile men or women who are unwilling to use contraceptives during HCT and up to 12
             months post-treatment

          -  Patients with fungal pneumonia with radiological progression after receipt of
             amphotericin formulation or mold-active azoles for greater than 1 month will not be
             eligible for this protocol (either regimen A or B)

          -  DONOR: Donor-recipient pairs in which the HLA-mismatch is only in the
             host-versus-graft (HVG) direction; patients are homozygous and donor is heterozygous

          -  DONOR: Donors who are not expected to meet the minimum target dose of marrow cells (1
             x 10^8 nucleated cells/kg recipient ideal body weight)

          -  DONOR: HIV-positive donors

          -  DONOR: A positive anti-donor cytotoxic cross match is absolute donor exclusion

          -  DONOR: < 6 months old and > 75 years old