Alemtuzumab, Fludarabine Phosphate, and Total-Body Irradiation Followed By a Donor Stem Cell Transplant in Treating Patients With Immunodeficiency or Other Nonmalignant Inherited Disorders

This phase II trial is studying giving fludarabine phosphate and total-body irradiation with or without alemtuzumab followed by donor stem cell transplant to see how well it works in treating patients with immunodeficiency or other nonmalignant inherited disorders. Giving chemotherapy, such as fludarabine phosphate, a monoclonal antibody such as alemtuzumab, and radiation therapy before a donor stem cell transplant helps stop the growth of abnormal cells. It may also stop the patient's immune system from rejecting the donor's stem cells. The donated stem cells may replace the patient's immune cells and help destroy any remaining abnormal cells

PRIMARY OBJECTIVES:

I. Improve donor chimerism levels in patients with inherited nonmalignant disorders undergoing hematopoietic cell transplantation (HCT) using a reduced intensity conditioning regimen either through the addition of Campath (alemtuzumab) or a slightly higher dose of total-body irradiation (TBI).

SECONDARY OBJECTIVES:

I. Decrease the incidence and severity of acute and chronic graft-versus-host disease (GVHD) through use of marrow as the stem cell source and Campath.

II. Assess disease response following HCT.

III. Immune reconstitution following HCT.

IV. Incidence of infections.

V. Overall survival.

VI. Percent of patients with cluster of differentiation (CD)33/CD19 donor chimerism > 50%.

OUTLINE:

CONDITIONING REGIMEN: *Patients with no life-threatening viral or fungal infections within 1 month before the planned hematopoietic cell transplantation (HCT) receive alemtuzumab intravenously (IV) over 6 hours on day -10 and fludarabine phosphate IV over 30 minutes on days -4 to -2. They also undergo low-dose TBI on day 0. Patients with hemophagocytic lymphohistiocytosis (HLH), immune dysregulation polyendocrinopathy enteropathy X-linked (IPEX) syndrome, DiGeorge syndrome, or life-threatening viral or fungal infections within 1 month before the planned HCT receive fludarabine phosphate IV over 30 minutes on days -4 to -2 and undergo 2 low doses of TBI on day 0.

HEMATOPOIETIC CELL TRANSPLANTATION: Patients undergo HCT on day 0.

IMMUNOSUPPRESSION: Patients receive cyclosporine IV or orally (PO) 2-3 times daily beginning on day -3 and continuing until day 100 followed by a taper until day 180. They also receive mycophenolate mofetil IV or PO 3 times daily beginning on day 0 and continuing until day 40 followed by a taper until day 96.

After completion of HCT, patients are followed up at day 84, at 6, 12, 18 and 24 months post-transplantation, and then once a year for 3 years.

• Biological: alemtuzumab
  Given IV
  Other Names:

  • anti-CD52 monoclonal antibody
  • Campath-1H
  • MoAb CD52
  • Monoclonal Antibody Campath-1H
  • Monoclonal Antibody CD52
• Drug: fludarabine phosphate
  Given IV
  Other Names:

  • 2-F-ara-AMP
  • Beneflur
  • Fludara
• Radiation: total-body irradiation
  Undergo low dose TBI
  Other Name: TBI
• Drug: cyclosporine
  Given PO or IV
  Other Names:

  • ciclosporin
  • cyclosporin
  • cyclosporin A
  • CYSP
  • Sandimmune
• Drug: mycophenolate mofetil
  Given PO or IV
  Other Names:

  • Cellcept
  • MMF
• Procedure: allogeneic bone marrow transplantation
  Undergo HCT
  Other Names:

  • bone marrow therapy, allogeneic
  • bone marrow therapy, allogenic
  • transplantation, allogeneic bone marrow
  • transplantation, allogenic bone marrow
• Procedure: allogeneic hematopoietic stem cell transplantation
  Undergo HCT
• Other: laboratory biomarker analysis
  Correlative study

Inclusion Criteria:

• Primary immunodeficiency disorder or other nonmalignant inherited disease (except aplastic anemia and 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 a conventional myeloablative HCT
• Donors: Related donor who is human leukocyte antigen (HLA) genotypically identical at least at one haplotype and may be genotypically or phenotypically identical for serological typing for HLA-A, B, -C, and at the allele level for -DRB1 and -DQB1; related donors must be a match or a single allele mismatch at HLA-A, B, and C (at highest resolution available at the time of donor selection) and matched at DRB1 and DQB1 by deoxyribonucleic acid (DNA) typing

• Donors: Unrelated donors who are prospectively:

  • Matched for HLA-A, B, C, DRB1 and DQB1 by DNA typing at the highest resolution routinely available at the time of donor selection
  • Only a single allele disparity will be allowed for HLA-A, B, or C as defined by high resolution typing (no mismatching for DRB1 or DQB1 is allowed)

Exclusion Criteria:

• Patients with Aplastic anemia and Fanconi anemia
• 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 of < 26%) on multi-gated acquisition (MUGA) scan or cardiac echo, symptomatic coronary artery disease, 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 < 26% may be enrolled if approved by a cardiologist
• 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 > 3mg/dl, or symptomatic biliary disease (Patients will be allowed on to the protocol with liver problems if gastroenterology approves the patient for HCT)
• Patients who are seropositive for human immunodeficiency virus (HIV)
• Females who are pregnant 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)
• Donors: Identical twin
• Donors: Pregnancy
• Donors: HIV seropositive
• Donors: A positive anti-donor cytotoxic cross match is absolute donor exclusion
• Donors: If a patient is homozygous at a particular loci, mismatching at that loci is not allowed due to an isolated graft rejection vector, i.e., patient A*0101 and the donor is A*0101, A*0201; such a mismatch may increase the risk of graft rejection; if patient and donor pairs are both homozygous at a mismatched loci, they are considered a two-HLA antigen mismatch, i.e., the patient is A*0101 and the donor is A*0201, and this type of mismatch is not allowed
• Donor: Donor < 6 months old, > 75 years old

• National Heart, Lung, and Blood Institute (NHLBI)
• National Cancer Institute (NCI)