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

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.

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 positive 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 positive

- 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