Risk-Adapted Allogeneic Stem Cell Transplantation For Mixed Donor Chimerism In Patients With Non-Malignant Diseases

Inclusion Criteria

Patients must meet the eligibility criteria for organ function regardless of diagnosis:

• Age \< 30 or = 30 years of age
• Adequate renal function defined as serum creatinine \< or = 1.5 x normal, or creatinine clearance or radioisotope glomerular filtration rate (GFR) > or =40 ml/min/m2 or >60 ml/min/1.73 m2 or an equivalent GFR as determined by the institutional normal range
• Adequate liver function defined as serum glutamic oxaloacetic transaminase (SGOT)(Aspartate transaminase (AST)) or serum glutamic-pyruvic transaminase (SGPT) (alanine aminotransferase (ALT)) \< 5.0 x normal
• Adequate cardiac function defined as shortening fraction of > or = 28% by echocardiogram, or ejection fraction of > or = 48% by radionuclide angiogram or echocardiogram
• Adequate pulmonary function defined as asymptomatic or, if symptomatic, carbon monoxide diffusing capacity test (DLCO) >45% of predicted (corrected for hemoglobin level). If unable to obtain pulmonary function test, O2 saturation >85% in room air.

Bone Marrow Failure Syndromes

Patients with the following diagnoses are eligible:

Severe Aplastic Anemia:

• Hypocellular bone marrow biopsy (\<25% cellularity) and 2/3 of the following (at diagnosis or nadir):
• Absolute Neutrophil Count (ANC) \<200/mm3,
• Platelets \<20,000/mm3
• Reticulocyte count \<60,000/mm3

Fanconi Anemia:

• Abnormal clastogenic studies (all patients) Severe Congenital Neutropenia (Kostmann's Syndrome) Amegakaryocytic Thrombocytopenia
• Severe thrombocytopenia (\< or =20,000/mm3) at diagnosis
• Severe depletion of megakaryocytes on bone marrow aspirate (\< or =25% normal)

Diamond-Blackfan Anemia:

• Corticosteroid dependent for > 6 months OR Transfusion dependent OR refractory acquired pure red cell aplasia.

Infantile Osteopetrosis Schwachman-Diamond Syndrome Dyskeratosis Congenita Other bone marrow failure syndromes at discretion of co-principal investigators All BM failure patients must have BM bx within 2 weeks prior to starting therapy to confirm disease status

Immunodeficiencies:

• SCIDS, all subtypes
• Combined Immunodeficiency Syndrome
• Wiskott-Aldrich Syndrome
• Chronic Granulomatous Disease
• Chediak-Higashi Syndrome
• Leukocyte Adhesion Deficiency
• Other immunodeficiencies at discretion of co-principal investigators

Inborn Errors of Metabolism (IEOM):

Transplant is recommended for the following disorders:

• Hurler syndrome (alpha-L-iduronidase deficiency, MPS-I), preferably before age 24 months
• Maroteaux-Lamy syndrome (galactosamine-4-sulfatase deficiency,MPSVI)
• Sly syndrome (beta-glucuronidase deficiency, MPS-VII)
• Globoid cell leukodystrophy (galactocerebrosidase deficiency), with careful attention to neurologic status in the infantile form
• Metachromatic leukodystrophy (arylsulfatase A deficiency),juvenile or adult onset form; late infantile MLD only if pre-symptomatic
• Childhood-onset X-linked adrenoleukodystrophy (X-ALD), at initial signs of neuropsychological deterioration, with dietary modification prior to transplant
• Fucosidosis (fucosidase deficiency)
• Mannosidosis
• Aspartylglucosaminuria
• Niemann-Pick Disease Type B (acid sphingomyelinase deficiency)
• Other diagnoses may be considered at the discretion of the co-principal investigators

Transplant is not recommended for Hunter syndrome (iduronate sulfatase deficiency), Sanfilippo syndrome Type A (heparan N-sulfatase deficiency), Sanfilippo syndrome Type B (-N-acetyl-transferase deficiency), Sanfilippo syndrome Type C (-acetyltransferase deficiency), Sanfilippo syndrome Type D (-acetylglucosamine-6-sulfatase deficiency), Morquio syndrome (galactose-6-sulfatase deficiency); or Niemann-Pick disease Type A or C.

For X-ALD patients greater than 5 years of age, IQ >80 is required. For other patients greater than 5 years of age, IQ > 70 is required.

For patients less than 5 years of age, the developmental quotient or clinical neurodevelopmental examination should demonstrate potential for stabilization at a level of functioning where continuous life support (e.g. mechanical ventilation) would not be predicted to be required in the year following transplantation.

For Gaucher disease (glucocerebrosidase deficiency) Type I (non-neuropathic), the primary therapy is enzyme replacement, but allogeneic stem cell transplant has been used effectively.

Histiocytoses:

• Hemophagocytic Lymphohistiocytosis (HLH)
• Familial Erythrophagocytic Lymphohistiocytosis
• Langerhans Cell Histiocytosis
• Patients with multi-system disease whose initial disease is stable or progressive after minimum 6 weeks of appropriate therapy, OR patients with recurrent multi-system disease.
• Malignant Histiocytosis
• All histiocytic patients must have BM bx within 2 weeks prior to starting therapy to confirm disease status

Other non-malignant diseases not listed above may be eligible if deemed appropriate by the co-principal investigators.