Conditioning SCID Infants Diagnosed Early

Inclusion Criteria

• •1\. Infants with SCID, either typical or leaky or Omenn syndrome.
• •1. Typical SCID is defined as either of the following
• •* Absence or very low number of T cells (CD3+ T cells \<300/microliter AND no or very low T cell function (\<10% of lower limit of normal) as measured by response to phytohemagglutinin OR
• •* Presence of maternally derived T cells
• •2. Leaky SCID is defined as the following
• •• Absence of maternally derived T cells
• •• AND either one or both of the following (i, ii): i) \<50% of lower limit of normal T cell function as measured by response to PHA OR \<30% of lower limit of normal T cell function as measured by response to CD3 ii) Absent or \<10% of lower limit of normal proliferative responses to candida and tetanus toxoid antigens (must document post vaccination or exposure for this criterion to apply)
• •• AND at least two of the following (i through iii): i) CD3 T cells \< 1500/microliter ii) \>80% of CD3+ or CD4+ T cells are CD45RO+ AND/OR \>80% of CD3+ or CD4+ T cells are CD62L negative AND/OR \>50% of CD3+ or CD4+ T cells express HLA-DR (at \< 4 years of age) AND/OR are oligoclonal T iii) Low TRECs and/or the percentage of CD4+/45RA+/CD31+ or CD4+/45RA+/CD62L+ cells is below the lower level of normal.
• •3. Omenn syndrome • Generalized skin rash
• •* Maternal lymphocytes tested for and not detected.
• •* \>80% of CD3+ or CD4+ T cells are CD45RO+ AND/OR \>80% of CD3+ or CD4+ T cells are CD62L negative AND/OR \>50% of CD3+ or CD4+ T cells express HLA-DR (\<2 years of age)
• •* Absent or low (up to 30% lower limit of normal (LLN)) T cell proliferation to antigens (Candida, tetanus) to which the patient has been exposed IF: Proliferation to antigen was not performed, but at least 4 of the following 8 supportive criteria, at least one of which must be among those marked with an asterisk (\*) below are present, the patient is eligible as Omenn Syndrome.
• •1. Hepatomegaly
• •2. Splenomegaly
• •3. Lymphadenopathy
• •4. Elevated IgE
• •5. Elevated absolute eosinophil count
• •6. \*Oligoclonal T cells measured by CDR3 length or flow cytometry (upload report)
• •7. \*Proliferation to PHA is reduced to \< 50% of lower limit of normal (LLN) or SI \< 30
• •8. \*Low TRECs and/or percentage of CD4+/RA+ CD31+ or CD4+/RA+ CD62L+ cells below the lower level of normal
• •2\. Documented mutation in one of the following SCID-related genes
• •a. Cytokine receptor defects (IL2RG, JAK3) b. T cell receptor rearrangement defects (RAG1, RAG2) 3. No available genotypically matched related donor (sibling) 4. Availability of a suitable donor and graft source
• •1. Haploidentical related mobilized peripheral blood cells
• •2. 9/10 or 10/10 allele matched (HLA-A, -B, -C, -DRB1, -DQB1) volunteer unrelated donor mobilized peripheral blood cells 5. Age 0 to 2 years at enrollment
• •Note: to ensure appropriate hepatic metabolism, age at time of busulfan start:
• •For IL2RG/JAK3: 8 weeks For RAG1/RAG2: 12 weeks
• •6\. Adequate organ function defined as:
• •1. Cardiac:
• •Left ventricular ejection fraction (LVEF) at rest ≥ 40% or, shortening fraction (SF) ≥ 26% by echocardiogram.
• •2. Hepatic:
• •Total bilirubin \< 3.0 x the upper limit of normal (ULN) for age (patients who have been diagnosed with Gilbert's Disease are allowed to exceed this limit) and AST and ALT \< 5.0 x ULN for age.
• •3. Renal:
• •GFR estimated by the updated Schwartz formula ≥ 90 mL/min/1.73 m2. If the estimated GFR is \< 90 mL/min/1.73 m2, then renal function must be measured by 24-hour creatinine clearance or nuclear GFR, and must be \> 50 mL/min/1.73 m2.
• •4. Pulmonary No need for supplemental oxygen and O2 saturation \> 92% on room air at sea level (with lower levels allowed at higher elevations per established center standard of care).