A Randomized Trial of Low Versus Moderate Exposure Busulfan for Infants With Severe Combined Immunodeficiency (SCID) Receiving TCRαβ+/CD19+ Depleted Transplantation: A Phase II Study by the Primary Immune Deficiency Treatment Consortium (PIDTC) and Pediatric Blood and Marrow Transplant Consortium (PBMTC)
The investigators want to study if lower doses of chemotherapy will help babies with SCID to achieve good immunity with less short and long-term risks of complications after transplantation. This trial identifies babies with types of immune deficiencies that are most likely to succeed with this approach and offers them transplant early in life before they get severe infections or later if their infections are under control. It includes only patients receiving unrelated or mismatched related donor transplants. The study will test if patients receiving transplant using either a low dose busulfan or a medium dose busulfan will have immune recovery of both T and B cells, measured by the ability to respond to immunizations after transplant. The exact regimen depends on the subtype of SCID the patient has. Donors used for transplant must be unrelated or half-matched related (haploidentical) donors, and peripheral blood stem cells must be used. To minimize the chance of graft-versus-host disease (GVHD), the stem cells will have most, but not all, of the T cells removed, using a newer, experimental approach of a well-established technology. Once the stem cell transplant is completed, patients will be followed for 3 years. Approximately 9-18 months after the transplant, vaccinations will be administered, and a blood test measuring whether your child's body has responded to the vaccine will be collected.
⁃ 1\. Infants with SCID, either typical or leaky or Omenn syndrome.
• 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
• 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.
• 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.
• Hepatomegaly
∙ Splenomegaly
∙ Lymphadenopathy
∙ Elevated IgE
∙ Elevated absolute eosinophil count
∙ \*Oligoclonal T cells measured by CDR3 length or flow cytometry (upload report)
∙ \*Proliferation to PHA is reduced to \< 50% of lower limit of normal (LLN) or SI \< 30
∙ \*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
• Haploidentical related mobilized peripheral blood cells
• 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:
• Cardiac:
• Left ventricular ejection fraction (LVEF) at rest ≥ 40% or, shortening fraction (SF) ≥ 26% by echocardiogram.
• 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.
• 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.
• 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).