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Severe Combined Immunodeficiency Syndrome

Severe Combined Immunodeficiency Syndrome. A heterogeneous group of congenital disorders which results in the absence of antigen-specific T and B cell responses 1/50-100, 000 live births Newborn screening estimate now 1/30-40,000 live birth

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Severe Combined Immunodeficiency Syndrome

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  1. Severe Combined Immunodeficiency Syndrome • A heterogeneous group of congenital disorders which results in the absence of antigen-specific T and B cell responses • 1/50-100, 000 live births • Newborn screening estimate now 1/30-40,000 live birth • Athabascan-speaking Native Americans, an incidence of 52/100,000 live births • Early classification based on presence or absence of adenosine deaminase and the % and absolute numbers of T, B, and NK cells

  2. Laboratory Evaluation • Lymphoid phenotype • PHA, MLC, NK function • ADA and PNP levels • Immunoglobulin levels • HIV Ab parents, HIV PCR child • HLA Class I and Class II expression • +/- phenotyping for CD127 (IL-7R)or CD132 (IL-2g chain) if consistent phenotype

  3. Response to PEG-ADA • 20% show no response • Majority see T cell immune response in the short term but it wanes with time • B cell immunity, 50% will need continued IVIG • B cell numbers increase within a few weeks of therapy • T cell numbers may require several months to increase

  4. RESPONSE TO PEG-ADA in two infants identified by NBS

  5. Response to PEG-ADA

  6. Results of HCT for ADA deficiency 81-100% 29%-63% *50% survivors had neurologic deficits

  7. Newborn Screening Allows early identification and treatment of affected infants EFS if HCT <2 months of age: 90-100% Currently how well young infants tolerate cytoreduction is unknown How much cytoreduction to ensure B cell engraftment unknown NBS also uncovers infants who may have transient lymphopenia or immune defects that previously were unrecognized and may or may be associated with an increased risk of infection. Need to determine best way to inform parents Current literature needs to be translated into multiple languages Available literature for parents is either too simplistic or too complicated

  8. Longitudinal lymphoid phenotype of female child with low-absent TRECS on newborn screen Normal TRECS No TRECS

  9. Longitudinal immune phenotype and function of female infant with low but detectable TRECs on newborn screen

  10. Why do children with SCID ever need cytoreduction Effect of pre-HCT NK function on engraftment following TCD MM-related SBA- E- BMT in the absence of cytoreduction To ensure donor B cell engraftment To prevent graft rejection in patients with NK activity via KIR pathways In pts with ADA deficiency-to ensure 100% donor chimerism including red cell lineage To prevent T cell mediated graft rejection in those with PHA >5% LLN CHI-SQUARE=17.9, p <.001

  11. Results of unmodified HLA-matched related BMT • Matched sibling transplant remains the treatment of choice • Cytoreduction or GVHD prophylaxis generally unnecessary • European Experience 1968-1999: 81%, n=104, • ADA def: 81%, Reticular Dysgenesis: 75%-HLA matched BMT • Single Center • MSKCC: 1971-2011, 87.5% survival, n=16 • Hopital Necker-Enfants Malades 1971-92, 80% survival, n=30 • Univ of Ulm: 81% survival, n=21 • DUMC: 1982-98, 100% survival, n=12 • Univ of Brescia: >80%, n=35

  12. T and B cell function following unmodified HLA-matched BMT for SCID • Normal T cell numbers rapidly restored 2-4 weeks • Normal T cell mitogen and specific antigen responses restored • B cell function returns by one year post transplant

  13. TCD HLA Mismatched BMT • Depending on efficiency of T cell depletion • Current outcomes: 70-80%, and if HCT <2 months: 90-100% • Low incidence of GVHD • Parent readily available What about patients who lack HLA matched sibling donor

  14. Probability of Overall Survival after Unrelated Donor Transplants for SCID, 1990-2004, n=200 Overall survival, 60% (95% CI 52-67) @ 5 years Probability • No significant advantage over parental T cell depleted HLA non-identical marrow grafts when comparable preparative regimens are used • Potential risk of infectious complications due to time needed to procure a donor • Increased Risk of GVHD Years

  15. Probability of Overall Survival after Unrelated Donor Transplants for SCID, 1990-2004, n=200 Overall survival, 60% (95% CI 52-67) @ 5 years Probability • No significant advantage over parental T cell depleted HLA non-identical marrow grafts when comparable preparative regimens are used • Potential risk of infectious complications due to time needed to procure a donor • Increased Risk of GVHD Years

  16. Probability of Overall Survival after Unrelated Donor Cord Blood Transplants for SCID, 1990-2005, n=76, CIBMTR Overall survival, 57%(95% CI 44-69) @ 5 years Probability of survival • Immediately available unlike MUD HCT • Viral naïve, CMV seronegative • Less acute and chronic GVHD despite 1-2 Ag MM • No clear advantage over HLA MM-Rel HCT • Higher risk of GHVD, appox 25% aGVHD, 13% chronic Years Post HCT CIBMTR data, 2007

  17. Immune Function • 50% of children have normal T cell function in the first 6 months post BMT • 80% have normal T cell function by 6 to 12 months post BMT • However, without cytoreduction, lack of donor B cell engraftment, IVIG dependent

  18. Recovery of T cells post SBA- E- parental BMT for SCID Median CD3+ cell count Months post Mis-related parental TCD BMT for SCID

  19. Recovery of CD4+ T cells post SBA- E- parental BMT for SCID Median CD4+ cell count Months post Mis-related parental TCD BMT for SCID

  20. Numbers of circulating naive CD4+ T cells post HCT For SCID

  21. Comparison of the percentage of children with normal PHA post SBA- E- BMT for SCID: With and Without pre-transplant cytoreduction

  22. Median serum IgG Levels post Mis-matched TCD BMT for SCID

  23. Median serum IgA Levels post Mis-matched TCD BMT for SCID

  24. Conclusions and Future directions • The majority of children with SCID can be cured by a HCT providing it is performed early • Primary immunodeficiency Treatment Consortium (PIDTC) • Retrospective study to determine variables associated with outcome • Prospective study to determine outcome of patients identified through newborn screening • HCT • Gene therapy • PEG-ADA • Trial under development to determine lowest amt of cytoreduction to ensure T and B cell engraftment • Need to determine the best way to inform parents of NBS which require further evaluation • Need to develop ways to promptly direct parents to centers which can quickly evaluate and treat children with PID

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