Outcomes Following Hematopoietic Cell Transplant in CD3δ SCID Patients in Canada

Introduction In the Low German Mennonite (LGM) population, CD3δ severe combined immunodeficiency (SCID) is the result of a homozygous c.202C>T; p.Arg68Ter pathogenic variant. The block in T cell development causes infant mortality without allogeneic hematopoietic cell transplantation (HCT). We evaluated outcomes following HCT in Canadian LGM infants from 2011-2023. Methods Data were collected and analyzed using descriptive statistics for 11 patients treated in Alberta and Manitoba in collaboration with the Primary Immune Deficiency Treatment Consortium. Results Trigger for diagnosis was newborn screening (NBS) in 4, family history in 1, infections prior to the implementation of NBS in 6. HCT donor and conditioning were as follows: matched related donor (MRD) (1): no conditioning; MRD (3), matched unrelated donor (2), and 9/10 mismatched unrelated donor (1): reduced intensity conditioning (RIC) alemtuzumab, treosulfan, and fludarabine; haploidentical TCRαβ/B cell deplete (3): myeloablative antithymocyte globulin, rituximab, treosulfan, and fludarabine; haploidentical with posttransplant cyclophosphamide (1): RIC with fludarabine and cyclophosphamide. Overall survival was 100%, with median follow-up of 3 years. Three patients developed grade I–II acute graft-versus-host disease (GVHD) and 2 chronic GVHD. By 12 months post-HCT, 7 patients achieved CD4 >500 × 106 cells/L. All but 1 patient had normal B cell numbers. Immunoglobulin was stopped by one year in all patients; one developed hypogammaglobulinemia 5 years post-HCT and restarted. All achieved full T cell chimerism (>95%); 4 had full chimerism in all cell lines. Myeloid and B cell chimerisms were <5% in 3 and mixed (5-95%) in 4. Conclusion Despite excellent survival, we observed incomplete T cell immune reconstitution, poor chimerism in myeloid and B cell lines, and GVHD. Further research is required to identify the optimal HCT approach and clinical significance of mixed chimerisms. Outcome data comprises the historical control for an upcoming clinical trial on base editing gene therapy for CD3δ SCID.