Long-Term Outcomes of Hematopoietic Stem Cell Transplantation for ZAP70 Deficiency

ZAP70 deficiency is a rare T + B + NK+ combined immunodeficiency with limited outcome data to help guide decisions around hematopoietic stem cell transplant (HSCT). We sought to understand the long-term clinical and immunologic outcomes of both conditioned and unconditioned HSCT for ZAP70 deficiency following transplant from a variety of graft sources. We performed a retrospective, single center review of all cases of HSCT for genetically confirmed ZAP70 deficiency since 1992. At a median of 13.5-year post-HSCT, 8/8 (100 %) patients are alive. Three received unconditioned bone marrow transplants from human leukocyte antigen (HLA)-matched siblings and achieved stable mixed donor-recipient T cell chimerism but low B cell (4-9 %) and absent to near-absent myeloid donor engraftment. Despite this, all three have normal immunoglobulin levels, have developed specific protective antibody responses to post-HSCT vaccinations, and have discontinued immunoglobulin replacement. Five patients received myeloablative conditioning (three T cell-depleted haploidentical and two unrelated cord blood) and have full donor chimerism for T and B cells and myeloid lineages. One patient experienced primary graft failure after serotherapy only. CD8 T cell count is normal in 5/8, high in 1/8, and low in 2/8. Infectious complications in 5/5 and autoimmune thrombocytopenia in one patient resolved post-HSCT. Mitogen proliferation to phytohemagglutinin was normal after HSCT in 8/8 patients. In total, seven have discontinued immunoglobulin replacement. In conclusion, HSCT using a variety of graft sources and approaches, including unconditioned matched sibling donor transplant, is a life-saving therapy for ZAP70 deficiency, providing excellent long-term immune function and resolution of clinical problems.