title: Long-Term Outcomes of Hematopoietic Stem Cell Transplantation for ZAP70 Deficiency.
abstract: 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.
authors.affiliation: Manitoba Blood and Marrow Transplant Program, Division of Pediatric Hematology-Oncology, CancerCare Manitoba, 675 McDermot Avenue, Winnipeg, Manitoba, Canada. gcuvelier@cancercare.mb.ca.|Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, Manitoba, Canada. gcuvelier@cancercare.mb.ca.|CancerCare Manitoba, ON2011-675 McDermot Avenue, Winnipeg, Manitoba, R3E 0V9, Canada. gcuvelier@cancercare.mb.ca.
authors.forename: Geoffrey D E
authors.initials: GD
authors.lastname: Cuvelier
authors.affiliation: Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, Manitoba, Canada.|Division of Allergy and Clinical Immunology, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Tamar S
authors.initials: TS
authors.lastname: Rubin
authors.affiliation: Manitoba Blood and Marrow Transplant Program, Division of Pediatric Hematology-Oncology, CancerCare Manitoba, 675 McDermot Avenue, Winnipeg, Manitoba, Canada.|Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Donna A
authors.initials: DA
authors.lastname: Wall
authors.affiliation: Manitoba Blood and Marrow Transplant Program, Division of Pediatric Hematology-Oncology, CancerCare Manitoba, 675 McDermot Avenue, Winnipeg, Manitoba, Canada.|Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Marlis L
authors.initials: ML
authors.lastname: Schroeder
mesh_terms: D015415:Biomarkers; D002675:Child, Preschool; D005260:Female; D005500:Follow-Up Studies; D006086:Graft vs Host Disease / Q000209:etiology / Q000517:prevention & control; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects / Q000379:methods; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D018655:Lymphocyte Count; D008297:Male; D009154:Mutation; D010641:Phenotype; D016511:Severe Combined Immunodeficiency / Q000175:diagnosis / Q000628:therapy*; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D013997:Time Factors; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous; D016896:Treatment Outcome; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000172:deficiency*
chemical_list: D015415:Biomarkers; D051746:ZAP-70 Protein-Tyrosine Kinase
keywords: T+ SCID; ZAP70 deficiency; atypical SCID; hematopoietic stem cell transplant; leaky SCID