BACKGROUND: Cytotoxic T-lymphocyte antigen 4 (CTLA-4) insufficiency causes a primary immune regulatory disorder characterized by lymphoproliferation, dysgammaglobulinemia, and multiorgan autoimmunity including cytopenias and colitis. OBJECTIVE: We examined the outcome of hematopoietic stem cell transplantation (HSCT) for CTLA-4 insufficiency and study the impact of pre-HSCT CTLA-4 fusion protein (CTLA-4-Ig) therapy and pre-HSCT immune dysregulation on survival and immunologic outcome. METHODS: This was a retrospective study of HSCT for CTLA-4 insufficiency and 2q33.2-3 deletion from the European Society for Blood and Marrow Transplantation Inborn Errors Working Party. Primary end points were overall survival (OS) and disease- and chronic graft-versus-host disease-free survival (DFS). Secondary end point was immunologic outcome assessed by immune dysregulation disease activity (IDDA) score. RESULTS: Forty patients were included over a 25-year period. Before HSCT, 60% received CTLA-4-Ig, and median (range) IDDA score was 23.3 (3.9-84.0). Median (range) age at HSCT was 14.2 (1.3-56.0) years. Patients received peripheral blood stem cell (58%) or marrow (43%) from a matched unrelated donor (75%), mismatched unrelated donor (12.5%), or matched family donor (12.5%). Median (range) follow-up was 3 (0.6-15) years, and 3-year OS was 76.7% (58-87%) and DFS was 74.4% (54.9-86.0%). At latest follow-up, disease of 28 of 30 surviving patients was in disease-free remission with median IDDA reduction of 16. Probability of OS and DFS was greater in patients with lower disease activity before HSCT (IDDA < 23, P = .002 and P = .006, respectively). CTLA-4-Ig receipt did not influence OS or DFS. Cause of death was transplant related in 7 of 8 patients. CONCLUSION: HSCT is an effective therapy to prevent ongoing disease progression and morbidity, with improving survival rates over time and in patients with lower pre-HSCT disease activity.

Adult Bone Marrow Transplant Unit ASST Spedali Civili Department of Clinical and Experimental Sciences University of Brescia Brescia Italy

Bone Marrow Transplant Unit Oncology Service Hospital Sant Joan de Déu Barcelona Spain

Department of Blood and Marrow Transplantation Royal Manchester Children's Hospital Manchester United Kingdom

Department of Haematology and Oncology University Hospital Freiburg Freiburg Germany

Department of Haematopoietic Stem Cell Transplantation Dmitry Rogachev National Medical Research Center of Pediatric Hematology Oncology and Immunology Moscow Russia

Department of Hematology Leiden University Medical Center Leiden The Netherlands

Department of Immunology Newcastle Hospitals NHS Foundation Trust Newcastle upon Tyne United Kingdom

Department of Pediatric Hematology and Oncology 2nd Medical School Charles University Motol Prague Czech Republic

Department of Pediatric Hematology Oncology and BMT Wroclaw Medical University Wroclaw Poland

Department of Pediatric Hematology Oncology and Transplantology Medical University of Lublin Lublin Poland

Department of Pediatrics Dr von Hauner Children's Hospital University Hospital Ludwig Maximilians Universität München Munich Germany

Department of Pediatrics Willem Alexander Children's Hospital Pediatric Stem Cell Transplantation Program Leiden University Medical Center Leiden The Netherlands

Institute for Immunodeficiency Center for Chronic Immunodeficiency Medical Center Faculty of Medicine University of Freiburg Freiburg Germany; Department of Medicine 1 Hematology Oncology and Stem Cell Transplantation Medical Center University of Freiburg Faculty of Medicine Freiburg Germany; CCI Medical Center University of Freiburg Faculty of Medicine University of Freiburg Freiburg Germany; Department of Rheumatology and Clinical Immunology CCI University Hospital Freiburg Freiburg Germany

Institute for Immunodeficiency Center for Chronic Immunodeficiency Medical Center Faculty of Medicine University of Freiburg Freiburg Germany; Department of Pediatrics and Adolescent Medicine Division of Pediatric Hematology and Oncology Medical Center Faculty of Medicine University of Freiburg Freiburg Germany

Paediatric Haematopoietic Stem Cell Transplant Unit Great North Children's Hospital Newcastle Hospitals NHS Foundation Trust Newcastle upon Tyne United Kingdom; Translational and Clinical Research Institute Newcastle University Newcastle upon Tyne United Kingdom

Paediatric Haematopoietic Stem Cell Transplant Unit University Hospital La Paz Madrid Spain

Paediatric Immunology Royal Hospital for Children Glasgow United Kingdom

Paediatric Stem Cell Transplantation Royal Hospital for Children Glasgow United Kingdom

Pediatric Immunology Hematology and Rheumatology Department Hôpital Necker Enfants Malades Assistance Publique Hôpitaux de Paris Paris France

Stem Cell Transplant Unit Aghia Sophia Children's Hospital Athens Greece

Translational and Clinical Research Institute Newcastle University Newcastle upon Tyne United Kingdom; Northern Centre for Bone Marrow Transplantation Newcastle Hospitals NHS Foundation Trust Newcastle upon Tyne United Kingdom

UCL Institute of Immunity and Transplantation UCL London The Netherlands; Department of Haematology University College London Hospitals NHS Foundation Trust London United Kingdom

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