BACKGROUND: CD40 ligand (CD40L) deficiency, an X-linked primary immunodeficiency, causes recurrent sinopulmonary, Pneumocystis and Cryptosporidium species infections. Long-term survival with supportive therapy is poor. Currently, the only curative treatment is hematopoietic stem cell transplantation (HSCT). OBJECTIVE: We performed an international collaborative study to improve patients' management, aiming to individualize risk factors and determine optimal HSCT characteristics. METHODS: We retrospectively collected data on 130 patients who underwent HSCT for CD40L deficiency between 1993-2015. We analyzed outcome and variables' relevance with respect to survival and cure. RESULTS: Overall survival (OS), event-free survival (EFS), and disease-free survival (DFS) were 78.2%, 58.1%, and 72.3% 5 years after HSCT. Results were better in transplantations performed in 2000 or later and in children less than 10 years old at the time of HSCT. Pre-existing organ damage negatively influenced outcome. Sclerosing cholangitis was the most important risk factor. After 2000, superior OS was achieved with matched donors. Use of myeloablative regimens and HSCT at 2 years or less from diagnosis associated with higher OS and DFS. EFS was best with matched sibling donors, myeloablative conditioning (MAC), and bone marrow-derived stem cells. Most rejections occurred after reduced-intensity or nonmyeloablative conditioning, which associated with poor donor cell engraftment. Mortality occurred mainly early after HSCT, predominantly from infections. Among survivors who ceased immunoglobulin replacement, T-lymphocyte chimerism was 50% or greater donor in 85.2%. CONCLUSION: HSCT is curative in patients with CD40L deficiency, with improved outcome if performed before organ damage development. MAC is associated with better OS, EFS, and DFS. Prospective studies are required to compare the risks of HSCT with those of lifelong supportive therapy.

Cancer Centre for Children Children's Hospital at Westmead Sydney Australia

Cancer Centre for Children Children's Hospital at Westmead Sydney Australia; University of Sydney Medical Program Sydney Australia

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

Center for Pediatrics and Center for Chronic Immunodeficiency Medical Center University of Freiburg Freiburg Germany

Center of Biostatistics for Clinical Epidemiology School of Medicine and Surgery University of Milano Bicocca Monza Italy

Department of Allergy and Immunology Royal Children's Hospital Melbourne Australia

Department of BMT Great Ormond Street Hospital for Children NHS Trust London United Kingdom

Department of Clinical Immunology and Transplantology Jagiellonian University Medical Collage Transplantation Center University Children's Hospital Cracow Poland

Department of Hematology Karolinska University Hospital Stockholm Sweden

Department of Pediatric Hematology and Oncology University Hospital Motol Prague Prague Czech Republic

Department of Pediatric Hematology and Oncology Wroclaw Medical University Wrocław Poland

Department of Pediatric Hematology and Stem Cell Transplantation United St István and St László Hospital Budapest Hungary

Department of Pediatric Immunology Allergy and BMT Unit Ankara University Medical School Ankara Turkey

Department of Pediatric Immunology and Allergy Ankara University School of Medicine Ankara Turkey

Department of Pediatric Immunology and HSCT Great North Children's Hospital Newcastle upon Tyne United Kingdom; Institute of Cellular Medicine Newcastle University Newcastle upon Tyne United Kingdom

Department of Pediatric Immunology and HSCT Great North Children's Hospital Newcastle upon Tyne United Kingdom; San Raffaele Telethon Institute for Gene Therapy Pediatric Immunohematology and Bone Marrow Transplantation Unit San Raffaele Scientific Institute Milan Italy; Vita Salute San Raffaele University Milan Italy

Department of Pediatric Immunology Great Ormond Street Hospital London United Kingdom

Department of Pediatrics Division of Allergology Clinical Immunology Respiratory Diseases and Rheumatology University Hospital Center Zagreb Zagreb Croatia

Department of Pediatrics King Faisal Specialist Hospital and Research Center Riyadh Saudi Arabia

Department of Pediatrics Sahlgrenska Academy at University of Gothenburg and Queen Silvia Children's Hospital Gothenburg Sweden

Department of Pediatrics University Hospitals Leuven Division of Pediatric Immunology Department of Immunology and Microbiology Catholic University Leuven Leuven Belgium

Department of Pediatrics University Medical Center Ulm Ulm Germany

Department of Pediatrics University Medical Centre Utrecht Utrecht University Utrecht The Netherlands; Princess Maxima Center for Pediatric Oncology Utrecht The Netherlands

Department of Pediatrics University Medical Centre Utrecht Utrecht University Utrecht The Netherlands; Princess Maxima Center for Pediatric Oncology Utrecht The Netherlands; Department of Pediatrics Memorial Sloan Kettering Cancer Center BMT and Cell Therapies Program New York NY; Laboratory for Translational Immunology Tumor immunology University Medical Center Utrecht Utrecht The Netherlands

Department of Pediatrics University of Texas Southwestern Medical Center Dallas Dallas Tex

Department of Pediatrics Willem Alexander Children's hospital Leiden University Medical Center Leiden The Netherlands

Division of Allergy Immunology Department of Pediatrics Children's Hospital of Philadelphia Philadelphia Pa

Division of Pediatric Allergy Immunology and Bone Marrow Transplantation University of California San Francisco Calif

Division of Pediatrics CLINTEC Karolinska Institutet Stockholm Sweden; Pediatric Blood Disorders Immunodeficiency and SCT Astrid Lindgren Children's Hospital Karolinska University Hospital Stockholm Sweden

Dmitry Rogachev Federal Research Centre of Pediatric Hematology Oncology and Immunology Moscow Russia

Hématologie Adulte Hôpital Necker AP HP Paris France; French National Reference Center for Primary Immune Deficiencies Necker Enfants Malades University Hospital AP HP Paris France

Immunology Department Children's Memorial Health Institute Warsaw Poland

Institut d'Hematologie et d'Oncologie Pediatrique Hospices Civils de Lyon Lyon France

L Hirszfeld Institute of Immunology and Experimental Therapy Polish Academy of Sciences Wrocław Poland; Lower Silesian Center for Cellular Transplantation and National Bone Marrow Donor Registry Wrocław Poland

Nationwide Children's Hospital Columbus Ohio

Paris Descartes Sorbonne Paris Cité University Imagine Institute Paris France; Biotherapy Department Necker Children's Hospital AP HP Paris France; Biotherapy Clinical Investigation Center Groupe Hospitalier Universitaire Ouest AP HP INSERM Paris France; INSERM UMR 1163 Laboratory of Human Lymphohematopoiesis Paris France

Paris Descartes Sorbonne Paris Cité University Imagine Institute Paris France; French National Reference Center for Primary Immune Deficiencies Necker Enfants Malades University Hospital AP HP Paris France

Paris Descartes Sorbonne Paris Cité University Imagine Institute Paris France; Pediatric Hematology Immunology and Rheumatology Unit Necker Enfants Malades Hospital Assistance Publique Hôpitaux de Paris Necker Enfants Malades University Hospital AP HP Paris France

Paris Descartes Sorbonne Paris Cité University Imagine Institute Paris France; Pediatric Hematology Immunology and Rheumatology Unit Necker Enfants Malades Hospital Assistance Publique Hôpitaux de Paris Necker Enfants Malades University Hospital AP HP Paris France; College de France Paris France

Paris Descartes Sorbonne Paris Cité University Imagine Institute Paris France; Pediatric Hematology Immunology and Rheumatology Unit Necker Enfants Malades Hospital Assistance Publique Hôpitaux de Paris Necker Enfants Malades University Hospital AP HP Paris France; INSERM UMR 1163 Laboratory of Human Genetics of Infectious Diseases Necker Branch Paris France

Pediatric Blood and Marrow Transplant University of Minnesota Minneapolis Minn

Pediatric Clinic Rigshospitalet Copenhagen Denmark

Pediatric Hematology and Oncology Department Hospital Universitario MaternoInfantil Vall d'Hebron Barcelona Spain

Pediatric Hematology Oncology and Stem Cell Transplantation Ghent University Hospital Ghent Belgium

Pediatric Hematology Oncology Dr von Hauner University Children's Hospital Munich Germany

Pediatric Oncology and Hematology Unit Children Hospital University Hospital Nancy Vandoeuvre les Nancy France; French National Reference Center for Primary Immune Deficiencies Necker Enfants Malades University Hospital AP HP Paris France

Pediatric Oncology Hematology and BMT Unit Spedali Civili di Brescia Brescia Italy

Pediatric Stem Cell Transplantation Columbia University College of Physicians and Surgeons New York NY

Service d'hématologie pédiatrique Hôpital de la Timone Enfants Marseille France; French National Reference Center for Primary Immune Deficiencies Necker Enfants Malades University Hospital AP HP Paris France

University Children's Hospital of Cracow Cracow Poland

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