Francesca Ferrua1, Stefania Galimberti2, Virginie Courteille3, Mary Anne Slatter4, Claire Booth5, Despina Moshous6, Benedicte Neven6, Stephane Blanche6, Marina Cavazzana7, Alexandra Laberko8, Anna Shcherbina8, Dmitry Balashov8, Elena Soncini9, Fulvio Porta9, Hamoud Al-Mousa10, Bandar Al-Saud10, Hasan Al-Dhekri10, Rand Arnaout10, Renata Formankova11, Yves Bertrand12, Andrzej Lange13, Joanne Smart14, Beata Wolska-Kusnierz15, Victor M Aquino16, Christopher C Dvorak17, Anders Fasth18, Fanny Fouyssac19, Carsten Heilmann20, Manfred Hoenig21, Catharina Schuetz21, Jadranka Kelečić22, Robbert G M Bredius23, Arjan C Lankester23, Caroline A Lindemans24, Felipe Suarez25, Kathleen E Sullivan26, Michael H Albert27, Krzysztof Kałwak28, Vincent Barlogis29, Monica Bhatia30, Victoria Bordon31, Wojciech Czogala32, Laura Alonso33, Figen Dogu34, Jolanta Gozdzik35, Aydan Ikinciogullari36, Gergely Kriván37, Per Ljungman38, Isabelle Meyts39, Peter Mustillo40, Angela R Smith41, Carsten Speckmann42, Mikael Sundin43, Steven John Keogh44, Peter John Shaw45, Jaap Jan Boelens46, Ansgar S Schulz21, Petr Sedlacek11, Paul Veys47, Nizar Mahlaoui48, Ales Janda49, E Graham Davies5, Alain Fischer50, Morton J Cowan17, Andrew Richard Gennery4. 1. Department of Pediatric Immunology and HSCT, Great North Children's Hospital, Newcastle upon Tyne, United Kingdom; San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), Pediatric Immunohematology and Bone Marrow Transplantation Unit, San Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy. Electronic address: ferrua.francesca@hsr.it. 2. Center of Biostatistics for Clinical Epidemiology, School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy. 3. Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France; French National Reference Center for Primary Immune Deficiencies (CEREDIH), Necker Enfants Malades University Hospital, AP-HP, Paris, France. 4. 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. 5. Department of Pediatric Immunology, Great Ormond Street Hospital, London, United Kingdom. 6. 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 (AP-HP), Paris, France; French National Reference Center for Primary Immune Deficiencies (CEREDIH), Necker Enfants Malades University Hospital, AP-HP, Paris, France. 7. 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. 8. Dmitry Rogachev Federal Research Centre of Pediatric Hematology, Oncology and Immunology, Moscow, Russia. 9. Pediatric Oncology-Hematology and BMT Unit, Spedali Civili di Brescia, Brescia, Italy. 10. Department of Pediatrics, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia. 11. Department of Pediatric Hematology and Oncology, University Hospital Motol Prague, Prague, Czech Republic. 12. Institut d'Hematologie et d'Oncologie Pediatrique, Hospices Civils de Lyon, Lyon, France. 13. L. Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wrocław, Poland; Lower Silesian Center for Cellular Transplantation & National Bone Marrow Donor Registry, Wrocław, Poland. 14. Department of Allergy and Immunology, Royal Children's Hospital, Melbourne, Australia. 15. Immunology Department, Children's Memorial Health Institute, Warsaw, Poland. 16. Department of Pediatrics, University of Texas Southwestern Medical Center Dallas, Dallas, Tex. 17. Division of Pediatric Allergy, Immunology & Bone Marrow Transplantation, University of California, San Francisco, Calif. 18. Department of Pediatrics, Sahlgrenska Academy at University of Gothenburg and Queen Silvia Children's Hospital, Gothenburg, Sweden. 19. Pediatric Oncology and Hematology Unit, Children Hospital, University Hospital Nancy, Vandoeuvre-les-Nancy, France; French National Reference Center for Primary Immune Deficiencies (CEREDIH), Necker Enfants Malades University Hospital, AP-HP, Paris, France. 20. Pediatric Clinic, Rigshospitalet, Copenhagen, Denmark. 21. Department of Pediatrics, University Medical Center Ulm, Ulm, Germany. 22. Department of Pediatrics, Division of Allergology, Clinical Immunology, Respiratory Diseases and Rheumatology, University Hospital Center Zagreb, Zagreb, Croatia. 23. Department of Pediatrics/Willem-Alexander Children's hospital, Leiden University Medical Center, Leiden, The Netherlands. 24. Department of Pediatrics, University Medical Centre Utrecht, Utrecht University, Utrecht, The Netherlands; Princess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands. 25. Hématologie Adulte, Hôpital Necker, AP-HP, Paris, France; French National Reference Center for Primary Immune Deficiencies (CEREDIH), Necker Enfants Malades University Hospital, AP-HP, Paris, France. 26. Division of Allergy Immunology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pa. 27. Pediatric Hematology/Oncology, Dr. von Hauner University Children's Hospital, Munich, Germany. 28. Department of Pediatric Hematology and Oncology, Wroclaw Medical University, Wrocław, Poland. 29. Service d'hématologie pédiatrique, Hôpital de la Timone Enfants, Marseille, France; French National Reference Center for Primary Immune Deficiencies (CEREDIH), Necker Enfants Malades University Hospital, AP-HP, Paris, France. 30. Pediatric Stem Cell Transplantation, Columbia University College of Physicians and Surgeons, New York, NY. 31. Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium. 32. University Children's Hospital of Cracow, Cracow, Poland. 33. Pediatric Hematology and Oncology Department, Hospital Universitario MaternoInfantil Vall d'Hebron, Barcelona, Spain. 34. Department of Pediatric Immunology and Allergy, Ankara University School of Medicine, Ankara, Turkey. 35. Department of Clinical Immunology and Transplantology, Jagiellonian University, Medical Collage, Transplantation Center, University Children's Hospital, Cracow, Poland. 36. Department of Pediatric Immunology-Allergy and BMT Unit, Ankara University Medical School, Ankara, Turkey. 37. Department of Pediatric Hematology and Stem Cell Transplantation United St. István and St László Hospital, Budapest, Hungary. 38. Department of Hematology, Karolinska University Hospital, Stockholm, Sweden. 39. Department of Pediatrics, University Hospitals Leuven, Division of Pediatric Immunology, Department of Immunology and Microbiology, Catholic University Leuven, Leuven, Belgium. 40. Nationwide Children's Hospital, Columbus, Ohio. 41. Pediatric Blood and Marrow Transplant, University of Minnesota, Minneapolis, Minn. 42. 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. 43. Division of Pediatrics, CLINTEC, Karolinska Institutet, Stockholm, Sweden; Pediatric Blood Disorders, Immunodeficiency and SCT, Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden. 44. Cancer Centre for Children, Children's Hospital at Westmead, Sydney, Australia. 45. Cancer Centre for Children, Children's Hospital at Westmead, Sydney, Australia; University of Sydney Medical Program, Sydney, Australia. 46. 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. 47. Department of BMT, Great Ormond Street Hospital for Children NHS Trust, London, United Kingdom. 48. 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 (AP-HP), Paris, France; French National Reference Center for Primary Immune Deficiencies (CEREDIH), Necker Enfants Malades University Hospital, AP-HP, Paris, France; INSERM UMR 1163, Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Paris, France. 49. Center for Pediatrics and Center for Chronic Immunodeficiency, Medical Center, University of Freiburg, Freiburg, Germany. 50. 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 (AP-HP), Paris, France; French National Reference Center for Primary Immune Deficiencies (CEREDIH), Necker Enfants Malades University Hospital, AP-HP, Paris, France; College de France, Paris, France.
Abstract
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.
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.
Authors: Valentina Vavassori; Elisabetta Mercuri; Genni E Marcovecchio; Maria C Castiello; Giulia Schiroli; Luisa Albano; Carrie Margulies; Frank Buquicchio; Elena Fontana; Stefano Beretta; Ivan Merelli; Andrea Cappelleri; Paola Mv Rancoita; Vassilios Lougaris; Alessandro Plebani; Maria Kanariou; Arjan Lankester; Francesca Ferrua; Eugenio Scanziani; Cecilia Cotta-Ramusino; Anna Villa; Luigi Naldini; Pietro Genovese Journal: EMBO Mol Med Date: 2021-01-21 Impact factor: 12.137
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Authors: Junghee J Shin; Jason Catanzaro; Jennifer R Yonkof; Ottavia Delmonte; Keith Sacco; Min Sun Shin; Srikar Reddy; Paula J Whittington; Gary Soffer; Peter J Mustillo; Kathleen E Sullivan; Luigi D Notarangelo; Roshini S Abraham; Neil Romberg; Insoo Kang Journal: J Clin Immunol Date: 2021-01-26 Impact factor: 8.317