Hematopoietic stem cell transplantation for CD40 ligand deficiency: Results from an EBMT/ESID-IEWP-SCETIDE-PIDTC study

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; SCETIDE, PIDTC, EBMT & ESID IEWP

Affiliations

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.

PMID: 30660643
DOI: 10.1016/j.jaci.2018.12.1010

Hematopoietic stem cell transplantation for CD40 ligand deficiency: Results from an EBMT/ESID-IEWP-SCETIDE-PIDTC study

Francesca Ferrua et al. J Allergy Clin Immunol. 2019 Jun.

. 2019 Jun;143(6):2238-2253.

doi: 10.1016/j.jaci.2018.12.1010. Epub 2019 Jan 17.

Authors

Affiliations

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.

PMID: 30660643
DOI: 10.1016/j.jaci.2018.12.1010

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.

Keywords: CD40 ligand; X-linked hyper-IgM syndrome; hematopoietic stem cell transplantation; primary immunodeficiency.

PubMed Disclaimer

Publication types

Actions
Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Hematopoietic stem cell transplantation for CD40 ligand deficiency: Results from an EBMT/ESID-IEWP-SCETIDE-PIDTC study

Affiliations

Hematopoietic stem cell transplantation for CD40 ligand deficiency: Results from an EBMT/ESID-IEWP-SCETIDE-PIDTC study

Authors

Affiliations

Abstract

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Research Materials