Long-term follow-up of IPEX syndrome patients after different therapeutic strategies: An international multicenter retrospective study - 07/03/18
Doi : 10.1016/j.jaci.2017.10.041
Federica Barzaghi, MD a, Laura Cristina Amaya Hernandez, MSc b, Benedicte Neven, MD c, Silvia Ricci, MD d, Zeynep Yesim Kucuk, MD e, Jack J. Bleesing, MD, PhD e, Zohreh Nademi, MD, PhD f, Mary Anne Slatter, MD f, Erlinda Rose Ulloa, MD, MSc g, Anna Shcherbina, MD, PhD h, Anna Roppelt, MD h, Austen Worth, MD, PhD i, Juliana Silva, MD j, Alessandro Aiuti, MD, PhD a, k, Luis Murguia-Favela, MD l, Carsten Speckmann, MD m, fff, Magda Carneiro-Sampaio, MD, PhD n, Juliana Folloni Fernandes, MD o, Safa Baris, MD p, Ahmet Ozen, MD p, Elif Karakoc-Aydiner, MD p, Ayca Kiykim, MD p, Ansgar Schulz, MD, PhD q, Sandra Steinmann, BS q, Lucia Dora Notarangelo, MD r, Eleonora Gambineri, MD s, Paolo Lionetti, MD, PhD t, William Thomas Shearer, MD, PhD u, Lisa R. Forbes, MD u, Caridad Martinez, MD v, Despina Moshous, MD c, Stephane Blanche, MD c, Alain Fisher, MD, PhD c, Frank M. Ruemmele, MD, PhD w, Come Tissandier, MD w, Marie Ouachee-Chardin, MD x, Frédéric Rieux-Laucat, PhD y, Marina Cavazzana, MD, PhD z, Waseem Qasim, MD, PhD aa, Barbarella Lucarelli, MD, PhD bb, Michael H. Albert, MD cc, Ichiro Kobayashi, MD, PhD dd, Laura Alonso, MD ee, Cristina Diaz De Heredia, MD ee, Hirokazu Kanegane, MD, PhD ff, Anita Lawitschka, MD, PhD gg, Jong Jin Seo, MD, PhD hh, Marta Gonzalez-Vicent, MD, PhD ii, Miguel Angel Diaz, MD, PhD ii, Rakesh Kumar Goyal, MD jj, Martin G. Sauer, MD kk, Akif Yesilipek, MD ll, Minsoo Kim, MD mm, Yesim Yilmaz-Demirdag, MD mm, Monica Bhatia, MD nn, Julie Khlevner, MD oo, Erick J. Richmond Padilla, MD pp, Silvana Martino, MD qq, Davide Montin, MD qq, Olaf Neth, MD rr, Agueda Molinos-Quintana, MD ss, Justo Valverde-Fernandez, MD tt, Arnon Broides, MD uu, Vered Pinsk, MD vv, Antje Ballauf, MD ww, Filomeen Haerynck, MD, PhD xx, Victoria Bordon, MD, PhD xx, Catharina Dhooge, MD, PhD xx, Maria Laura Garcia-Lloret, MD yy, Robbert G. Bredius, MD, PhD zz, Krzysztof Kałwak, MD, PhD aaa, Elie Haddad, MD, PhD bbb, Markus Gerhard Seidel, MD ccc, Gregor Duckers, MD ww, Sung-Yun Pai, MD g, ddd, Christopher C. Dvorak, MD eee, Stephan Ehl, MD, PhD fff, Franco Locatelli, MD, PhD bb, Frederick Goldman, MD ggg, Andrew Richard Gennery, MD f, Mort J. Cowan, MD eee, Maria-Grazia Roncarolo, MD, PhD b, Rosa Bacchetta, MD b, ⁎ 
on behalf of the
on behalf of the
Primary Immune Deficiency Treatment Consortium (PIDTC) and the Inborn Errors Working Party (IEWP) of the European Society for Blood and Marrow Transplantation (EBMT)
a San Raffaele Telethon Institute for Gene Therapy, Pediatric Immunohematology and Bone Marrow Transplantation Unit, Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele Scientific Institute, Milan, Italy
b Division of Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, Calif
c Paediatric Immunology, Haematology and Rheumatology Department, Necker-Enfants Malades University Hospital, Assistance Publique-Hôpitaux de Paris, Paris Descartes–Université Sorbonne Paris Cité, Institut Imagine, Paris, France
w Pediatric Gastroenterology unit, Necker-Enfants Malades University Hospital, Assistance Publique-Hôpitaux de Paris, Paris Descartes–Université Sorbonne Paris Cité, Paris, France
z Biotherapy Department, Necker-Enfants Malades University Hospital, Paris Descartes -Université Sorbonne Paris Cité, Institut Imagine, Paris, France
x Hematology Unit, Robert Debré Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
d Pediatric Immunology, “Anna Meyer” Children's Hospital, Florence, Italy
s Department of Hematology-Oncology: Bone Marrow Transplant (BMT) Unit, “Anna Meyer” Children's Hospital, Florence, Italy
t Gastroenterology Unit, University of Florence, Department of “NEUROFARBA”: Section of Child's Health, “Anna Meyer” Children's Hospital, Florence, Italy
e Bone Marrow Transplantation and Immune Deficiency, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
f Institute of Cellular Medicine, Newcastle University and Children's Bone Marrow Transplant Unit, Great North Children's Hospital, Newcastle Upon Tyne, United Kingdom
g Pediatrics, Boston Children's Hospital, Boston, Mass
h Department of Immunology, Research and Clinical Center for Pediatric Hematology, Oncology and Immunology, Moscow, Russia
i Department of Immunology and Gene Therapy, Great Ormond Street Hospital, London, United Kingdom
j Department of Stem Cell Transplantation, Great Ormond Street Hospital, London, United Kingdom
k Vita-Salute San Raffaele University, Milan, Italy
l Division of Clinical Immunology and Allergy, Department of Pediatrics, Hospital for Sick Children, Toronto, Ontario, Canada
m Department of Pediatrics and Adolescent Medicine, University of Freiburg, Freiburg, Germany
fff Center for Chronic Immunodeficiency, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
n Department of Pediatrics, Faculdade de Medicina da Universidade de São Paulo and Hospital Albert Einstein, São Paulo, Brazil
o Stem Cell Transplantation Unit, Instituto da Criança, Faculdade de Medicina da Universidade de São Paulo and Hospital Albert Einstein, São Paulo, Brazil
p Pediatric Allergy and Immunology, Marmara University, Istanbul, Turkey
q Department of Pediatrics, University Medical Center, Ulm, Germany
r Pediatric Onco-Hematology and Bone Marrow Transplant (BMT) Unit, Children's Hospital, Spedali Civili, Brescia, Italy
u Department of Pediatrics, Section of Immunology Allergy Rheumatology, Baylor College of Medicine Texas Children's Hospital, Houston, Tex
v Department of Pediatric Hematology and Oncology, Baylor College of Medicine Texas Children's Hospital, Houston, Tex
y Institut national de la santé et de la recherche médicale (INSERM) UMR 1163, Laboratory of Immunogenetics of Pediatric Autoimmune Disease, Paris, France
aa Great Ormond Street Institute of Child Health, University College London, London, United Kingdom
bb Department of Pediatric Hematology-Oncology, University of Pavia, Istituto di Ricovero e Cura a Carattere Scientifico, Bambino Gesù Children's Hospital, Rome, Italy
cc Pediatric Hematology-Oncology, Dr. von Hauner Children's hospital, Ludwig-Maximilians Universität, Munich, Germany
dd Center for Pediatric Allergy and Rheumatology, KKR Sapporo Medical Center, Sapporo, Japan
ee Paediatric Haematology and Oncology, Hospital Universitario Vall D'Hebron, Barcelona, Spain
ff Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo, Japan
gg St. Anna Children's Hospital, Medical University Vienna, Vienna, Austria
hh Pediatrics, University of Ulsan College of Medicine and Asan Medical Center, Seoul, Korea
ii Hematopoietic Stem Cell Transplantation Unit, Pediatric Department, Children's University Hospital Niño Jesús, Madrid, Spain
jj Division of Blood and Marrow Transplantation and Cellular Therapies, Department of Pediatrics, Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center, Pittsburgh, Pa
kk Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany
ll Pediatric Stem Cell Transplantation Unit, Medicalpark Hospital Goztepe and Antalya Hospitals, Antalya, Turkey
mm Pediatric Allergy, Immunology and Rheumatology, Columbia Medical Center, New York, NY
nn Pediatric Hematology, Oncology and Stem Cell Transplantation, Columbia Medical Center, New York, NY
oo Pediatric Gastroenterology, Hepatology, and Nutrition, Columbia Medical Center, New York, NY
pp Pediatric Endocrinology, National Children's Hospital, San Jose, Israel
qq Division of Immunology and Rheumatology, Department of Paediatric Infectious Diseases, University of Turin, Regina Margherita Children's Hospital, Turin, Italy
rr Department of Paediatric Infectious Diseases, Rheumatology and Immunodeficiency, Instituto de Biomedicina de Sevilla/CSIC/Universidad de Sevilla, Seville, Spain
ss Department of Pediatric Hematology, Instituto de Biomedicina de Sevilla/CSIC/Universidad de Sevilla, Seville, Spain
tt Department of Paediatirc Gastroenterology, Hospital Universitario Virgen del Rocío, Instituto de Biomedicina de Sevilla/Unite Mixte de Recherche (UMR) or Mixed Unit of Research Consejo Superior de Investigaciones Científicas (CSIC)/Universidad de Sevilla, Seville, Spain
uu Pediatric Immunology Clinic, Soroka University Medical Center, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel
vv Pediatric Ambulatory Care Unit, Soroka University Medical Center, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel
ww Department of Pediatrics, Helios Children's Hospital, Krefeld, Germany
xx Department of Pediatrics, Center for Primary Immunodeficiencies, Ghent University Hospital, Ghent, Belgium
yy Division of Pediatric Allergy, Immunology and Rheumatology, University of California–Los Angeles School of Medicine, Los Angeles, Calif
zz Pediatric Immunology, Infections and Stem Cell Transplantation (SCT), Leiden University Medical Center, Leiden, The Netherlands
aaa Department of Pediatric Hematology, Oncology and Bone Marrow Transplant (BMT) Unit, Wroclaw Medical University, Wroclaw, Poland
bbb Department of Pediatrics, Saint Justine Hospital, University of Montreal, Montreal, Quebec, Canada
ccc Division of Pediatric Hematology-Oncology, Research Unit Pediatric Hematology and Immunology, Medical University Graz, Graz, Austria
ddd Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Mass
eee Pediatric Allergy, Immunology and Bone Marrow Transplant, University of California–San Francisco Benioff Children's Hospital, San Francisco, Calif
ggg Pediatrics, University of Alabama, Birmingham, Ala
∗Corresponding author: Rosa Bacchetta, MD, Stanford University, Division of Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, 265 Campus Drive, Lokey Stem Cell G3015, Stanford, CA 94305.Stanford UniversityDivision of Stem Cell Transplantation and Regenerative MedicineDepartment of Pediatrics265 Campus DriveLokey Stem Cell G3015StanfordCA94305
Abstract |
Background |
Immunodysregulation polyendocrinopathy enteropathy x-linked (IPEX) syndrome is a monogenic autoimmune disease caused by FOXP3 mutations. Because it is a rare disease, the natural history and response to treatments, including allogeneic hematopoietic stem cell transplantation (HSCT) and immunosuppression (IS), have not been thoroughly examined.
Objective |
This analysis sought to evaluate disease onset, progression, and long-term outcome of the 2 main treatments in long-term IPEX survivors.
Methods |
Clinical histories of 96 patients with a genetically proven IPEX syndrome were collected from 38 institutions worldwide and retrospectively analyzed. To investigate possible factors suitable to predict the outcome, an organ involvement (OI) scoring system was developed.
Results |
We confirm neonatal onset with enteropathy, type 1 diabetes, and eczema. In addition, we found less common manifestations in delayed onset patients or during disease evolution. There is no correlation between the site of mutation and the disease course or outcome, and the same genotype can present with variable phenotypes. HSCT patients (n = 58) had a median follow-up of 2.7 years (range, 1 week-15 years). Patients receiving chronic IS (n = 34) had a median follow-up of 4 years (range, 2 months-25 years). The overall survival after HSCT was 73.2% (95% CI, 59.4-83.0) and after IS was 65.1% (95% CI, 62.8-95.8). The pretreatment OI score was the only significant predictor of overall survival after transplant (P = .035) but not under IS.
Conclusions |
Patients receiving chronic IS were hampered by disease recurrence or complications, impacting long-term disease-free survival. When performed in patients with a low OI score, HSCT resulted in disease resolution with better quality of life, independent of age, donor source, or conditioning regimen.
Le texte complet de cet article est disponible en PDF.Graphical abstract |
Key words : IPEX, primary immune deficiency, FOXP3, Treg cells, hematopoietic stem cell transplantation, immunosuppression, rapamycin, enteropathy, neonatal diabetes, genetic autoimmunity
Abbreviations used : DFS, FKH, GvHD, HSCT, IPEX, IS, OI, RIT, T1D, Treg
Plan
| This work has been supported by Telethon (Tele10-A4 to R.B.), the Jeffrey Modell Foundation Travel Award to F.B., and a generous gift to the Stanford Center for Genetic Immune Diseases. |
|
| Disclosure of potential conflict of interest: E. Gambineri serves as a consultant for Baxalta/Shire. M. Cavazzana receives grant support from the Institut National de la Santé et de la Recherche Médicale/Assistance Publique-Hôpitaux de Paris–European Research Council (ERC) Advanced Grant. W. Qasim receives grant support from the National Institute of Health Research, Cellectis SA, Cellmedica, Bellicum and Autolus; serves as a consultant for Autolus Ltd and Servier; receives royalties from Orchard; owns stock options for Autolus. M. H. Albert serves as a consultant for GlaxoSmithKline; receives grant support from GlaxoSmithKline; receives payment for lectures from MSD and Jazz; holds stock options for Amgen, Bristol-Myers S, and Juno; and receives travel support from Jazz and Medac. F. Haerynck receives grant support from Jeffery Modell Foundation (JMF) Diagnostic and Research Centre. C. Dhooge receives payment for lectures for nurses; travel support for Society for industrial and organizational psychology (SIOP), European Society for Blood and Marrow Transplantation, and European Musculo-Skeletal Oncology Society meetings. R. G. Bredius. E. Haddad serves as a consultant for Leadiant; and receives grant support from CSL Behring. S.-Y. Pai receives grant support from the Boston Children's Hospital. F. Goldman serves as a consultant for Jazz Pharmaceuticals; receives grant support from the Department of Defense; and payment for lectures from Jazz Pharmaceuticals. M. J. Cowan receives grant support from the National Institutes of Health–National Institute of Allergy and Infectious Diseases and California Institute of Regenerative Medicine; serves on the board for Bluebird Bio, Exogen Bio, and Homology Medicine; holds a patent for lentiviral vector; and has stock options with Homology Medicine and Exogen Bio. The rest of the authors declare that they have no relevant conflicts of interest. |
© 2017
The Authors. Publié par Elsevier Masson SAS. Tous droits réservés.
Vol 141 - N° 3
P. 1036 - mars 2018 Retour au numéro
Article précédent
- Cancer in primary immunodeficiency diseases: Cancer incidence in the United States Immune Deficiency Network Registry
- Paul C. Mayor, Kevin H. Eng, Kelly L. Singel, Scott I. Abrams, Kunle Odunsi, Kirsten B. Moysich, Ramsay Fuleihan, Elizabeth Garabedian, Patricia Lugar, Hans D. Ochs, Francisco A. Bonilla, Rebecca H. Buckley, Kathleen E. Sullivan, Zuhair K. Ballas, Charlotte Cunningham-Rundles, Brahm H. Segal
- Exaggerated follicular helper T-cell responses in patients with LRBA deficiency caused by failure of CTLA4-mediated regulation
- Fayhan J. Alroqi, Louis-Marie Charbonnier, Safa Baris, Ayca Kiykim, Janet Chou, Craig D. Platt, Abdulrahman Algassim, Sevgi Keles, Bandar K. Al Saud, Fowzan S. Alkuraya, Michael Jordan, Raif S. Geha, Talal A. Chatila
Bienvenue sur EM-consulte, la référence des professionnels de santé.
L’accès au texte intégral de cet article nécessite un abonnement.
Déjà abonné à cette revue ?