Hematopoietic stem cell transplantation for CD40 ligand deficiency: Results from an EBMT/ESID-IEWP-SCETIDE-PIDTC study - 06/06/19
Doi : 10.1016/j.jaci.2018.12.1010
Francesca Ferrua, MD a, b, c, ⁎ 
, Stefania Galimberti, PhD d, Virginie Courteille, PhD e, eee, Mary Anne Slatter, MD a, f, Claire Booth, MD, PhD g, Despina Moshous, MD, PhD e, h, eee, Benedicte Neven, MD, PhD e, h, eee, Stephane Blanche, MD e, h, eee, Marina Cavazzana, MD, PhD e, i, j, k, Alexandra Laberko, MD, PhD l, Anna Shcherbina, MD, PhD l, Dmitry Balashov, MD, PhD l, Elena Soncini, MD m, Fulvio Porta, MD, PhD m, Hamoud Al-Mousa, MD n, Bandar Al-Saud, MD n, Hasan Al-Dhekri, MD n, Rand Arnaout, MD n, Renata Formankova, MD o, Yves Bertrand, MD p, Andrzej Lange, MD q, r, Joanne Smart, MD s, Beata Wolska-Kusnierz, PhD t, Victor M. Aquino, MD u, Christopher C. Dvorak, MD v, Anders Fasth, MD, PhD w, Fanny Fouyssac, MD x, eee, Carsten Heilmann, MD y, Manfred Hoenig, MD z, Catharina Schuetz, MD, PhD z, Jadranka Kelečić, MD aa, Robbert G.M. Bredius, MD, PhD bb, Arjan C. Lankester, MD, PhD bb, Caroline A. Lindemans, MD, PhD cc, dd, Felipe Suarez, MD ee, eee, Kathleen E. Sullivan, MD, PhD ff, Michael H. Albert, MD, PhD gg, Krzysztof Kałwak, MD hh, Vincent Barlogis, MD ii, eee, Monica Bhatia, MD jj, Victoria Bordon, MD, PhD kk, Wojciech Czogala, MD ll, ∗, Laura Alonso, MD mm, Figen Dogu, MD nn, Jolanta Gozdzik, MD oo, Aydan Ikinciogullari, MD pp, Gergely Kriván, MD, PhD qq, Per Ljungman, MD rr, Isabelle Meyts, MD, PhD ss, Peter Mustillo, MD tt, Angela R. Smith, MD, MS uu, Carsten Speckmann, MD vv, ww, Mikael Sundin, MD, PhD xx, yy, Steven John Keogh, MD zz, Peter John Shaw, MD zz, aaa, Jaap Jan Boelens, MD, PhD cc, dd, bbb, ccc, Ansgar S. Schulz, MD z, Petr Sedlacek, MD, PhD o, Paul Veys, MD ddd, Nizar Mahlaoui, MD, MSc, MPH e, h, eee, fff, Ales Janda, MD, PhD ggg, E. Graham Davies, MD, PhD g, Alain Fischer, MD, PhD e, h, eee, hhh, Morton J. Cowan, MD v, Andrew Richard Gennery, MD a, f
on behalf of
, Stefania Galimberti, PhD d, Virginie Courteille, PhD e, eee, Mary Anne Slatter, MD a, f, Claire Booth, MD, PhD g, Despina Moshous, MD, PhD e, h, eee, Benedicte Neven, MD, PhD e, h, eee, Stephane Blanche, MD e, h, eee, Marina Cavazzana, MD, PhD e, i, j, k, Alexandra Laberko, MD, PhD l, Anna Shcherbina, MD, PhD l, Dmitry Balashov, MD, PhD l, Elena Soncini, MD m, Fulvio Porta, MD, PhD m, Hamoud Al-Mousa, MD n, Bandar Al-Saud, MD n, Hasan Al-Dhekri, MD n, Rand Arnaout, MD n, Renata Formankova, MD o, Yves Bertrand, MD p, Andrzej Lange, MD q, r, Joanne Smart, MD s, Beata Wolska-Kusnierz, PhD t, Victor M. Aquino, MD u, Christopher C. Dvorak, MD v, Anders Fasth, MD, PhD w, Fanny Fouyssac, MD x, eee, Carsten Heilmann, MD y, Manfred Hoenig, MD z, Catharina Schuetz, MD, PhD z, Jadranka Kelečić, MD aa, Robbert G.M. Bredius, MD, PhD bb, Arjan C. Lankester, MD, PhD bb, Caroline A. Lindemans, MD, PhD cc, dd, Felipe Suarez, MD ee, eee, Kathleen E. Sullivan, MD, PhD ff, Michael H. Albert, MD, PhD gg, Krzysztof Kałwak, MD hh, Vincent Barlogis, MD ii, eee, Monica Bhatia, MD jj, Victoria Bordon, MD, PhD kk, Wojciech Czogala, MD ll, ∗, Laura Alonso, MD mm, Figen Dogu, MD nn, Jolanta Gozdzik, MD oo, Aydan Ikinciogullari, MD pp, Gergely Kriván, MD, PhD qq, Per Ljungman, MD rr, Isabelle Meyts, MD, PhD ss, Peter Mustillo, MD tt, Angela R. Smith, MD, MS uu, Carsten Speckmann, MD vv, ww, Mikael Sundin, MD, PhD xx, yy, Steven John Keogh, MD zz, Peter John Shaw, MD zz, aaa, Jaap Jan Boelens, MD, PhD cc, dd, bbb, ccc, Ansgar S. Schulz, MD z, Petr Sedlacek, MD, PhD o, Paul Veys, MD ddd, Nizar Mahlaoui, MD, MSc, MPH e, h, eee, fff, Ales Janda, MD, PhD ggg, E. Graham Davies, MD, PhD g, Alain Fischer, MD, PhD e, h, eee, hhh, Morton J. Cowan, MD v, Andrew Richard Gennery, MD a, fon behalf of
SCETIDE, PIDTC, EBMT & ESID IEWP
a Department of Pediatric Immunology and HSCT, Great North Children's Hospital, Newcastle upon Tyne, United Kingdom
b San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), Pediatric Immunohematology and Bone Marrow Transplantation Unit, San Raffaele Scientific Institute, Milan, Italy
c Vita-Salute San Raffaele University, Milan, Italy
d Center of Biostatistics for Clinical Epidemiology, School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
e Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France
f Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom
g Department of Pediatric Immunology, Great Ormond Street Hospital, London, United Kingdom
h Pediatric Hematology-Immunology and Rheumatology Unit, Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France
i Biotherapy Department, Necker Children's Hospital, AP-HP, Paris, France
j Biotherapy Clinical Investigation Center, Groupe Hospitalier Universitaire Ouest, AP-HP, INSERM, Paris, France
k INSERM UMR 1163, Laboratory of Human Lymphohematopoiesis, Paris, France
l Dmitry Rogachev Federal Research Centre of Pediatric Hematology, Oncology and Immunology, Moscow, Russia
m Pediatric Oncology-Hematology and BMT Unit, Spedali Civili di Brescia, Brescia, Italy
n Department of Pediatrics, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia
o Department of Pediatric Hematology and Oncology, University Hospital Motol Prague, Prague, Czech Republic
p Institut d'Hematologie et d'Oncologie Pediatrique, Hospices Civils de Lyon, Lyon, France
q L. Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wrocław, Poland
r Lower Silesian Center for Cellular Transplantation & National Bone Marrow Donor Registry, Wrocław, Poland
s Department of Allergy and Immunology, Royal Children's Hospital, Melbourne, Australia
t Immunology Department, Children's Memorial Health Institute, Warsaw, Poland
u Department of Pediatrics, University of Texas Southwestern Medical Center Dallas, Dallas, Tex
v Division of Pediatric Allergy, Immunology & Bone Marrow Transplantation, University of California, San Francisco, Calif
w Department of Pediatrics, Sahlgrenska Academy at University of Gothenburg and Queen Silvia Children's Hospital, Gothenburg, Sweden
x Pediatric Oncology and Hematology Unit, Children Hospital, University Hospital Nancy, Vandoeuvre-les-Nancy, France
y Pediatric Clinic, Rigshospitalet, Copenhagen, Denmark
z Department of Pediatrics, University Medical Center Ulm, Ulm, Germany
aa Department of Pediatrics, Division of Allergology, Clinical Immunology, Respiratory Diseases and Rheumatology, University Hospital Center Zagreb, Zagreb, Croatia
bb Department of Pediatrics/Willem-Alexander Children's hospital, Leiden University Medical Center, Leiden, The Netherlands
cc Department of Pediatrics, University Medical Centre Utrecht, Utrecht University, Utrecht, The Netherlands
dd Princess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands
ee Hématologie Adulte, Hôpital Necker, AP-HP, Paris, France
ff Division of Allergy Immunology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pa
gg Pediatric Hematology/Oncology, Dr. von Hauner University Children's Hospital, Munich, Germany
hh Department of Pediatric Hematology and Oncology, Wroclaw Medical University, Wrocław, Poland
ii Service d'hématologie pédiatrique, Hôpital de la Timone Enfants, Marseille, France
jj Pediatric Stem Cell Transplantation, Columbia University College of Physicians and Surgeons, New York, NY
kk Pediatric Hematology–Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium
ll University Children's Hospital of Cracow, Cracow, Poland
mm Pediatric Hematology and Oncology Department, Hospital Universitario MaternoInfantil Vall d’Hebron, Barcelona, Spain
nn Department of Pediatric Immunology and Allergy, Ankara University School of Medicine, Ankara, Turkey
oo Department of Clinical Immunology and Transplantology, Jagiellonian University, Medical Collage, Transplantation Center, University Children's Hospital, Cracow, Poland
pp Department of Pediatric Immunology-Allergy and BMT Unit, Ankara University Medical School, Ankara, Turkey
qq Department of Pediatric Hematology and Stem Cell Transplantation United St. István and St László Hospital, Budapest, Hungary
rr Department of Hematology, Karolinska University Hospital, Stockholm, Sweden
ss Department of Pediatrics, University Hospitals Leuven, Division of Pediatric Immunology, Department of Immunology and Microbiology, Catholic University Leuven, Leuven, Belgium
tt Nationwide Children's Hospital, Columbus, Ohio
uu Pediatric Blood and Marrow Transplant, University of Minnesota, Minneapolis, Minn
vv Center for Chronic Immunodeficiency, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
ww Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
xx Division of Pediatrics, CLINTEC, Karolinska Institutet, Stockholm, Sweden
yy Pediatric Blood Disorders, Immunodeficiency and SCT, Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden
zz Cancer Centre for Children, Children's Hospital at Westmead, Sydney, Australia
aaa University of Sydney Medical Program, Sydney, Australia
bbb Department of Pediatrics, Memorial Sloan Kettering Cancer Center, BMT and Cell Therapies Program, New York, NY
ccc Laboratory for Translational Immunology, Tumor-immunology, University Medical Center Utrecht, Utrecht, The Netherlands
ddd Department of BMT, Great Ormond Street Hospital for Children NHS Trust, London, United Kingdom
eee French National Reference Center for Primary Immune Deficiencies (CEREDIH), Necker Enfants Malades University Hospital, AP-HP, Paris, France
fff INSERM UMR 1163, Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Paris, France
ggg Center for Pediatrics and Center for Chronic Immunodeficiency, Medical Center, University of Freiburg, Freiburg, Germany
hhh College de France, Paris, France
∗Corresponding author: Francesca Ferrua, MD, San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), Pediatric Immunohematology and Bone Marrow Transplantation Unit, San Raffaele Scientific Institute, Milan, Italy, Via Olgettina, 60, 20132 Milan, Italy.San Raffaele Telethon Institute for Gene Therapy (SR-Tiget)Pediatric Immunohematology and Bone Marrow Transplantation UnitSan Raffaele Scientific Institute, Milan, ItalyVia Olgettina, 60Milan20132Italy
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.
Le texte complet de cet article est disponible en PDF.Graphical abstract |
Key words : CD40 ligand, hematopoietic stem cell transplantation, X-linked hyper-IgM syndrome, primary immunodeficiency
Abbreviations used : BM, CD40L, DFS, DLI, EBMT, EFS, ESID, FU, GVHD, HSCT, IEWP, MAC, MAC low tox, MMFD, MMUD, MSD, MUD, NMA, OS, PBSC, PID, PIDTC, RIC, SCETIDE, UCB
Plan
| F.F. received an ESID Medium Term Fellowship. M. J. Cowan, C. C. Dvorak, and K. E. Sullivan are supported by the Division of Allergy, Immunology and Transplantation, National Institute of Allergy and Infectious Diseases (NIAID), and the Office of Rare Diseases Research (ORDR), National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH), Bethesda, Maryland (Public Health Service grant/cooperative agreements U54-AI082973 and R13-AI094943). The SCETIDE registry is funded by CEREDIH and the French Ministry of Health. Research was supported by the National Institute for Health Research (NIHR) Newcastle Biomedical Research Centre based at Newcastle Hospitals NHS Foundation Trust and Newcastle University. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health. |
|
| Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest. |
© 2019
The Authors. Publié par Elsevier Masson SAS. Tous droits réservés.
Vol 143 - N° 6
P. 2238-2253 - juin 2019 Retour au numéro
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