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Journal of Allergy and Clinical Immunology

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A prospective study on the natural history of patients with profound combined immunodeficiency: An interim analysis - 19/04/17

Doi : 10.1016/j.jaci.2016.07.040 
Carsten Speckmann, MD a, b, Sam Doerken, MSc c, Alessandro Aiuti, MD d, e, Michael H. Albert, MD f, Waleed Al-Herz, MD g, Luis M. Allende, PhD h, Alessia Scarselli, MD e, Tadej Avcin, MD i, Ruy Perez-Becker, MD j, Caterina Cancrini, MD, PhD e, Andrew Cant, MD, PhD k, Silvia Di Cesare, BSc e, Andrea Finocchi, MD e, Alain Fischer, MD, PhD l, H. Bobby Gaspar, MD, PhD m, Sujal Ghosh, MD n, Andrew Gennery, MD k, Kimberly Gilmour, PhD m, Luis I. González-Granado, MD h, o, Monica Martinez-Gallo, PhD p, Sophie Hambleton, MD, PhD k, Fabian Hauck, MD, PhD q, Manfred Hoenig, MD r, Despina Moshous, MD, PhD l, t, Benedicte Neven, MD l, Tim Niehues, MD j, Luigi Notarangelo, MD s, Capucine Picard, MD, PhD l, t, Nikolaus Rieber, MD u, v, Ansgar Schulz, MD r, Klaus Schwarz, MD w, Markus G. Seidel, MD x, Pere Soler-Palacin, MD p, Polina Stepensky, MD y, Brigitte Strahm, MD a, Thomas Vraetz, MD a, Klaus Warnatz, MD b, Christine Winterhalter b, z, Austen Worth, MD m, Sebastian Fuchs, PhD b, Annette Uhlmann, Dr rer nat b, z, Stephan Ehl, MD a, b, ⁎
on behalf of the

P-CID study of the Inborn Errors Working Party of the EBMT

a Department of Pediatric Hematology and Oncology, Center for Pediatrics, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany 
b Center for Chronic Immunodeficiency, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany 
c Institute for Medical Biometry and Statistics, Center for Medical Biometry and Medical Informatics, Medical Center – University of Freiburg, Freiburg, Germany 
d Pediatric Immunohematology and Bone Marrow Transplant Unit, San Raffaele Scientific Institute, Milan, Italy 
e Department of Pediatrics, Ospedale Pediatrico Bambino Gesù and University of Rome “Tor Vergata,” Rome, Italy 
f Dr von Hauner Children's Hospital, Ludwig-Maximilians-University, Munich, Germany 
g Department of Pediatrics, Faculty of Medicine, Kuwait University, Kuwait City, Kuwait 
h Servicio de Inmunología, Hospital Universitario 12 de Octubre and Instituto de Investigación i+12, Madrid, Spain 
i Department of Allergology, Rheumatology and Clinical Immunology, University Children's Hospital, University Medical Center, Ljubljana, Slovenia 
j Center for Pediatrics and Adolescent Medicine, Helios Hospital Krefeld, Krefeld, Germany 
k Immunodeficiency Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom 
l AP-HP, Hôpital Necker–Enfants Malades, Immunologie et Hématologie Pédiatriques, Paris, France 
m Department of Immunology, Great Ormond Street Hospital NHS Foundation Trust, London, United Kingdom 
n Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Center of Child and Adolescent Health, Heinrich-Heine-University, Düsseldorf, Germany 
o Immunodeficiencies Unit, Hematology & Oncology Unit, Pediatrics, Hospital 12 Octubre, Madrid, Spain 
p Immunology Division, Hospital Universitari Vall d'Hebron, Vall d'Hebron Institut de Recerca, Universitat Autònoma de Barcelona, Barcelona, Spain 
q Immunodeficiency Unit and Immunological Diagnostics Laboratory, Dr von Hauner Children's Hospital Ludwig-Maximilians-University, Munich, Germany 
r Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany 
s Division of Immunology, Boston Children's Hospital, and Department of Pediatrics, Harvard Medical School, Boston, Mass 
t INSERM UMR1163, Genome Dynamics in the Immune System, Université Paris Descartes – Sorbonne Paris Cité, Institut Imagine, Paris, France 
u Department of Pediatrics I, University of Tübingen, Tübingen, Germany 
v Department of Pediatrics, StKM GmbH and Technical University Muenchen, Munich, Germany 
w Institute for Transfusion Medicine, University of Ulm, and the Institute for Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Service, Baden-Württemberg-Hessen, Ulm, Germany 
x Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology-Oncology, Medical University Graz, Graz, Austria 
y Pediatric Hematology-Oncology and Bone Marrow Transplantation, Hadassah Hebrew University Hospital, Jerusalem, Israel 
z Clinical Trials Unit, Medical Center – University of Freiburg, Freiburg, Germany 

∗Corresponding author: Stephan Ehl, MD, Centre for Chronic Immunodeficiency, University Medical Centre Freiburg, 79106 Freiburg, Germany.Centre for Chronic ImmunodeficiencyUniversity Medical Centre FreiburgFreiburg79106Germany

Abstract

Background

Absent T-cell immunity resulting in life-threatening infections provides a clear rationale for hematopoetic stem cell transplantation (HSCT) in patients with severe combined immunodeficiency (SCID). Combined immunodeficiencies (CIDs) and “atypical” SCID show reduced, not absent T-cell immunity. If associated with infections or autoimmunity, they represent profound combined immunodeficiency (P-CID), for which outcome data are insufficient for unambiguous early transplant decisions.

Objectives

We sought to compare natural histories of severity-matched patients with/without subsequent transplantation and to determine whether immunologic and/or clinical parameters may be predictive for outcome.

Methods

In this prospective and retrospective observational study, we recruited nontransplanted patients with P-CID aged 1 to 16 years to compare natural histories of severity-matched patients with/without subsequent transplantation and to determine whether immunologic and/or clinical parameters may be predictive for outcome.

Results

A total of 51 patients were recruited (median age, 9.6 years). Thirteen of 51 had a genetic diagnosis of “atypical” SCID and 14 of 51 of CID. About half of the patients had less than 10% naive T cells, reduced/absent T-cell proliferation, and at least 1 significant clinical event/year, demonstrating their profound immunodeficiency. Nineteen patients (37%) underwent transplantation within 1 year of enrolment, and 5 of 51 patients died. Analysis of the HSCT decisions revealed the anticipated heterogeneity, favoring an ongoing prospective matched-pair analysis of patients with similar disease severity with or without transplantation. Importantly, so far neither the genetic diagnosis nor basic measurements of T-cell immunity were good predictors of disease evolution.

Conclusions

The P-CID study for the first time characterizes a group of patients with nontypical SCID T-cell deficiencies from a therapeutic perspective. Because genetic and basic T-cell parameters provide limited guidance, prospective data from this study will be a helpful resource for guiding the difficult HSCT decisions in patients with P-CID.

Le texte complet de cet article est disponible en PDF.

Key words : T-cell deficiency, combined immunodeficiency, hematopoietic stem cell transplantation, natural history

Abbreviations used : CID, CVID, HSCT, IL2Rg, ITK, NBS, ORAI1, P-CID, QOL, RAG, SCID, ZAP70


Plan


 The P-CID study is funded by the German Federal Ministry of Education and Research (BMBF grant no. 01 EO 0803) and a Chaim Roifman Scholar Award from the Canadian Immunodeficiency Society. This project has further received funding from the European Union's Horizon 2020 Research and Innovation Programme under the ERA-NET Cofund action N°643578.
 Disclosure of potential conflict of interest: C. Speckmann receives grant support from the German Ministry for Education and Research (BMBF); payments for lectures from Octapharma and CSL Behring; and travel support from Orphan Europe and CSL Behring. A. Aiuti receives grant support from the European Research Council, Fondazione Telethon Rome, Italian Ministry of Health, and GSK. M. H. Albert receives grant support from GSK; receives payment for lectures from Biotest, MSD, and Jazz; holds stock in Amen and BMS; and receives travel support from Octapharma. T. Avcin serves as a consultant for Octapharma and receives payment for lectures from Octapharma. C. Cancrini receives grant support from Ministero della Salute and European Community and serves as a consultant for UCB CellTech UK. A. Finocchi receives grant support from Telethon. H. Bobby Gaspar serves as a consultant for Orchard Therapeutics and holds stock in Orchard Therapeutis. K. Gilmour receives travel support from UKPIN. M. Hoenig receives payment for lectures from CSL Behring and Jazz Pharma and travel support from CSL Behring and Jazz Pharma. L. Notarangelo serves on the board of Novimmune and receives grant support from the National Institutes of Health and royalties from Up-to-Date. M. G. Seidel serves as a consultant for Baxalta and Novartis; received payments for lectures from Jazz Pharmaceuticals, Novartis, and CSL Behring; and received travel support from Jazz Pharmaceuticals, Octapharma, and Amgen. P. Soler-Palacin receives travel support from the P-CID study group; expert testimony from CSL Behring, Octapharma, Grifols, and Baxter; grant support from CSL Behring; and payments for lectures from Grifols. K. Warnatz serves on the board for BioTest, CSL Behring, and LFB Biomedicaments; receives grant support from BMS, CSL Behring, and BioTest; and receives payments for lecture from LFB Biomedicaments, Baxter, GSK, CSL Behring, Pfizer, BioTest, Novartis Pharma, Roche, Octapharma, and UCB Pharma. A. Worth receives research support from the National Institute of Health Research and Wellcome Trust. A. Uhlmann receives travel support from BMBF. S. Ehl receives research support from BMBF, the Canadian Immunodeficiency Society, and European Union's Horizon 2020 Research and Innovation Programme; serves as a consultant for UCD and Novartis but not in the context of this study; and received payments from lectures for CSL Behring. The rest of the authors declare that they have no relevant conflicts of interest.


© 2016  American Academy of Allergy, Asthma & Immunology. Publié par Elsevier Masson SAS. Tous droits réservés.
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