Hypomorphic RAG deficiency: impact of disease burden on survival and thymic recovery argues for early diagnosis and HSCT

Author:

Schuetz C.1ORCID,Gerke J.1,Ege M.23ORCID,Walter J.45ORCID,Kusters M.6ORCID,Worth A.6,Kanakry J. A.7,Dimitrova D.7ORCID,Wolska-Kuśnierz B.8ORCID,Chen K.9ORCID,Unal E.10,Karakukcu M.10ORCID,Pashchenko O.11,Leiding J.12,Kawai T.13,Amrolia P. J.14ORCID,Berghuis D.15,Buechner J.16ORCID,Buchbinder D.17,Cowan M. J.18,Gennery A. R.19ORCID,Güngör T.20ORCID,Heimall J.2122,Miano M.23ORCID,Meyts I.24,Morris E. C.25ORCID,Rivière J.26ORCID,Sharapova S. O.27ORCID,Shaw P. J.28ORCID,Slatter M.29,Honig M.30,Veys P.31,Fischer A.323334,Cavazzana M.333536ORCID,Moshous D.3233ORCID,Schulz A.30,Albert M. H.37ORCID,Puck J. M.18ORCID,Lankester A. C.15,Notarangelo L. D.38ORCID,Neven B.32

Affiliation:

1. 1Department of Paediatrics, Universitätsklinikum Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

2. 2Dr. von Hauner Children’s Hospital at Ludwig-Maximilians-Universität, München, Germany

3. 3Helmholtz Zentrum München, Neuherberg, Germany

4. 4Division of Allergy and Immunology, Department of Pediatrics, Morsani College of Medicine, University of South Florida, Tampa, FL

5. 5Division of Allergy and Immunology, Department of Medicine, Johns Hopkins All Children’s Hospital, St. Petersburg, FL

6. 6Department of Immunology and Gene therapy, Great Ormond Street Hospital, NHS Foundation trust, London, United Kingdom

7. 7Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD

8. 8Department of Immunology, Children's Memorial Health Institute, Warsaw, Poland

9. 9Division of Allergy and Immunology, Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT

10. 10Division of Pediatric Hematology and Oncology, Department of Pediatrics, Erciyes University, Kayseri, Turkey

11. 11Department of Immunology, Pirogov Russian National Research Medical University, Moscow, Russia

12. 12Division of Allergy and Immunology, Department of Pediatrics, Johns Hopkins University, Orlando Health Arnold Pamer Hospital for Children, Orlando, FL

13. 13Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD

14. 14Bone Marrow Transplant Unit, Great Ormond Street Hospital NHS Foundation Trust, London, United Kingdom

15. 15Department of Pediatrics, Willem-Alexander Children’s Hospital, Leiden University Medical Center, Leiden, The Netherlands

16. 16Department of Pediatric Hematology and Oncology, Oslo University Hospital, Oslo, Norway

17. 17Division of Hematology, Children's Hospital of Orange County, Orange, CA

18. 18Division of Allergy, Immunology, and Blood and Marrow Transplant, Department of Pediatrics, University of California San Francisco, San Francisco, CA

19. 19Translational and Clinical Research Institute, Newcastle University, Paediatric Haematopoietic Stem Cell Transplant Unit, Great North Children’s Hospital, Newcastle upon Tyne, United Kingdom

20. 20Department of Hematology/Oncology/Immunology, Gene-therapy, and Stem Cell Transplantation, University Children’s Hospital Zurich–Eleonore Foundation & Children’s Research Center, Zürich, Switzerland

21. 21Division of Allergy and Immunology, Children’s Hospital of Philadelphia, Philadelphia, PA

22. 22Department of Pediatrics, Perelman School of Medicine at University of Pennsylvania, Philadelphia, PA

23. 23IRCCS Istituto Giannina Gaslini, Genova, Italy

24. 24Department of Pediatrics, Department of Microbiology and Immunology, University Hospitals Leuven, Leuven, Belgium

25. 25UCL Institute of Immunity & Transplantation, University College London Hospitals NHS Foundation Trust, Royal Free London Hospital NHS Foundation Trust, London, United Kingdom

26. 26Pediatric Infectious Diseases and Immunodeficiencies Unit, Vall d'Hebron Research Institute, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain

27. 27Research Department, Belarusian Research Center for Pediatric Oncology, Hematology and Immunology, Minsk, Belarus

28. 28Blood Transplant and Cell Therapies, Children’s Hospital at Westmead, Sydney, Australia

29. 29Paediatric Immunology & HSCT, Great North Children's Hospital, Newcastle upon Tyne, United Kingdom

30. 30Department of Pediatrics and Adolescent Medicine, Ulm University, Ulm, Germany

31. 31Bone Marrow Transplant Unit, Great Ormond Street Hospital NHS Foundation Trust, London, United Kingdom

32. 32Paediatric Immunology, Department of Immunology, Haematology and Rheumatology, Necker-Enfants Malades, Paris, France

33. 33Institut Imagine, Paris Descartes-Sorbonne Paris Cité University, Paris, France

34. 34Collège de France, Paris, France

35. 35Département de Biothérapie, Hôpital Universitaire Necker-Enfants Malades, Groupe Hospitalier Paris Centre, Assistance Publique–Hopitaux de Paris, Paris, France

36. 36Centre d’Investigation Clinique Biothérapie, Groupe hospitalier Universitaire paris centre, Assistance Publique-Hôpitaux de Paris, INSERM CIC 1416, Paris, France

37. 37Pediatric SCT Program, Dr. von Hauner University Children’s Hospital, Ludwig-Maximilians Universität, München, Germany

38. 38Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD

Abstract

AbstractPatients with hypomorphic mutations in the RAG1 or RAG2 gene present with either Omenn syndrome or atypical combined immunodeficiency with a wide phenotypic range. Hematopoietic stem cell transplantation (HSCT) is potentially curative, but data are scarce. We report on a worldwide cohort of 60 patients with hypomorphic RAG variants who underwent HSCT, 78% of whom experienced infections (29% active at HSCT), 72% had autoimmunity, and 18% had granulomas pretransplant. These complications are frequently associated with organ damage. Eight individuals (13%) were diagnosed by newborn screening or family history. HSCT was performed at a median of 3.4 years (range 0.3-42.9 years) from matched unrelated donors, matched sibling or matched family donors, or mismatched donors in 48%, 22%, and 30% of the patients, respectively. Grafts were T-cell depleted in 15 cases (25%). Overall survival at 1 and 4 years was 77.5% and 67.5% (median follow-up of 39 months). Infection was the main cause of death. In univariable analysis, active infection, organ damage pre-HSCT, T-cell depletion of the graft, and transplant from a mismatched family donor were predictive of worse outcome, whereas organ damage and T-cell depletion remained significant in multivariable analysis (hazard ratio [HR] = 6.01, HR = 8.46, respectively). All patients diagnosed by newborn screening or family history survived. Cumulative incidences of acute and chronic graft-versus-host disease were 35% and 22%, respectively. Cumulative incidences of new-onset autoimmunity was 15%. Immune reconstitution, particularly recovery of naïve CD4+ T cells, was faster and more robust in patients transplanted before 3.5 years of age, and without organ damage. These findings support the indication for early transplantation.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

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