Wiskott-Aldrich syndrome: a study of 577 patients defines the genotype as a biomarker for disease severity and survival

Author:

Vallée Tanja C.1,Glasmacher Jannik S.1,Buchner Hannes2ORCID,Arkwright Peter D.3,Behrends Uta4,Bondarenko Anastasia5ORCID,Browning Michael J.6,Buchbinder David7,Cattoni Alessandro89ORCID,Chernyshova Liudmyla10,Ciznar Peter11ORCID,Cole Theresa12,Czogała Wojciech13ORCID,Dueckers Gregor14,Edgar John David M.15,Erbey Fatih16,Fasth Anders17ORCID,Ferrua Francesca18ORCID,Formankova Renata19,Gambineri Eleonora2021,Gennery Andrew R.22,Goldman Frederick D.23,Gonzalez-Granado Luis I.24ORCID,Heilmann Carsten25,Heiskanen-Kosma Tarja26ORCID,Juntti Hanna27,Kainulainen Leena28ORCID,Kanegane Hirokazu29ORCID,Karaca Neslihan E.30,Kilic Sara S.31ORCID,Klein Christoph1,Kołtan Sylwia32ORCID,Kondratenko Irina33ORCID,Meyts Isabelle34,Nasrullayeva Gulnara M.35ORCID,Notarangelo Lucia D.36,Pasic Srdjan37ORCID,Pellier Isabelle38ORCID,Pignata Claudio39,Misbah Siraj40ORCID,Schulz Ansgar41ORCID,Segundo Gesmar R.42,Shcherbina Anna43,Slatter Mary22,Sokolic Robert44ORCID,Soler-Palacin Pere45ORCID,Stepensky Polina46,van Montfrans Joris M.47,Ryhänen Samppa48ORCID,Wolska-Kuśnierz Beata49,Ziegler John B.50,Zhao Xiaodong5152,Aiuti Alessandro18,Ochs Hans D.53,Albert Michael H.1ORCID

Affiliation:

1. 1Pediatric Hematology/Oncology, Dr von Hauner University Children's Hospital, Munich, Germany

2. 2Staburo GmbH, Munich, Germany

3. 3Lydia Becker Institute of Immunology and Inflammation, The University of Manchester & Royal Manchester Children's Hospital, Manchester, United Kingdom

4. 4Children's Hospital, School of Medicine, Technical University Munich, Munich, Germany

5. 5Department of Pediatrics, Immunology, Infectious and Rare Diseases and Allergology, European Medical School, International European University, Kyiv, Ukraine

6. 6Department of Infection, Immunity and Inflammation, University of Leicester, Leicester, United Kingdom

7. 7Department of Hematology, Children's Hospital of Orange County, Orange, CA

8. 8Department of Pediatrics, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy

9. 9School of Medicine and Surgery, University of Milano-Bicocca, Milan, Italy

10. 10Department of Pediatrics, Pediatric Infectious Diseases, Immunology and Allergology, Shupyk National Healthcare University of Ukraine, Kyiv, Ukraine

11. 11Department of Pediatrics, Faculty of Medicine, Comenius University, Bratislava, Slovakia

12. 12Department of Allergy and Immunology, The Royal Children's Hospital, Melbourne, Australia

13. 13Department of Pediatric Oncology and Hematology, Institute of Pediatrics, Jagiellonian University Medical College, Krakow, Poland

14. 14Helios Kliniken Krefeld, Children's Hospital, Krefeld, Germany

15. 15St James's Hospital & School of Medicine, Trinity College, Dublin, Ireland

16. 16Department of Pediatric Hematology/Oncology, Koç University School of Medicine, İstanbul, Turkey

17. 17Department of Pediatrics, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

18. 18Pediatric Immunohematology and Stem Cell Program, San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy

19. 19Department of Pediatric Hematology and Oncology, Charles University and University Hospital Motol, Prague, Czech Republic

20. 20Department of NEUROFARBA, Section of Child’s Health, University of Florence, Florence, Italy

21. 21Department of Haematology-Oncology, Anna Meyer University Children's Hospital (AOU Meyer IRCCS), Florence, Italy

22. 22Translational and Clinical Research Institute, Newcastle University, and Paediatric Stem Cell Transplant Unit, Great North Children's Hospital, Newcastle upon Tyne, United Kingdom

23. 23Department of Pediatrics, The University of Alabama at Birmingham, Birmingham, AL

24. 24Department of Pediatrics, Primary Immunodeficiencies Unit, Research Institute, Hospital 12 Octubre, School of Medicine, Complutense University of Madrid, Madrid, Spain

25. 25Department for Children and Adolescents, Pediatric Hematopoietic Stem Cell Transplantation and Immunodeficiency, Copenhagen University Hospital Rigshospitalet, København, Denmark

26. 26Department of Pediatrics, Kuopio University Hospital, Kuopio, Finland

27. 27Department of Pediatrics and Adolescent Medicine, Oulu University Hospital and Research Unit of Clinical Medicine, University of Oulu, Oulu, Finland

28. 28Division of Pediatric Hematology and Oncology, Department of Pediatrics, Turku University Hospital, Turku, Finland

29. 29Department of Child Health and Development, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan

30. 30Division of Pediatric Immunology, Department of Pediatrics, Ege University, The Medical School, Izmir, Turkey

31. 31Pediatric Immunology and Rheumatology, Bursa Uludag University School of Medicine, Bursa, Turkey

32. 32Department of Paediatrics, Haematology and Oncology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, Toruń, Poland

33. 33Russian Children’s Clinical Hospital, Pirogov National Research Medical University, Moscow, Russia

34. 34Department of Pediatrics, University Hospitals Leuven, Leuven, Belgium

35. 35Azerbaijan Medical University, Baku, Azerbaijan

36. 36Medical Direction, Children’s Hospital, ASST Spedali Civili, Brescia, Italy

37. 37Department of Immunology, Mother and Child Health Care Institute of Serbia, Belgrade, Serbia

38. 38Centre de référence des déficits immunitaires primitifs CEREDIH, CHU d'Angers, Angers, France

39. 39Department of Translational Medical Science, Section of Pediatrics, Federico II University, Napoli, Italy

40. 40Clinical Immunology, John Radcliffe Hospital, Oxford, United Kingdom

41. 41Department of Pediatrics, University Medical Center Ulm, Ulm, Germany

42. 42Allergy and Immunology Division, Pediatrics Department, Universidade Federal de Uberlândia, Uberlândia, Brazil

43. 43Dmitry Rogachev National Research and Clinical Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia

44. 44Hematologic Malignancies Branch, Office of Therapeutic Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD

45. 45Pediatric Infectious Diseases and Immunodeficiencies Unit, Children's Hospital, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain

46. 46Bone Marrow Transplantation Department, Hadassah-Hebrew, University Medical Center, Jerusalem, Israel

47. 47Department of Pediatric Immunology and Infectious Diseases, University Medical Centre Utrecht, Utrecht, The Netherlands

48. 48Children’s Hospital, University of Helsinki and Helsinki University Hospital, Pediatric Research Center, Helsinki, Finland

49. 49Department of Immunology, Children's Memorial Health Institute, Warsaw, Poland

50. 50School of Women's & Children's Health, University of New South Wales, Sydney, Australia

51. 51Department of Rheumatism and Immunology, Children's Hospital of Chongqing Medical University, Chongqing, China

52. 52Vita-Salute San Raffaele University, Milan, Italy

53. 53University of Washington School of Medicine, Seattle, WA

Abstract

Abstract Wiskott-Aldrich syndrome (WAS) is a multifaceted monogenic disorder with a broad disease spectrum and variable disease severity and a variety of treatment options including allogeneic hematopoietic stem cell transplantation (HSCT) and gene therapy (GT). No reliable biomarker exists to predict disease course and outcome for individual patients. A total of 577 patients with a WAS variant from 26 countries and a median follow-up of 8.9 years (range, 0.3-71.1), totaling 6118 patient-years, were included in this international retrospective study. Overall survival (OS) of the cohort (censored at HSCT or GT) was 82% (95% confidence interval, 78-87) at age 15 years and 70% (61-80) at 30 years. The type of variant was predictive of outcome: patients with a missense variant in exons 1 or 2 or with the intronic hot spot variant c.559+5G>A (class I variants) had a 15-year OS of 93% (89-98) and a 30-year OS of 91% (86-97), compared with 71% (62-81) and 48% (34-68) in patients with any other variant (class II; P < .0001). The cumulative incidence rates of disease-related complications such as severe bleeding (P = .007), life-threatening infection (P < .0001), and autoimmunity (P = .004) occurred significantly later in patients with a class I variant. The cumulative incidence of malignancy (P = .6) was not different between classes I and II. It confirms the spectrum of disease severity and quantifies the risk for specific disease-related complications. The class of the variant is a biomarker to predict the outcome for patients with WAS.

Publisher

American Society of Hematology

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