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Wiskott-Aldrich Syndrome: A Retrospective Study on 575 Patients Analyzing the Impact of Splenectomy, Stem Cell Transplantation, or No Definitive Treatment on Frequency of Disease-Related Complications and Physician-Perceived Quality of Life
Journal article

Wiskott-Aldrich Syndrome: A Retrospective Study on 575 Patients Analyzing the Impact of Splenectomy, Stem Cell Transplantation, or No Definitive Treatment on Frequency of Disease-Related Complications and Physician-Perceived Quality of Life

  • Glasmacher, Jannik S Pediatric Hematology/Oncology, Dr von Hauner University Children's Hospital, Munich, Germany
  • Bittner, Tanja C Pediatric Hematology/Oncology, Dr von Hauner University Children's Hospital, Munich, Germany
  • Ochs, Hans D University of Washington, Seattle, WA
  • Aiuti, Alessandro Pediatric Immunohematology and Bone Marrow Transplantation Unit, San Raffaele Scientific Institute, Milano, Italy
  • Arkwright, Peter D Department of Paediatric Allergy & Immunology, University of Manchester, Royal Manchester Children's Hospital, Manchester, United Kingdom
  • Balashov, Dmitry Dmitry Rogachev Federal Research Centre of Pediatric Hematology, Oncology and Immunology, Moscow, Russian Federation
  • Behrends, Uta Pediatric Department, Technische Universität München, Munich, Germany
  • Belohradsky, Bernd H. Dr. von Hauner Children's Hospital, Ludwig-Maximilians-Universität (LMU), Munich, Germany
  • Bertoni, Elisa Spedali Civili, Brescia, Italy
  • Buchbinder, David K. Department of Hematology, CHOC Children's Hospital, Orange, CA
  • Browning, Michael Departement of Immunology, University Hospitals of Leicester, Leicester, United Kingdom
  • Bondarenko, Anastasiia Department of Paediatric Infectious Diseases and Paediatric Immunology, Shupik National Medical Academy of Postgraduate Education, Kiev, Ukraine
  • Candotti, Fabio University Hospital of Lausanne, Lausanne, Switzerland
  • Cattoni, Alessandro Pediatric Department, San Gerardo Hospital, Monza, Italy
  • Chernyshova, Liudmyla Department of Paediatric Infectious Diseases and Paediatric Immunology, Shupik National Medical Academy of Postgraduate Education, Kiev, Ukraine
  • Chewning, Joseph H. Pediatrics, University of Alabama at Birmingham, Birmingham, AL
  • Ciznar, Peter Department of Pediatrics, Children University Hospital Bratislava, Bratislava, Slovakia
  • Cole, Theresa Department of Allergy and Immunology, The Royal Children's Hospital, Melbourne, Australia
  • Costa-Carvalho, Beatriz T Escola Paulista de Medicina, Federal University of São Paulo, Sao Paolo, Brazil
  • Czogala, Wojciech Department of Pediatrics, University Children's Hospital of Cracow, Cracow, Poland
  • Dueckers, Gregor Pädiatrische Immunologie/Rheumatologie, Helios Klinikum Krefeld, Krefeld, Germany
  • Edgar, David M Regional Immunology Service, The Royal Hospitals, Belfast, United Kingdom
  • Erbey, Fatih Pediatric BMT Unit, Bahcelievler Medicalpark Hospital, Istanbul, Turkey
  • Fasth, Anders Department of Pediatrics, University of Göteborg, Gothenburg, Sweden
  • Formankova, Renata Dept. of Pediatric Haematology and Oncology, University Hospital Motol, Prague, Czech Republic
  • Freiberger, Tomas Centre of Cardiovascular and Transplantation Surgery, Brno, Czech Republic
  • Gambineri, Eleonora University of Florence, Dept NEUROFARBA, Florence, Italy
  • Gennery, Andrew Paediatric Immunology and Haematopoietic Stem Cell Transplantation, Great North Children's Hospital, Newcaslte, United Kingdom
  • Goldman, Frederick D Department of Pediatrics, Division of Hematology Oncology, Children's Hospital of Alabama, University of Alabama at Birmingham, Birmingham, AL
  • Gonzalez-Granado, Luis I Pediatrics, Infectious Diseases, Immunology, Hospital Universitario 12 de Octubre, Madrid, Spain
  • Gulmaraes, Tiago N Division of Pediatric, Federal University of Minas Gerais, Belo Horizonte, Brazil
  • Hagin, David University of Washington, Seattle, WA
  • Hauck, Fabian Department of Pediatric Hematology, Oncology and Immunology, Dr von Hauner Children's Hospital, Ludwig Maximilians University Munich, Munich, Germany
  • Heiskanen-Kosma, Tarja Department of Pediatrics, Kuopio University Hospital, Kuopio, Finland
  • Hoenig, Manfred Universitätsklinik für Kinder- und Jugendmedizin, Ulm, Germany
  • Juntti, Hanna Department of Pediatrics, Univ. Hospital of Oulu, Oulu, Finland
  • Kanegane, Hirokazu Department of Pediatrics, University of Toyama, Toyama, Japan
  • Kainulainen, Leena Department of Pediatrics, Turku University Hospital, Turku, Finland
  • Karaca, Neslihan E Department of Pediatrics, Ege University Faculty Of Medicine, Izmir, Turkey
  • Kilic, Sara S Department of Pediatric Immunology, Uludag Universty Faculty of Medicine, Uludag, Turkey
  • Klein, Christoph Department of Pediatrics, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-Universität München, Munich, Germany
  • Koltan, Sylwia Department of Pediatric, Hematology and Oncology, Collegium Medicum Bydgoszcz, Bydgoszcz, Poland
  • Kondratenko, Irina Department of Pediatric Immunology, Russian Children's Clinical Hospital, Moscow, Russian Federation
  • Liu, Dawei Chongqing Medical University, Chongqing, China
  • Matthes, Susanne St Anna Children's Hospital, Vienna, Austria
  • Mazzucchelli, Juliana T L Federal University of Sao Paulo, Sao Paulo, Brazil
  • Meyts, Isabelle Department of Pediatrics, University Hospital Leuven, Leuven, Belgium
  • Misbah, Siraj Clinical Immunology, John Radcliffe Hospital, Oxford, United Kingdom
  • Nademi, Zohreh Great North Children's Hospital, Newcastle upon Tyne, United Kingdom
  • Nasrullayeva, Gulnara Immunology Department, Azerbaijan Medical University, Azerbaijan, Azerbaijan
  • Notarangelo, Lucia D Onco-hematology and BMT Unit, Spedali Civili, Brescia, Italy
  • Soler-Palacin, Pere Pediatric Infectious Diseases and Immunodeficiencies Unit, Hospital Universitari Vall d'Hebron, Barcelona, Spain
  • Pashchenko, Olga Department of Pediatric Immunology, Russian Children's Clinical Hospital, Moskov, Russian Federation
  • Pasic, Srdjan Mother and Child Health Institute, Belgrad, Serbia
  • Pellier, Isabelle CHU Angers, Angers Cedex, France
  • Pignata, Claudio Department of Translational Medical Sciences, Federico II University, Naples, Italy
  • Roepstorff, Camilla Department of Pediatrics, Rigshospitalet, Copenhagen, Denmark
  • Schuetz, Catharina Universitätsklinik für Kinder- und Jugendmedizin, Ulm, Germany
  • Schulz, Ansgar S Klinik f. Kinder- und Jugendmedizin, University Hospital Ulm, Ulm, Germany
  • Segundo, Gesmar R S Department of Pediatrics, Universidade Federal de Uberlandia, Uberlandia, Brazil
  • Shcherbina, Anna Clinical and Research Center for Pediatric Hematology, Oncology and Immunology, Moscow, Russian Federation
  • Smart, Joanne Royal Children's Hospital, Melbourne, Australia
  • Sokolic, Robert A. Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD
  • Stepensky, Polina Pediatric Hematology/Oncology Department, Hadassah - Hebrew University Medical Center, Jerusalem, Israel
  • Torgerson, Troy University of Washington, Seattle, WA
  • Vakhlyarskaya, Svetlana Russian Children's Clinical Hospital, Moscow, Russian Federation
  • van Montfrans, Joris Pediatrics, University Medical Center Utrecht, Utrecht, Netherlands
  • Vettenranta, Kim University of Helsinki Children's Hosp., Helsinki, Finland
  • Wolska-Kusnierz, Beata Immunology Department, Children's Memorial Health Institute, Warsaw, Poland
  • Zhao, Xiaodong Children's Hospital, Chongqing Medical University, Chongqing, China
  • Ziegler, John B Department of Immunology & Infectious Diseases, Sydney Children's Hospital, Sydney, Australia
  • Zhang, Xuan Chongqing Medical University, Chongqing, China
  • Albert, Michael H. Pediatric Hematology/Oncology, Dr von Hauner University Children's Hospital, Munich, Germany
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Published in:
  • Blood. - American Society of Hematology. - 2016, vol. 128, no. 22, p. 366-366
Immunology
Cell Biology
Biochemistry
Hematology
English Abstract
Background: The Wiskott-Aldrich syndrome (WAS) including X-linked thrombocytopenia (XLT) is a complex disorder with a wide range of disease severity and unique hematological and immunological manifestations. Based on this complexity, several approaches are available to these patients, including observation, symptomatic treatment, splenectomy, gene therapy (GT), or allogeneic hematopoietic stem cell transplantation (HSCT). In many instances more than one of these therapeutic options may seem appropriate for any given patient. A prospective, randomized study comparing the pros and cons of these therapeutic options in WAS/XLT would be desirable, but is not feasible due to the rarity and variable severity of the disease, as well as the need for long-term follow-up.
Methods and Definitions: We retrospectively assessed via an international, anonymized, file-based survey the consequences of different therapies based on the severity of the disease phenotype and how these therapies affected patients' quality of life as perceived by their treating physician. The frequency of disease- and therapy-related complications with respect to the specific treatment was recorded. "Severe events" were defined as: all fatal events or sepsis, meningitis, pneumonia requiring respiratory support, systemic viral/fungal infections or serious bleeding episodes (intracranial and gastrointestinal) requiring transfusion support. Allogeneic HSCT, splenectomy and GT were defined as "procedures", HSCT and GT as "definitive".
Results: A total of 575 patients with a documented WAS gene mutation from 51 centers in 27 countries with a median follow-up of 7.4 years (range: 0.2-75.6), resulting in 5632 patient years, were included in the study. Of these, 240 (42%) carried missense, 67 (12%) nonsense, 90 (16%) splice-site mutations, 77 (13%) deletions, 40 (7%) insertions and 61 (11%) had incomplete or inconclusive mutation information. An allogeneic HSCT was performed in 252 (44%), splenectomy in 78 (14%), GT in 14 (2%) patients, while 264 (46%) patients never had a procedure. At the time of last follow-up or before the first procedure the WAS disease severity score was 1 in 55 (10%), 2 in 144 (25%), 3 in 161 (28%), 4 in 109 (19%) and 5 in 86 (15%) patients. Overall survival of the entire cohort (censored at the time of first definitive procedure, thereby representing the "natural" disease outcome) was 82% (95% confidence interval 78-87) at 15 years and 70% (61-80) at 30 years of age. Ten year overall survival after HSCT was 80 % (74-85). The cumulative incidence (CI) of severe bleeding, severe infection, autoimmunity or malignancy in patients without a procedure at last follow-up or censored before the first procedure was 45% (39-50), 61% (55-66), 46% (40-52) and 31% (25-37) respectively at 15 years of age and 61% (51-69), 70% (62-76), 62% (52-70) and 45% (35-53) at 30 years. The frequency of definitive procedures (HSCT or GT) increased in patients with higher WAS scores, while better natural disease outcomes were associated with lower WAS scores. Overall quality of life (QoL) as perceived by the treating physician was very good, good, limited or unacceptable in 85/457 (19%), 172/457 (38%), 176/457 (39%) and 24/457 (5%) of patients without or before a procedure respectively. QoL was also strongly correlated with the WAS score. At last follow-up after successful HSCT QoL improved to very good in 123/184 (67%), good in 47/184 (26%), limited in 12/184 (7%) and unacceptable in 2/184 (1%). Splenectomy also had a favorable effect on QoL with 16/52 (31%) very good, 24/52 (46%) good, 9/52 (17%) limited and 3/52 (6%) unacceptable. Platelet counts improved from a baseline mean of 36G/l to 91G/l after GT, 159G/l after splenectomy and 204G/l after HSCT.
Conclusion: This study presents outcome data of the largest cohort of patients with a WAS gene mutation studied so far and confirms the anticipated spectrum of disease severity and the curative effect of HSCT. The data show that untreated patients with WAS suffer from increasing rates of disease-associated complications over time which correlates well with a significant reduction of QoL. Both HSCT and splenectomy have a positive effect on physician-perceived QoL. Due to the large cohort size this study's data will allow us to assess the influence of specific genotypes on outcome in WAS (analysis ongoing), possibly allowing for more individualized treatment recommendations in the future.

Disclosures
Albert: GSK: Research Funding.
Language
  • English
Open access status
bronze
Identifiers
Persistent URL
https://folia.unifr.ch/global/documents/113770
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