Jennifer W Leiding1, Satoshi Okada2, David Hagin3, Mario Abinun4, Anna Shcherbina5, Dmitry N Balashov5, Vy H D Kim6, Adi Ovadia6, Stephen L Guthery7, Michael Pulsipher8, Desa Lilic9, Lisa A Devlin10, Sharon Christie11, Mark Depner12, Sebastian Fuchs12, Annet van Royen-Kerkhof13, Caroline Lindemans13, Aleksandra Petrovic14, Kathleen E Sullivan15, Nancy Bunin16, Sara Sebnem Kilic17, Fikret Arpaci18, Oscar de la Calle-Martin19, Laura Martinez-Martinez19, Juan Carlos Aldave20, Masao Kobayashi2, Teppei Ohkawa21, Kohsuke Imai21, Akihiro Iguchi22, Chaim M Roifman6, Andrew R Gennery4, Mary Slatter4, Hans D Ochs3, Tomohiro Morio23, Troy R Torgerson24. 1. Division of Allergy and Immunology, Department of Pediatrics, University of South Florida at Johns Hopkins - All Children's Hospital, St Petersburg, Fla. 2. Department of Pediatrics, Hiroshima University Graduate School of Biomedical & Health Sciences, Hiroshima, Japan. 3. Department of Pediatrics, University of Washington and Seattle Children's Research Institute, Seattle, Wash. 4. Great North Children's Hospital, RVI, Newcastle upon Tyne, United Kingdom; Primary Immunodeficiency Group, ICM, Newcastle University, Newcastle upon Tyne, United Kingdom. 5. Federal Research and Clinical Center for Pediatric Hematology, Oncology, and Immunology, Moscow, Russia. 6. Canadian Center for Primary Immunodeficiency, Hospital for Sick Children, Toronto, Ontario, Canada. 7. Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, University of Utah, Salt Lake City, Utah. 8. Division of Hematology, Oncology, and Blood and Marrow Transplantation, Children's Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles, Calif. 9. Primary Immunodeficiency Group, ICM, Newcastle University, Newcastle upon Tyne, United Kingdom. 10. Regional Immunology Service, Royal Hospitals, Belfast, United Kingdom. 11. Department of Pediatrics, Royal Hospitals, Belfast, United Kingdom. 12. Center for Chronic Immunodeficiency, University Medical Center Freiburg and University of Freiburg, Freiburg, Germany. 13. Pediatric Blood and Marrow Transplantation Program, University Medical Center Utrecht, Utrecht, The Netherlands. 14. Department of Pediatrics, University of Washington and Seattle Children's Research Institute, Seattle, Wash; Blood and Bone Marrow Transplant Program, Johns Hopkins Medicine-All Children's Hospital, St Petersburg, Fla. 15. Division of Allergy and Immunology, University of Pennsylvania Perelman School of Medicine and the Children's Hospital of Philadelphia, Philadelphia, Pa. 16. Division of Oncology, Department of Pediatrics, University of Pennsylvania Perelman School of Medicine and the Children's Hospital of Philadelphia, Philadelphia, Pa. 17. Division of Pediatric Immunology, Department of Pediatrics, Uludag University Medical Faculty, Gorukle-Bursa, Turkey. 18. GATA Faculty, Bone Marrow Transplant Center, Ankara, Turkey. 19. Department of Immunology, Hospital de la Sant Creu i Sant Pau, Barcelona, Spain. 20. Allergy and Immunology, Hospital Rebagliati, Lima, Peru. 21. Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Graduate School of Medical and Dental Sciences, Tokyo, Japan. 22. Department of Pediatrics, Hokkaido University Graduate School of Medicine, Sapporo, Japan. 23. Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Graduate School of Medical and Dental Sciences, Tokyo, Japan. Electronic address: tmorio.ped@tmd.ac.jp. 24. Department of Pediatrics, University of Washington and Seattle Children's Research Institute, Seattle, Wash. Electronic address: troy.torgerson@seattlechildrens.org.
Abstract
BACKGROUND: Gain-of-function (GOF) mutations in signal transducer and activator of transcription 1 (STAT1) cause susceptibility to a range of infections, autoimmunity, immune dysregulation, and combined immunodeficiency. Disease manifestations can be mild or severe and life-threatening. Hematopoietic stem cell transplantation (HSCT) has been used in some patients with more severe symptoms to treat and cure the disorder. However, the outcome of HSCT for this disorder is not well established. OBJECTIVE: We sought to aggregate the worldwide experience of HSCT in patients with GOF-STAT1 mutations and to assess outcomes, including donor engraftment, overall survival, graft-versus-host disease, and transplant-related complications. METHODS: Data were collected from an international cohort of 15 patients with GOF-STAT1 mutations who had undergone HSCT using a variety of conditioning regimens and donor sources. Retrospective data collection allowed the outcome of transplantation to be assessed. In vitro functional testing was performed to confirm that each of the identified STAT1 variants was in fact a GOF mutation. RESULTS: Primary donor engraftment in this cohort of 15 patients with GOF-STAT1 mutations was 74%, and overall survival was only 40%. Secondary graft failure was common (50%), and posttransplantation event-free survival was poor (10% by 100 days). A subset of patients had hemophagocytic lymphohistiocytosis before transplant, contributing to their poor outcomes. CONCLUSION: Our data indicate that HSCT for patients with GOF-STAT1 mutations is curative but has significant risk of secondary graft failure and death.
BACKGROUND: Gain-of-function (GOF) mutations in signal transducer and activator of transcription 1 (STAT1) cause susceptibility to a range of infections, autoimmunity, immune dysregulation, and combined immunodeficiency. Disease manifestations can be mild or severe and life-threatening. Hematopoietic stem cell transplantation (HSCT) has been used in some patients with more severe symptoms to treat and cure the disorder. However, the outcome of HSCT for this disorder is not well established. OBJECTIVE: We sought to aggregate the worldwide experience of HSCT in patients with GOF-STAT1 mutations and to assess outcomes, including donor engraftment, overall survival, graft-versus-host disease, and transplant-related complications. METHODS: Data were collected from an international cohort of 15 patients with GOF-STAT1 mutations who had undergone HSCT using a variety of conditioning regimens and donor sources. Retrospective data collection allowed the outcome of transplantation to be assessed. In vitro functional testing was performed to confirm that each of the identified STAT1 variants was in fact a GOF mutation. RESULTS: Primary donor engraftment in this cohort of 15 patients with GOF-STAT1 mutations was 74%, and overall survival was only 40%. Secondary graft failure was common (50%), and posttransplantation event-free survival was poor (10% by 100 days). A subset of patients had hemophagocytic lymphohistiocytosis before transplant, contributing to their poor outcomes. CONCLUSION: Our data indicate that HSCT for patients with GOF-STAT1 mutations is curative but has significant risk of secondary graft failure and death.
Keywords:
Hematopoietic stem cell transplantation; Janus kinase; chronic mucocutaneous candidiasis; gain of function; graft rejection; graft-versus-host disease; hemophagocytic lymphohistiocytosis; signal transducer and activator of transcription
Authors: Stella P Hartono; Alexander Vargas-Hernández; Mark J Ponsford; Ivan K Chinn; Stephen Jolles; Keith Wilson; Lisa R Forbes Journal: J Clin Immunol Date: 2018-10-13 Impact factor: 8.317
Authors: Markéta Bloomfield; Veronika Kanderová; Zuzana Paračková; Petra Vrabcová; Michael Svatoň; Eva Froňková; Martina Fejtková; Radana Zachová; Michal Rataj; Irena Zentsová; Tomáš Milota; Adam Klocperk; Tomáš Kalina; Anna Šedivá Journal: J Clin Immunol Date: 2018-06-22 Impact factor: 8.317