TY - JOUR
T1 - Hematopoietic stem cell transplantation in patients with gain-of-function signal transducer and activator of transcription 1 mutations
AU - Leiding, Jennifer W.
AU - Okada, Satoshi
AU - Hagin, David
AU - Abinun, Mario
AU - Shcherbina, Anna
AU - Balashov, Dmitry N.
AU - Kim, Vy H.D.
AU - Ovadia, Adi
AU - Guthery, Stephen L.
AU - Pulsipher, Michael A.
AU - Lilic, Desa
AU - Devlin, Lisa A.
AU - Christie, Sharon
AU - Depner, Mark
AU - Fuchs, Sebastian
AU - van Royen-Kerkhof, Annet
AU - Lindemans, Caroline
AU - Petrovic, Aleksandra
AU - Sullivan, Kathleen E.
AU - Bunin, Nancy
AU - Kilic, Sara Sebnem
AU - Arpaci, Fikret
AU - Calle-Martin, Oscar de la
AU - Martinez-Martinez, Laura
AU - Aldave Becerra, Juan Carlos
AU - Kobayashi, Masao
AU - Ohkawa, Teppei
AU - Imai, Kohsuke
AU - Iguchi, Akihiro
AU - Roifman, Chaim M
AU - Gennery, Andrew R.
AU - Slatter, Mary
AU - Ochs, Hans D.
AU - Morio, Tomohiro
AU - Torgerson, Troy R
N1 - Funding Information:
Funding from the following grants contributed to this work: National Institutes of Health (NIH) grants R13 AI094943 and R01DK091374 and NIH grant U54 AI082973, Grants in Aid for Scientific Research from the Japan Society for the Promotion of Science (16H05355, 25713039, and 26293244), and the Practical Research Project for Rare/Intractable Diseases from the Japan Agency for Medical Research and Development (AMED). The authors were also provided support from the Jeffrey Modell Foundation.
Publisher Copyright:
© 2017
PY - 2017/4
Y1 - 2017/4
N2 - 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.
AB - 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.
KW - Chronic mucocutaneous candidiasis
KW - Gain of function
KW - Graft rejection
KW - Graft-versus-host disease
KW - Hematopoietic stem cell transplantation
KW - Hemophagocytic lymphohistiocytosis
KW - Janus kinase
KW - Signal transducer and activator of transcription
UR - http://www.scopus.com/inward/record.url?scp=85025832226&partnerID=8YFLogxK
U2 - 10.1016/j.jaci.2017.03.049
DO - 10.1016/j.jaci.2017.03.049
M3 - Article
AN - SCOPUS:85025832226
SN - 0091-6749
VL - 13
SP - 244
EP - 256
JO - Journal of Allergy and Clinical Immunology
JF - Journal of Allergy and Clinical Immunology
IS - 2
ER -