Hematopoietic stem cell transplantation in patients with gain-of-function signal transducer and activator of transcription 1 mutations
Jennifer W Leiding, Satoshi Okada, David Hagin, Mario Abinun, Anna Shcherbina, Dmitry N Balashov, Vy H D Kim, Adi Ovadia, Stephen L Guthery, Michael Pulsipher, Desa Lilic, Lisa A Devlin, Sharon Christie, Mark Depner, Sebastian Fuchs, Annet van Royen-Kerkhof, Caroline Lindemans, Aleksandra Petrovic, Kathleen E Sullivan, Nancy Bunin, Sara Sebnem Kilic, Fikret Arpaci, Oscar de la Calle-Martin, Laura Martinez-Martinez, Juan Carlos Aldave, Masao Kobayashi, Teppei Ohkawa, Kohsuke Imai, Akihiro Iguchi, Chaim M Roifman, Andrew R Gennery, Mary Slatter, Hans D Ochs, Tomohiro Morio, Troy R Torgerson, Inborn Errors Working Party of the European Society for Blood and Marrow Transplantation and the Primary Immune Deficiency Treatment Consortium, Jennifer W Leiding, Satoshi Okada, David Hagin, Mario Abinun, Anna Shcherbina, Dmitry N Balashov, Vy H D Kim, Adi Ovadia, Stephen L Guthery, Michael Pulsipher, Desa Lilic, Lisa A Devlin, Sharon Christie, Mark Depner, Sebastian Fuchs, Annet van Royen-Kerkhof, Caroline Lindemans, Aleksandra Petrovic, Kathleen E Sullivan, Nancy Bunin, Sara Sebnem Kilic, Fikret Arpaci, Oscar de la Calle-Martin, Laura Martinez-Martinez, Juan Carlos Aldave, Masao Kobayashi, Teppei Ohkawa, Kohsuke Imai, Akihiro Iguchi, Chaim M Roifman, Andrew R Gennery, Mary Slatter, Hans D Ochs, Tomohiro Morio, Troy R Torgerson, Inborn Errors Working Party of the European Society for Blood and Marrow Transplantation and the Primary Immune Deficiency Treatment Consortium
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.
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.
Conflict of interest statement
Disclosure of potential conflict of interest: S. Okada has received grants from the Japan Agency for Medical Research and development, AMED, and the Japan Society for the Promotion of Science (16H05355 and 25713039). S. L. Guthery has received grants from the National Institute of Diabetes and Digestive and Kidney Diseases and Regeneron Pharmaceuticals. C. Lindemans has consultant arrangements with Chimerix and has a US patent for IL-22 and F-652 as ISC growth factors (US 61/901,151). K. E. Sullivan has consultant arrangements with Immune Deficiency Foundation, ADMA Pharmaceuticals, and UpToDate; has received grants from Baxter; has received payment for lectures from the American Academy of Allergy, Asthma & Immunology; and has received royalties from Elsevier. K. Imai has consultant arrangements with CSL Behring K.K., has received grants from CSL Behring K.K. and Sony, and has received payment for lectures from CSL Behring K.K. H.D. Ochs has consultant arrangements with Grifols Pharma and has received a grant from the Jeffrey Modell Foundation. T.R. Torgerson has consultant arrangements with Baxalta Biosciences, CSL Behring, and ADMA Biosciences; has received grants from Baxalta Biosciences, CSL Behring, and the National Institutes of Health; and has received payment for lectures from Baxalta Biosciences, CSL Behring, Questcor Pharmaceuticals, and the Robert Wood Johnson Foundation. The rest of the authors declare that they have no relevant conflicts of interest.
Copyright © 2017. Published by Elsevier Inc.
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Source: PubMed