Hematopoietic stem cell transplantation in patients with Gain of Function STAT1 Mutation

Publication date: Available online 7 June 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): 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
BackgroundGain of function mutations in signal transducer and activator of transcription 1 (GOF-STAT1) cause a 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 utilized in some patients with more severe symptoms to treat and cure the disorder. The outcome of HSCT for this disorder is, however, not well established.ObjectiveTo aggregate the worldwide experience of HSCT in GOF-STAT1 patients and to assess outcomes including donor engraftment, overall survival, graft versus host disease, and transplant related complications.MethodsData were collected from an international cohort of 15 GOF-STAT1 patients that 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 gain of function mutation.ResultsPrimary donor engraftment in this cohort of 15 GOF-STAT1 patients was 74% and overall survival was only 40%. Secondary graft failure was common (50%) and post-transplant event free survival was poor (10% by 100 days). A subset of patients developed hemophagocytic lymphohistiocytosis (HLH) prior to their transplant, contributing to their poor outcomes.ConclusionOur data indicate that HSCT for patients with GOF-STAT1 mutations is curative but has significant risk of secondary graft failure and death.

Teaser

Hematopoietic stem cell transplantation (HSCT) in GOF-STAT1 patients can be curative. HSCT in this cohort is however associated with a relatively high rate of graft failure and other complications that lead to decreased overall survival.


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