Impact of JAK Inhibitors in Pediatric Patients with STAT1 Gain of Function (GOF) Mutations—10 Children and Review of the Literature

Introduction Since the frst description of gain of function (GOF) mutations in signal transducer and activator of transcrip tion (STAT) 1, more than 300 patients have been described with a broad clinical phenotype including infections and severe immune dysregulation. Whilst Jak inhibitors (JAKinibs)...

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Authors: Deyà-Martínez, Angela, Rivière, Jaques G., Roxo-Junior, Pérsio, Ramakers, Jan, Bloomfield, Markéta, Guisado Hernandez, Paloma, Olbrich, Peter
Format: article
Status:Published version
Publication Date:2022
Country:España
Institution:Universidad de Sevilla (US)
Repository:idUS. Depósito de Investigación de la Universidad de Sevilla
OAI Identifier:oai:idus.us.es:11441/139515
Online Access:https://hdl.handle.net/11441/139515
https://doi.org/10.1007/s10875-022-01257-x
Access Level:Open access
Keyword:Primary immunodefciency disease
Inborn errors of immunity
Pediatrics
Children
JAK-STAT pathway
Chronic mucocutaneous candidiasis
Ruxolitinib
Baricitinib
STAT1 GOF
JAK inhibitors
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spelling Impact of JAK Inhibitors in Pediatric Patients with STAT1 Gain of Function (GOF) Mutations—10 Children and Review of the LiteratureDeyà-Martínez, AngelaRivière, Jaques G.Roxo-Junior, PérsioRamakers, JanBloomfield, MarkétaGuisado Hernandez, PalomaOlbrich, PeterPrimary immunodefciency diseaseInborn errors of immunityPediatricsChildrenJAK-STAT pathwayChronic mucocutaneous candidiasisRuxolitinibBaricitinibSTAT1 GOFJAK inhibitorsIntroduction Since the frst description of gain of function (GOF) mutations in signal transducer and activator of transcrip tion (STAT) 1, more than 300 patients have been described with a broad clinical phenotype including infections and severe immune dysregulation. Whilst Jak inhibitors (JAKinibs) have demonstrated benefts in several reported cases, their indica tions, dosing, and monitoring remain to be established. Methods A retrospective, multicenter study recruiting pediatric patients with STAT1 GOF under JAKinib treatment was performed and, when applicable, compared with the available reports from the literature. Results Ten children (median age 8.5 years (3–18), receiving JAKinibs (ruxolitinib (n=9) and baricitinib (n=1)) with a median follow-up of 18 months (2–42) from 6 inborn errors of immunity (IEI) reference centers were included. Clinical profle and JAKinib indications in our series were similar to the previously published 14 pediatric patients. 9/10 (our cohort) and 14/14 patients (previous reports) showed partial or complete responses. The median immune defciency and dysregulation activity scores were 15.99 (5.2–40) pre and 7.55 (3–14.1) under therapy (p=0.0078). Infection, considered a likely adverse event of JAKinib therapy, was observed in 1/10 patients; JAKinibs were stopped in 3/10 children, due to hepatotoxicity, pre-HSCT, and absence of response. Conclusions Our study supports the potentially benefcial use of JAKinibs in patients with STAT1 GOF, in line with previ ously published data. However, consensus regarding their indications and timing, dosing, treatment duration, and monitor ing, as well as defning biomarkers to monitor clinical and immunological responses, remains to be determined, in form of international prospective multicenter studies using established IEI registries.SPRINGERFarmacología, Pediatría y RadiologíaConsejería de Salud, Junta de AndalucíaAgencia de Innovación y Desarrollo de AndalucíaInstituto de Salud Carlos IIIEuropean Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER)2022info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfhttps://hdl.handle.net/11441/139515https://doi.org/10.1007/s10875-022-01257-xreponame:idUS. Depósito de Investigación de la Universidad de Sevillainstname:Universidad de Sevilla (US)InglésJournal of Clinical Immunology, 422 (5), 1071-1082.SA0051/2020PI-0184–2018PI18/00223PI21/00211https://link.springer.com/article/10.1007/s10875-022-01257-xinfo:eu-repo/semantics/openAccessoai:idus.us.es:11441/1395152026-06-17T12:51:07Z
dc.title.none.fl_str_mv Impact of JAK Inhibitors in Pediatric Patients with STAT1 Gain of Function (GOF) Mutations—10 Children and Review of the Literature
title Impact of JAK Inhibitors in Pediatric Patients with STAT1 Gain of Function (GOF) Mutations—10 Children and Review of the Literature
spellingShingle Impact of JAK Inhibitors in Pediatric Patients with STAT1 Gain of Function (GOF) Mutations—10 Children and Review of the Literature
Deyà-Martínez, Angela
Primary immunodefciency disease
Inborn errors of immunity
Pediatrics
Children
JAK-STAT pathway
Chronic mucocutaneous candidiasis
Ruxolitinib
Baricitinib
STAT1 GOF
JAK inhibitors
title_short Impact of JAK Inhibitors in Pediatric Patients with STAT1 Gain of Function (GOF) Mutations—10 Children and Review of the Literature
title_full Impact of JAK Inhibitors in Pediatric Patients with STAT1 Gain of Function (GOF) Mutations—10 Children and Review of the Literature
title_fullStr Impact of JAK Inhibitors in Pediatric Patients with STAT1 Gain of Function (GOF) Mutations—10 Children and Review of the Literature
title_full_unstemmed Impact of JAK Inhibitors in Pediatric Patients with STAT1 Gain of Function (GOF) Mutations—10 Children and Review of the Literature
title_sort Impact of JAK Inhibitors in Pediatric Patients with STAT1 Gain of Function (GOF) Mutations—10 Children and Review of the Literature
dc.creator.none.fl_str_mv Deyà-Martínez, Angela
Rivière, Jaques G.
Roxo-Junior, Pérsio
Ramakers, Jan
Bloomfield, Markéta
Guisado Hernandez, Paloma
Olbrich, Peter
author Deyà-Martínez, Angela
author_facet Deyà-Martínez, Angela
Rivière, Jaques G.
Roxo-Junior, Pérsio
Ramakers, Jan
Bloomfield, Markéta
Guisado Hernandez, Paloma
Olbrich, Peter
author_role author
author2 Rivière, Jaques G.
Roxo-Junior, Pérsio
Ramakers, Jan
Bloomfield, Markéta
Guisado Hernandez, Paloma
Olbrich, Peter
author2_role author
author
author
author
author
author
dc.contributor.none.fl_str_mv Farmacología, Pediatría y Radiología
Consejería de Salud, Junta de Andalucía
Agencia de Innovación y Desarrollo de Andalucía
Instituto de Salud Carlos III
European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER)
dc.subject.none.fl_str_mv Primary immunodefciency disease
Inborn errors of immunity
Pediatrics
Children
JAK-STAT pathway
Chronic mucocutaneous candidiasis
Ruxolitinib
Baricitinib
STAT1 GOF
JAK inhibitors
topic Primary immunodefciency disease
Inborn errors of immunity
Pediatrics
Children
JAK-STAT pathway
Chronic mucocutaneous candidiasis
Ruxolitinib
Baricitinib
STAT1 GOF
JAK inhibitors
description Introduction Since the frst description of gain of function (GOF) mutations in signal transducer and activator of transcrip tion (STAT) 1, more than 300 patients have been described with a broad clinical phenotype including infections and severe immune dysregulation. Whilst Jak inhibitors (JAKinibs) have demonstrated benefts in several reported cases, their indica tions, dosing, and monitoring remain to be established. Methods A retrospective, multicenter study recruiting pediatric patients with STAT1 GOF under JAKinib treatment was performed and, when applicable, compared with the available reports from the literature. Results Ten children (median age 8.5 years (3–18), receiving JAKinibs (ruxolitinib (n=9) and baricitinib (n=1)) with a median follow-up of 18 months (2–42) from 6 inborn errors of immunity (IEI) reference centers were included. Clinical profle and JAKinib indications in our series were similar to the previously published 14 pediatric patients. 9/10 (our cohort) and 14/14 patients (previous reports) showed partial or complete responses. The median immune defciency and dysregulation activity scores were 15.99 (5.2–40) pre and 7.55 (3–14.1) under therapy (p=0.0078). Infection, considered a likely adverse event of JAKinib therapy, was observed in 1/10 patients; JAKinibs were stopped in 3/10 children, due to hepatotoxicity, pre-HSCT, and absence of response. Conclusions Our study supports the potentially benefcial use of JAKinibs in patients with STAT1 GOF, in line with previ ously published data. However, consensus regarding their indications and timing, dosing, treatment duration, and monitor ing, as well as defning biomarkers to monitor clinical and immunological responses, remains to be determined, in form of international prospective multicenter studies using established IEI registries.
publishDate 2022
dc.date.none.fl_str_mv 2022
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/11441/139515
https://doi.org/10.1007/s10875-022-01257-x
url https://hdl.handle.net/11441/139515
https://doi.org/10.1007/s10875-022-01257-x
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Journal of Clinical Immunology, 422 (5), 1071-1082.
SA0051/2020
PI-0184–2018
PI18/00223
PI21/00211
https://link.springer.com/article/10.1007/s10875-022-01257-x
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv SPRINGER
publisher.none.fl_str_mv SPRINGER
dc.source.none.fl_str_mv reponame:idUS. Depósito de Investigación de la Universidad de Sevilla
instname:Universidad de Sevilla (US)
instname_str Universidad de Sevilla (US)
reponame_str idUS. Depósito de Investigación de la Universidad de Sevilla
collection idUS. Depósito de Investigación de la Universidad de Sevilla
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,301603

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