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Article

PubMed

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JAK inhibitor treatment for inborn errors of JAK/STAT signaling: An ESID/EBMT-IEWP retrospective study

The Journal of allergy and clinical immunology. 2024 Jan ; 153 (1) : 275-286.e18. [epub] 20231105

J Allergy Clin Immunol
ISSN 1097-6825 | 0091-6749
Source

Language English Country United States Media print-electronic

Document type Multicenter Study, Journal Article, Research Support, Non-U.S. Gov't

Persistent link https://www.medvik.cz/link/pmid37935260

PubMed 37935260
DOI 10.1016/j.jaci.2023.10.018
PII: S0091-6749(23)01390-8
Knihovny.cz E-resources

Keywords
JAK inhibitor, JAK/STAT signaling, autoimmunity, baricitinib, chronic mucocutaneous candidiasis, gain of function, immune dysregulation, inborn error of immunity, primary immunodeficiency, ruxolitinib,
MeSH
Child MeSH
Janus Kinase Inhibitors * therapeutic use MeSH
Humans MeSH
Prospective Studies MeSH
Retrospective Studies MeSH
Immunologic Deficiency Syndromes * therapy MeSH
Treatment Outcome MeSH
Check Tag
Child MeSH
Humans MeSH
Publication type
Journal Article MeSH
Multicenter Study MeSH
Research Support, Non-U.S. Gov't MeSH
Names of Substances
Janus Kinase Inhibitors * MeSH

BACKGROUND: Inborn errors of immunity (IEI) with dysregulated JAK/STAT signaling present with variable manifestations of immune dysregulation and infections. Hematopoietic stem cell transplantation (HSCT) is potentially curative, but initially reported outcomes were poor. JAK inhibitors (JAKi) offer a targeted treatment option that may be an alternative or bridge to HSCT. However, data on their current use, treatment efficacy and adverse events are limited. OBJECTIVE: We evaluated the current off-label JAKi treatment experience for JAK/STAT inborn errors of immunity (IEI) among European Society for Immunodeficiencies (ESID)/European Society for Blood and Marrow Transplantation (EBMT) Inborn Errors Working Party (IEWP) centers. METHODS: We conducted a multicenter retrospective study on patients with a genetic disorder of hyperactive JAK/STAT signaling who received JAKi treatment for at least 3 months. RESULTS: Sixty-nine patients (72% children) were evaluated (45 STAT1 gain of function [GOF], 21 STAT3-GOF, 1 STAT5B-GOF, 1 suppressor of cytokine signaling 1 [aka SOCS1] loss of function, 1 JAK1-GOF). Ruxolitinib was the predominantly prescribed JAKi (80%). Overall, treatment resulted in improvement (partial or complete remission) of clinical symptoms in 87% of STAT1-GOF and in 90% of STAT3-GOF patients. We documented highly heterogeneous dosing and monitoring regimens. The response rate and time to response varied across different diseases and manifestations. Adverse events including infection and weight gain were frequent (38% of patients) but were mild (grade I-II) and transient in most patients. At last follow-up, 52 (74%) of 69 patients were still receiving JAKi treatment, and 11 patients eventually underwent HSCT after receipt of previous JAKi bridging therapy, with 91% overall survival. CONCLUSIONS: Our study suggests that JAKi may be highly effective to treat symptomatic JAK/STAT IEI patients. Prospective studies to define optimal JAKi dosing for the variable clinical presentations and age ranges should be pursued.

Aflac Cancer and Blood Disorder Center Department of Pediatrics Children's Healthcare of Atlanta Emory University School of Medicine Atlanta Ga

Allergy and Clinical Immunology Unit Tel Aviv Sourasky Medical Center Tel Aviv Israel

Children's Health Ireland Crumlin Dublin Ireland; University of Dublin Trinity College Dublin Ireland

Children's Hematopoietic Stem Cell Transplant Unit Great North Children's Hospital Newcastle upon Tyne England United Kingdom

Clinic for General Pediatrics University Hospital Schleswig Holstein Kiel Germany

Clinical Immunology and Primary Immunodeficiencies Unit Pediatric Allergy and Clinical Immunology Department Hospital Sant Joan de Déu Barcelona Spain; Universitat de Barcelona Institut de Recerca Sant Joan de Déu Barcelona Spain

Department of Immunology 2nd Faculty of Medicine Charles University Prague and University Hospital in Motol 1st Faculty of Medicine Charles University Prague Prague Czech Republic

Department of Immunology and Allergology Faculty of Medicine and Faculty Hospital Pilsen Czech Republic

Department of Paediatric Haematology and Oncology Motol University Hospital and 2nd Faculty of Medicine Charles University Prague Czech Republic

Department of Paediatric Immunology and Gene Therapy Great Ormond Street Hospital London London England United Kingdom

Department of Pediatric Hematology and Oncology Faculty of Medicine Erciyes University Kayseri Turkey

Department of Pediatric Immunology and Infectious Diseases Wilhelmina's Children Hospital University Medical Center Utrecht Utrecht University Utrecht The Netherlands