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

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

  • Marco Fischer - , University of Zurich (Author)
  • Peter Olbrich - , Hospital Universitario Virgen del Rocio (Author)
  • Jérôme Hadjadj - , Sorbonne Université (Author)
  • Volker Aumann - , University Hospital Magdeburg (Author)
  • Shahrzad Bakhtiar - , University Hospital Frankfurt (Author)
  • Vincent Barlogis - , Assistance publique - Hôpitaux de Marseille (Author)
  • Philipp von Bismarck - , University Hospital Schleswig-Holstein Campus Kiel (Author)
  • Md PhD Markéta Bloomfield - , University Hospital Motol (Author)
  • Claire Booth - , Great Ormond Street Hospital for Children NHS Trust (Author)
  • Emmeline P Buddingh - , Leiden University (Author)
  • Deniz Cagdas - , Hacettepe University Medical School (Author)
  • Martin Castelle - , Necker Children's Hospital (Author)
  • Alice Y Chan - , University of California at Irvine (Author)
  • Shanmuganathan Chandrakasan - , Emory University (Author)
  • Kritika Chetty - , Great Ormond Street Hospital for Children NHS Trust (Author)
  • Pierre Cougoul - , Oncopole (Author)
  • Etienne Crickx - , Hôpital Henri Mondor (Author)
  • Jasmeen Dara - , University of California at Irvine (Author)
  • Angela Deyà-Martínez - , Hospital Sant Joan de Déu Barcelona (Author)
  • Susan Farmand - , University Hospital Hamburg Eppendorf (Author)
  • Renata Formankova - , Charles University Prague (Author)
  • Andrew R Gennery - , Great North Children's Hospital (Author)
  • Luis Ignacio Gonzalez-Granado - , Complutense University (Author)
  • David Hagin - , Tel Aviv Sourasky Medical Center (Author)
  • Leif Gunnar Hanitsch - , Charité – Universitätsmedizin Berlin (Author)
  • Jana Hanzlikovà - , Faculty of Medicine and Faculty Hospital in Pilsen (Author)
  • Fabian Hauck - , University Hospital Münster (Author)
  • José Ivorra-Cortés - , Hospital Universitario La Fe (Author)
  • Kai Kisand - , University of Tartu (Author)
  • Ayca Kiykim - , Istanbul University Cerrahpaşa (Author)
  • Julia Körholz - , Department of Paediatrics (Author)
  • Timothy Ronan Leahy - , Trinity College Dublin (Author)
  • Joris van Montfrans - , Utrecht University (Author)
  • Zohreh Nademi - , Great North Children's Hospital (Author)
  • Brigitte Nelken - , University Hospital of Lille (Author)
  • M D Suhag Parikh - , Emory University (Author)
  • Silvi Plado - , Tallinn Children's Hospital (Author)
  • Jan Ramakers - , Balearic Island Health Research Institute (Author)
  • Antje Redlich - , University Hospital Magdeburg (Author)
  • Frédéric Rieux-Laucat - , Imagine Institute (Author)
  • Jacques G Rivière - , Vall d'Hebron University Hospital (Author)
  • Yulia Rodina - , Dmitry Rogachev National Medical Research Center of Pediatric Hematology (Author)
  • Pérsio Roxo Júnior - , Federal University of São Paulo (Author)
  • Sarah Salou - , Biruni Universitesi (Author)
  • Catharina Schuetz - , Department of Paediatrics (Author)
  • Anna Shcherbina - , Dmitry Rogachev National Medical Research Center of Pediatric Hematology (Author)
  • Mary A Slatter - , Great North Children's Hospital (Author)
  • Fabien Touzot - , Innsbruck Medical University (Author)
  • Ekrem Unal - , Erciyes University (Author)
  • Arjan C Lankester - , Leiden University (Author)
  • T. Siobhan Burns - , University College London (Author)
  • Mikko R J Seppänen - , University Hospital Münster (Author)
  • Olaf Neth - , Hospital Universitario Virgen del Rocio (Author)
  • Michael H Albert - , University Hospital Münster (Author)
  • Stephan Ehl - , Biruni Universitesi (Author)
  • Bénédicte Neven - , Necker Children's Hospital (Author)
  • Carsten Speckmann - , Biruni Universitesi (Author)

Abstract

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 (AE) are limited.

OBJECTIVE: We evaluated the current off-label JAKi treatment experience for JAK/STAT IEI among ESID/EBMT-IEWP centers.

METHODS: 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-GOF, 21 STAT3-GOF, 1 STAT5B-GOF, 1 SOCS1-LOF, 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 very heterogeneous dosing and monitoring regimens. The response rate and time to response varied across different diseases and manifestations. AE (i.e. infections and weight gain) were frequent (38% of patients), but mild (grade I-II) and transient in most patients. At last follow-up, 52/69 (74%) of patients are still receiving JAKi treatment, while 11 patients eventually underwent HSCT following previous JAKi bridging therapy with a 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.

Details

Original languageEnglish
Pages (from-to)275-286.e18
JournalJournal of Allergy and Clinical Immunology
Volume153
Issue number1
Publication statusE-pub ahead of print - 5 Nov 2023
Peer-reviewedYes

External IDs

ORCID /0009-0003-6519-0482/work/147674512
ORCID /0000-0001-6313-4434/work/147674966
Scopus 85178371751

Keywords