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

• DOI: 10.1016/j.jaci.2023.10.018
• Publication Date: 2023-11-05T15:20:21Z
• Authors: Marco Fischer; Peter Olbrich; Jérôme Hadjadj; Volker Aumann; Shahrzad Bakhtiar; Vincent Barlogis; Philipp von Bismarck; Markéta Bloomfield; Claire Booth; Emmeline P. Buddingh; Deniz Cagdas; Martin Castelle; Alice Y. Chan; Shanmuganathan Ch...; Kritika Chetty; Pierre Cougoul; Etienne Crickx; Jasmeen Dara; Angela Deyà-Martínez; Susan Farmand; Renata Formankova; Andrew R. Gennery; Luis Ignacio Gonz...; David Hagin; Leif Gunnar Hanitsch; Jana Hanzlikovà; Fabian Hauck; José Ivorra-Cortés; Kai Kisand; Ayca Kiykim; Julia Körholz; Timothy Ronan Leahy; Joris van Montfrans; Zohreh Nademi; Brigitte Nelken; Suhag Parikh; Silvi Plado; Jan Ramakers; Antje Redlich; Frédéric Rieux-La...; Jacques G. Rivière; Yulia Rodina; Pérsio Roxo Júnior; Sarah Salou; Catharina Schuetz; Anna Shcherbina; Mary A. Slatter; Fabien Touzot; Ekrem Unal; Arjan C. Lankester; Siobhan Burns; Mikko R.J. Seppänen; Olaf Neth; Michael H. Albert; Stephan Ehl; Bénédicte Neven; Carsten Speckmann
• Keywords: ruxolitinib; gain of function; Immunology; autoimmunity; 610; chronic mucocutaneous candidiasis; primary immunodeficiency; General medicine, internal medicine and other clinical medicine; 3. Good health; JAK/STAT signaling; inborn error of immunity; JAK inhibitor; immune dysregulation; Immunology and Allergy; baricitinib

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.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.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.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.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.