Efficacy and safety of azacitidine for VEXAS syndrome: a large-scale retrospective study from FRENVEX
Vincent Jachiet, Olivier Kosmider, Maxime Beydon, Jérôme Hadjadj, Lin‐Pierre Zhao, Vincent Grobost, Valentin Lacombe, G. Le Guenno, Yann Nguyen, Jean Benoît Arlet, Jérémie Dion, Maël Heiblig, Alice Garnier, Maxime Samson, Achille Aouba, Sylvain Thépot, Sophie Dimicoli‐Salazar, F. Dutasta, Benoit Faucher, Estibaliz Lazaro, Véronique Morel, A. Néel, R. Outh, H. Bézanahary, Julien Rossignol, Anne‐Sophie Alary, Audrey Bidet, Pauline Blateau, Anne Bouvier, Guilaine Boursier, Matthieu Décamp, Benjamin Lebecque, Yannick Le Bris, Pierre Sujobert, Alice Marceau‐Renaut, Cédric Pastoret, David Rizzo, Nathalie Boiret‐Dupré, Lara Boucher, Stéphanie Dulucq, Franck Geneviève, Cassandra Jadeau, Pierre Lemaire, Romain Vazquez, Jean‐Baptiste Rieu, Olivier Fain, Sophie Georgin‐Lavialle, Lucie Rigolot, Lise Larcher, Pierre Hirsch, Benjamin Terrier, Pierre Fenaux, A. Mékinian, Thibault Comont
Abstract
ABSTRACT: VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is a severe monogenic disorder caused by somatic mutations in ubiquitin-like modifier activating enzyme 1 (UBA1), characterized by inflammation, cytopenias, and frequent association with myelodysplastic neoplasms (MDS). Steroid dependence is common, and targeted therapies have demonstrated limited efficacy. Azacitidine (AZA), a hypomethylating agent used in MDS, has shown potential in VEXAS syndrome but data remain limited. This multicenter retrospective study assessed AZA efficacy and safety in 88 patients with genetically confirmed VEXAS syndrome from FRENVEX (French VEXAS study group), 80% meeting World Health Organization 2022 MDS criteria. Inflammatory response rates were 41% at 6 months and 54% at 12 months, regardless of MDS status. A total of 50 (61%) patients achieved inflammatory response, with 70% occurring at 6 months, suggesting a delayed median response. Among responders, relapse-free survival on AZA was 90% at 1 year and 85% at 5 years. Of the 12 responders who discontinued AZA, 9 relapsed after a median of 3.1 years (range, 0.4-5.6), with effective reexposure in 4 of 5 patients. Hematological responses included red blood cell transfusion independence in 65% and platelet improvement in 77% of patients. Molecular response, defined as a ≥25% reduction in UBA1 variant allele frequency (VAF), was observed in 65% of patients, all of whom achieved inflammatory and hematological responses; and VAF dropped to <2% in 43% of cases. Infections (34%) and cytopenias (36%) were common, particularly during the first 3 cycles. This study establishes AZA as an effective therapy for VEXAS syndrome, improving inflammation, cytopenias, and UBA1 clonal burden, warranting larger prospective trials.