Efficacy and safety of azacitidine for VEXAS syndrome: a large-scale retrospective study from FRENVEX

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.

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Journal
Blood
Published
2025-05-15
DOI
https://doi.org/10.1182/blood.2024028133
Citations
18
Primary Topic
Otitis Media and Relapsing Polychondritis
Type
article
Field-Weighted Citation Impact
30.03
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article

Efficacy and safety of azacitidine for VEXAS syndrome: a large-scale retrospective study from FRENVEX

Jean‐Baptiste Rieu, Maël Heiblig, Sophie Georgin‐Lavialle, Romain Vazquez et al.
18 citations
Blood
Otitis Media and Relapsing Polychondritis
30.03
article

Efficacy and safety of azacitidine for VEXAS syndrome: a large-scale retrospective study from FRENVEX

Jean‐Baptiste Rieu, Maël Heiblig, Sophie Georgin‐Lavialle, Romain Vazquez, Julien Rossignol, R. Outh, Sylvain Thépot, Yannick Le Bris, Pierre Fenaux, F. Dutasta, Sophie Dimicoli‐Salazar, Olivier Kosmider, Maxime Samson, Benoit Faucher, Jérôme Hadjadj, Audrey Bidet, Matthieu Décamp, Anne‐Sophie Alary, Jérémie Dion, Guilaine Boursier, Lucie Rigolot, Alice Garnier, Stéphanie Dulucq, Lise Larcher, Maxime Beydon, Alice Marceau‐Renaut, Valentin Lacombe, Nathalie Boiret‐Dupré, Benjamin Lebecque, Pauline Blateau, Vincent Grobost, Thibault Comont, H. Bézanahary, Vincent Jachiet, Lin‐Pierre Zhao, Estibaliz Lazaro, Cédric Pastoret, Pierre Sujobert, G. Le Guenno, A. Mékinian, Lara Boucher, Véronique Morel, Benjamin Terrier, Anne Bouvier, David Rizzo, Olivier Fain, Pierre Hirsch, Pierre Lemaire, Yann Nguyen, Franck Geneviève, Achille Aouba, Jean Benoît Arlet, Antoine Néel, Cassandra Jadeau
article en
18 citations

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.

BloodVol. 146(12)
Hôpital Necker-Enfants Malades (FR), Université de Bordeaux (FR), Inserm (FR), Centre de Recherche en Mathématiques de la Décision (FR), Université Fédérale de Toulouse Midi-Pyrénées (FR), Université Clermont Auvergne (FR), Université Paris Cité (FR), Institut National Polytechnique de Toulouse (FR), Université de Lille (FR), Hôpital Beaujon (FR), Centre Hospitalier Universitaire de Bordeaux (FR), Centre Hospitalier Universitaire de Lille (FR), Centre Hospitalier Universitaire de Nantes (FR), Centre Hospitalier Universitaire de Toulouse (FR), Sorbonne Université (FR), Hewlett-Packard (France) (FR), Assistance Publique Hôpitaux de Marseille (FR), Centre Hospitalier de Perpignan (FR), Hôpital Cochin (FR), Centre Hospitalier Universitaire de Montpellier (FR), Assistance Publique – Hôpitaux de Paris (FR), Institut universitaire du cancer de Toulouse Oncopole (FR), Centre de Référence des Maladies Autoinflammatoires et des Amyloses (FR), Hospices Civils de Lyon (FR), Hôpital Européen Georges-Pompidou (FR), Hôpital Saint-Antoine (FR), Bordeaux Population Health (FR), Hôpital Européen (FR), Centre Hospitalier Universitaire d'Angers (FR), Hôpital Lyon Sud (FR), Centre Hospitalier Universitaire de Caen Normandie (FR), Institut de Génétique Moléculaire de Montpellier (FR), CHU Dijon Bourgogne (FR), Centre Hospitalier Universitaire de Limoges (FR), Hôpital Cardiologique du Haut-Lévêque (FR), Pitié-Salpêtrière Hospital (FR), Centre Hospitalier Universitaire de Clermont-Ferrand (FR), Institut Pierre Louis d‘Épidémiologie et de Santé Publique (FR), Hôpital d'Instruction des Armées Sainte-Anne (FR), Centre Hospitalier d'Albi (FR), Hôpital Universitaire Dupuytren (FR), Institut Universitaire de Recherche Clinique (FR), Hôpital Saint-Louis (FR), Institut Paoli-Calmettes (FR), Centre Hospitalier Universitaire de Rennes (FR), Hôpital Dupuytren (FR), Hôpital de la Timone (FR), Hôpital Tenon (FR), Université d'Angers (FR), Nantes Université (FR), Université de Caen Normandie (FR)
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