Efficacy and safety of azacitidine for VEXAS syndrome: a large-scale retrospective study from FRENVEX
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.
Article Details
Authors (54)
Vincent Jachiet
8Département Médico-Universitaire, Médecine interne, Centre de Référence des Maladies Auto-inflammatoires et des Amyloses Inflammatoire, Sorbonne Université, Hôpital Saint Antoine, Paris, France
Olivier Kosmider
11Centre National de la Recherche Scientifique UMR8104, INSERM U1016, Institut Cochin, Université de Paris Cité, Paris, France
Maxime Beydon
3Institut Pierre Louis d'Epidémiologie et de Santé Publique, Equipe Pharmacoépidémiologie et Évaluation des Soins, Hôpital Pitié-Salpétrière, Assistance Publique-Hôpitaux de Paris, Sorbonne Université, Paris, France
Jérome Hadjadj
Lin-Pierre Zhao
Vincent Grobost
Valentin Lacombe
Guillaume Le Guenno
6Médecine Interne, CHU Estaing, Clermont-Ferrand, France, Clermont-Ferrand, France
Yann Nguyen
7Service de Médecine Interne, Hôpital Beaujon, Assistance Publique-Hôpitaux de Paris, Université Paris Cité, Clichy, France
Jean-Benoit Arlet
1Université Paris Cité, Inserm U1163, Institut Imagine, Laboratoire « Mécanismes cellulaires et moléculaires des désordres hématologiques et implications thérapeutiques », F-75015, Paris, France
Jeremie Dion
1The Cancer University of Toulouse Oncopole, University Hospital Center of Toulouse, Internal Medicine and Immunopathology Department, Toulouse, France
Maël Heiblig
9Department of Hematology, Centre Hospitalier Universitaire de Lyon, Lyon, France
Alice Garnier
3University Hospital of Nantes, Department for Clinical Hematology, Nantes, France
Maxime Samson
Achille Aouba
Sylvain Thépot
10CHU de Angers, Angers, France
Sophie Dimicoli-Salazar
6University Hospital of Bordeaux, Hématology, Bordeaux, France
Fabien Dutasta
16Service de Médecine Interne, HIA Sainte-Anne, Toulon, France
Benoit Faucher
30Department of Internal Medicine, La Timone Hospital, Assistance Publique-Hôpitaux de Marseille, Marseille, France
Estibaliz Lazaro
Véronique Morel
19Service d'Hématologie Clinique, Hôpital Pitié Salpétrière, Assistance Publique-Hôpitaux de Paris, Sorbonne Université, Paris, France
Antoine Neel
Roderau Outh
Holy Bezanahary
Julien Rossignol
Anne-Sophie Alary
3Aix-Marseille Univ, Inserm, CNRS, Institut Paoli-Calmettes, CRCM, Marseille, France
Audrey Bidet
21Laboratory of Hematology, Bordeaux University Hospital, Bordeaux, France
Pauline Blateau
26Unité de Génétique Chromosomique, Service de Génétique Moléculaire et Cytogénomique, Centre Hospitalier Universitaire de Montpellier, Université de Montpellier, Montpellier, France
Anne Bouvier
1Angers University Hospital, Angers, France
Guilaine Boursier
28Unité des Maladies Autoinflammatoires, Service de Génétique Moléculaire et Cytogénomique, Centre de Référence des Maladies Auto-Inflammatoires et des Amyloses, Centre Hospitalier Universitaire de Montpellier, Université de Montpellier, Montpellier, France
Matthieu Decamp
5Department of Cytogenetic, University Hospital of Caen, Caen, France
Benjamin Lebecque
30Service d’Hématologie Biologique, Centre Hospitalier Universitaire de Estaing, Clermont-Ferrand, France
Yannick Le Bris
Centre de Recherche en Cancérologie et Immunologie Intégrée Nantes Angers, INSERM, Centre National de la Recherche Scientifique, Université d’Angers, Université de Nantes, Nantes, France
Pierre Sujobert
Alice Marceau-Renaut
1CHU LILLE, Department of Hematolgy, LILLE, France
Cédric Pastoret
10Laboratoire d’Hématologie, Centre Hospitalier Universitaire de Rennes, Rennes, France
David Rizzo
35Laboratoire d’Hématologie, Centre Hospitalier Universitaire de Dupuytren, Limoges, France
Nathalie Boiret-Dupré
30Service d’Hématologie Biologique, Centre Hospitalier Universitaire de Estaing, Clermont-Ferrand, France
Lara Boucher
2Service d'Hématologie Biologique, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, Paris, France
Stéphanie Dulucq
2Fi LMC, Lyon, France
Franck Genevieve
27Centre Hospitalier Universitaire d'Angers, Laboratoire d'Hématologie, Angers, France
Cassandra Jadeau
35Laboratoire d’Hématologie, Centre Hospitalier Universitaire de Dupuytren, Limoges, France
Pierre Lemaire
36Laboratoire d’Hématologie, Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris, Paris, France
Romain Vazquez
2Service d'Hématologie Biologique, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, Paris, France
Jean-Baptiste Rieu
37Laboratoire d'Hématologie, Institut Universitaire du Cancer de Toulouse Oncopole, Centre Hospitalier Universitaire de Toulouse, Université de Toulouse, Toulouse, France
Olivier Fain
Sophie Georgin-Lavialle
9Internal Medicine Department, Sorbonne University, Assistance Publique–Hôpitaux de Paris, Tenon Hospital, Paris, France
Lucie Rigolot
26Laboratory of Hematology, Centre Hospitalier Universitaire de Toulouse, Toulouse, France
Lise Larcher
7Institut de Recherche Saint-Louis, Université Paris Cité, Paris, France
Pierre Hirsch
Benjamin Terrier
1INSERM U970, Paris Centre de Recherche Cardiovasculaire, Université Paris Cité, Paris, France
Pierre Fenaux
Arsène Mekinian
Thibault Comont