Article title: Efficacy and safety of azacitidine for VEXAS syndrome: a large-scale retrospective study from FRENVEX
First author: Vincent Jachiet
Journal: Blood
Link to the article: https://pubmed.ncbi.nlm.nih.gov/40373272/
Author of the abstract: Philippe Mertz
Three key points to remember:
Azacitidine is an effective treatment option for VEXAS syndrome even without associated myelodysplasia, with simultaneous effects on inflammation, cytopenias, and the UBA1 clone.
The response is often delayed and requires prolonged exposure (≥6 cycles) before evaluation. Adverse effects, particularly infectious ones, occur mainly in the first 3 cycles of treatment. Discontinuation of AZA leads to relapse in the majority of cases, suggesting a suspensive rather than curative effect.
Molecular monitoring (UBA1 VAF) allows for objective assessment of clonal response and could become a biomarker for monitoring this disease.
VEXAS syndrome is an acquired monogenic autoinflammatory disease associated with somatic mutations in the UBA1 gene. Patients present with a wide spectrum of severe inflammatory manifestations and cytopenias, which may be associated with myelodysplastic syndrome (MDS). Treatment is mainly based on corticosteroids, with frequent corticosteroid dependence despite associated sparing therapy with targeted therapies (anti-IL-6, anti-JAK, etc.) that have inconsistent efficacy. Azacitidine (AZA), a hypomethylating agent used in MDS, has shown potential in VEXAS, but published data remain limited.
This is a retrospective multicenter study conducted in France by the FRENVEX group, including 88 patients with genetically confirmed VEXAS who received at least one cycle of AZA between 2009 and 2024.
In this study, inflammatory response was defined as both clinical and biological improvement in systemic manifestations, including reduction in inflammatory symptoms and sustained decrease in biological markers such as CRP. The hematologic response followed the 2018 International Working Group criteria for MDS and corresponded to a significant improvement in cytopenias, including an increase in hemoglobin, platelets, or neutrophils, or a reduction in transfusion requirements. Finally, the molecular response was established on the basis of at least a 25% reduction in the mutational burden (VAF) of the UBA1 variant, assessed by targeted sequencing during treatment. Treatment side effects were described according to the Common Terminology Criteria for Adverse Events (version 5.0).
Inflammatory, hematological, and molecular responses were evaluated, as well as tolerance, regardless of the presence of associated MDS (present in 80%).
The main results of this study show:
A partial or complete inflammatory response observed in 61% of patients (41% at 6 months, 54% at 12 months). The median response time was sometimes delayed (>6 cycles).
A hematological response with improvement in hemoglobin in 65% and platelet count in 77%, with clinical benefit in terms of cytopenias and transfusion requirements.
A molecular response with at least a 25% reduction in UBA1 mutation burden was observed in 65% of patients, correlating with the clinical response.
Severe adverse events (grade III and IV) occurred in 60% of patients, mainly infections (34%) and cytopenias (36%), occurring predominantly in the first 3 cycles.
75% of patients relapse after stopping AZA (median duration of treatment-free period of 3.1 years), but resumption of treatment is effective in 80% of cases.
This study supports the use of AZA as first-line treatment in patients with VEXAS syndrome and severe cytopenias, or as second-line treatment in cases of failure of anti-inflammatory biotherapies, even in the absence of associated MDS. Treatment-related adverse effects, particularly infections, appear to occur mainly during the first 3 cycles of treatment. Prospective studies are needed to confirm its positioning and optimize the therapeutic strategy.
