Longitudinal immunomics of VEXAS/MDS: a study on behalf of the EHA MDS-SWG

Full project title

Project lead

Dr Carmelo Gurnari (Junior faculty PI, Associate Professor)

University of Rome Tor Vergata, Italy

Project background and aims

VEXAS is a late-onset hemato-inflammatory syndrome caused by somatic mutations in the X-linked UBA1 gene, most commonly involving substitutions at the Met41 hotspot. The disease presents with overlapping rheumatologic and hematologic features, including myelodysplastic syndromes in up to 60% of cases, and is frequently refractory to standard therapies. Current treatment strategies either target the UBA1-mutant clone (e.g., azacitidine or allogeneic hematopoietic cell transplantation) or aim to control systemic inflammation, yet no established management exists and the clinical value of longitudinal UBA1 clonal burden monitoring remains poorly defined.

We recently validated a droplet digital PCR assay to quantify UBA1 Met41 variant allele frequencies in patients with VEXAS and observed highly heterogeneous clonal dynamics during treatment. Building on these findings, we propose under the purview of the EHA MDS-SWG an integrated immune–molecular framework combining longitudinal clonal burden assessment with high-dimensional immune profiling by mass cytometry. Coupling UBA1 ddPCR with single-cell immune signatures may enable identification of biomarkers of treatment response and support personalized therapeutic decision-making.

In addition, given the high response rates reported with azacitidine, we will investigate DNA methylation patterns in treated VEXAS patients by analyzing paired pre- and post-treatment samples from responders and non-responders. Integrating epigenetic data with clonal and immune profiling may reveal mechanisms underlying treatment response and resistance, improving understanding of VEXAS pathogenesis and refining precision treatment strategies.