DP096 | COMBINATION OF 5-AZACITIDINE AND RUXOLITINIB IN VEXAS SYNDROME: A RETROSPECTIVE STUDY

• Published in: Haematologica
• Main Authors: G.M. Bergonzi, E. Cozzo, A. Tomelleri, C. Piccolo, G. Scorpio, L. Vago, F. Ciceri, L. Dagna, C. Campochiaro, E. Diral
• Format: Article
• Language: English
• Published: Ferrata Storti Foundation 2025-09-01
• Online Access: https://haematologica.org/article/view/12563
• ISSN: 0390-6078; 1592-8721

Introduction: VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) syndrome is an autoinflammatory condition caused by somatic UBA1 mutations in hematopoietic progenitors, frequently associated with cytopenias and myelodysplastic syndromes (MDS) in ~50% of cases. No standardized therapy exists, and most patients are steroid-dependent. Allogeneic stem cell transplant is the only curative option, though limited to selected cases. The aim of our study is to assess safety and effectiveness of the combination therapy with ruxolitinib (Ruxo) and 5-azacitidine (Aza) in patients with VEXAS and MDS. Methods: This retrospective study included patients with genetically diagnosed VEXAS syndrome and concomitant MDS treated with Ruxo and Aza. Data collected included disease and clinical features, C-Reactive Protein (CRP) levels and Variant Allele Fraction (VAF) of UBA1 mutations by ddPCR, at several timepoints, including diagnosis and during treatment. Results: 8 male patients (median age at diagnosis 68.5 years, IQR 62–70) with VEXAS syndrome and concomitant MDS were enrolled. MDS was classified as lower-risk in six cases and higher-risk in two, according to IPSS-R/IPSS-M. Median Ruxo dose was 22,5 mg/day (IQR 17,5-40). Aza was added after a median of 4,5 months (IQR 3-14) since Ruxo initiation. The combination led to sustained normalization of CRP levels and allowed prednisone tapering from a median dose of 15 to 6.25 mg/day, after a median of 5,5 (IQR 5-8,5) azacitidine cycles (Figure 1A). Hemoglobin and platelet count, despite an initial reduction with Ruxo monotherapy, significantly improved after the addition of Aza (Figure 1C and 1D). Regarding safety, no patient discontinued treatments due to infections or thrombosis; 2 patients discontinued Aza due to intolerance. No patient died during the median follow-up of 39 months (IQR 27-45). Regarding the dynamic of the UBA1 mutant clone using ddPCR in 5 patients: all showed a reduction in clone size, and 3 achieved a complete molecular response (undetectable VAF of UBA1 mutations) after a median of 5 Aza cycles (IQR 3,5-10) (Figure 1E). Conclusions: Despite the small cohort, the Aza–Ruxo combination showed promising effectiveness and safety, with good inflammatory control, hematologic improvement, and no increase in morbidity or mortality. A reduction in UBA1 clone size was observed in ~50% of patients, suggesting potential long-term benefit. Prospective studies are warranted to validate these findings.