Therapeutic Outcomes in VEXAS Syndrome: A Multicenter Comparative Cohort of Allogeneic Hematopoietic Stem Cell Transplantation and Hypomethylating Agents

First author: Saubia Fathima

Journal: American Journal of Hematology, 2026

Link to the article: https://pubmed.ncbi.nlm.nih.gov/42260942/

Authors of the abstract: Pr Sophie Georgin-Lavialle et Pr Olivier Kosmider

Key points

- In this multicenter cohort of 66 patients with VEXAS syndrome, allogeneic hematopoietic stem cell transplantation (allo-HSCT) was associated with better overall survival than hypomethylating agents (HMAs).

- Allo-HSCT achieved molecular remission in all evaluable patients, compared with 22% under HMAs.

- Corticosteroid withdrawal was markedly more frequent after transplantation than with HMAs.

- HMAs -mainly azacitidine- remained active in some patients, but with a high rate of discontinuation due to toxicity or lack of efficacy.

- These findings support allo-HSCT as a potentially curative strategy in selected patients.

Summary

VEXAS syndrome is an acquired hematoinflammatory disease caused by somatic mutations in the UBA1 gene, affecting mainly men over 50 years of age. It combines systemic autoinflammatory manifestations, cytopenias, and sometimes an associated myelodysplastic syndrome. Management remains challenging, with frequent corticosteroid dependence and often limited effectiveness of steroid-sparing treatments. In this context, this retrospective multicenter U.S. study compared outcomes of two approaches targeting the pathological clone: hypomethylating agents and allogeneic hematopoietic stem cell transplantation.

Sixty-six patients with confirmed VEXAS were included between 2019 and 2025, including 31 treated with allo-HSCT and 35 with an HMA, mainly azacitidine. Indications for therapy were glucocorticoid-refractory inflammation, progressive bone marrow failure or associated myeloid neoplasia, or combinations of these manifestations. The two groups were broadly comparable clinically and biologically, except for older age in the HMA group.

After a median follow-up of 18 months, 14 deaths were observed 3 in the transplant group and 11 in the HMA group. Allo-HSCT was associated with a significant improvement in overall survival, with median survival not reached versus 29.6 months with HMAs, including after adjustment for age and comorbidities. This superiority persisted across several sensitivity analyses, strengthening the robustness of the signal despite methodological limitations inherent to the retrospective design.

Beyond survival, allo-HSCT was associated with major clinical and biological benefit. All evaluable patients achieved molecular remission, with no re-emergence of the UBA1 clone at last follow-up. Corticosteroid discontinuation was also far more frequent after transplantation, with steroid cessation in 58% of patients, versus only 6% with HMAs. By contrast, HMAs showed real but more modest activity, with molecular remission in 22% of evaluable patients and a high treatment discontinuation rate. Nearly one in two patients stopped treatment, mainly due to infections, prolonged cytopenias, toxicity, or lack of response.

Overall, this North American study suggests that allo-HSCT is currently, as expected, the most effective and potentially curative option for eligible patients with VEXAS, particularly in severe disease, steroid dependence, or bone marrow involvement. HMAs may still have a role in patients not immediately eligible for transplant, as bridging therapy or a step toward transplantation, but in this study their benefit appeared more modest and less durable.