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.

VEXAS syndrome: key points to remember

In this article, Journal des Femmes Santé reviews the causes, symptoms, and management of the disease, with insights from Professor Sophie Georgin-Lavialle, an internist at Tenon Hospital.

VEXAS syndrome is a rare inflammatory disease, first described in 2020. Its name is an acronym standing for Vacuoles, E1 enzyme (UBA1), X-linked, Autoinflammatory, Somatic. It is caused by an acquired (somatic) mutation of the UBA1 gene, located on the X chromosome, leading to excessive chronic inflammation throughout the body.

This disease primarily affects men over the age of 50. Because the mutations are not present at birth, symptoms appear in adulthood (the youngest patient described was 46 years old).

Common symptoms include:

• Anemia

• Persistent fever

• Severe fatigue

• Pain in large joints

• Skin lesions

• Weight loss and loss of appetite

• Cartilage inflammation (ears, nose – chondritis)

• Possible lung involvement

• Markedly elevated inflammatory markers (CRP)

Diagnosis relies on genetic sequencing, which has made it possible to identify many patients who were previously misdiagnosed with other inflammatory or hematological diseases.

There is no typical acute phase: inflammation is continuous, sometimes with flares.

VEXAS syndrome remains poorly understood, particularly regarding why some individuals develop this mutation while others do not.

https://sante.journaldesfemmes.fr/fiches-maladies/2905657-syndrome-vexas-symptomes-traitement-c-est-quoi/

VEXAS syndrome and the risk of infections: what do we know and how can they be prevented?

Article title: Mapping the infectious burden in VEXAS syndrome:a systematic review and rationale for prevention

First author: Valentine Ribier

Journal: Lancet Rheumatology

Link to the article: https://doi.org/10.1016/S2665-9913(25)00225-5

Author of the abstract: Rim BOURGUIBA

Introduction:

VEXAS syndrome is an autoinflammatory disease associated with somatic mutations in the X‑linked UBA1 gene. Patients present with systemic inflammatory manifestations and an increased susceptibility to infections. In the French cohort, more than 50% of mortality was attributed to infections. Several factors have been identified as contributors to infection risk in these patients: long‑term corticosteroid therapy, combination and prolonged use of immunosuppressive treatments such as JAK inhibitors, and a likely functional immune deficiency of myeloid cells related to the disease itself. Multiple publications have reported opportunistic and invasive infections in VEXAS even in the absence of immunosuppressive or immunomodulatory therapy. Few recommendations existed regarding infection prophylaxis in VEXAS. The objectives of this review were: 1) to characterize the spectrum of infections in VEXAS, 2) to identify a high‑risk subgroup for infections, and 3) to propose a preventive strategy to reduce infection‑related complications.

Methods:

This systematic review followed PRISMA guidelines. The literature search included publications from October 2020 to October 31, 2024 without language restrictions on PubMed. The authors included case reports and case series. Eligibility criteria were the presence of infection, its frequency, and its nature among patients with VEXAS syndrome. Infection was confirmed when a pathogen was identified. A severe infection was defined as one requiring hospitalization with intravenous antibiotic therapy or resulting in death.

Results:

The authors identified 506 potentially eligible studies; after exclusions, 57 studies were retained, encompassing 813 patients.

Infection frequency was high: 37–60% of patients experienced at least one infection, with 12–15% dying from infections in large cohorts. Severe infections accounted for up to 60% of cases. The most frequent infection sites were respiratory (28–59%), skin and soft tissue (10–49%), and bloodstream (bacteremia 8–13%), with genitourinary and gastrointestinal infections less common. Main pathogens included bacteria (Gram‑negative bacilli and Gram‑positive cocci), and opportunistic infections such as Legionella, atypical mycobacteria, Pneumocystis jirovecii, VZV, CMV, HSV, Aspergillus, and Nocardia. (Figure 1)

Factors associated with infections included exposure to immunosuppressive treatments: azacitidine was associated with 44–62% infections, including deaths; IL‑6 inhibitors with 29–47%; and JAK inhibitors with 18–37%. IL‑1 inhibitors were associated with a lower rate (3%). Chronic corticosteroid therapy was associated with mycobacterial infections or pneumocystosis.

The authors proposed the following prevention strategy:

• Targeted anti‑infective prophylaxis, for example co‑trimoxazole to prevent Pneumocystis jirovecii pneumonia and valaciclovir to prevent VZV reactivation.

• Systematic vaccinations, including influenza, pneumococcus, VZV, and SARS‑CoV‑2, despite a potential for reduced vaccine responses.

• Comprehensive infectious disease screening before initiating immunosuppression, including serologies (HIV, HBV, HCV, TB) and chest CT.

Conclusion:

VEXAS syndrome is associated with a major predisposition to infections, resulting from both an intrinsic immune deficit linked to UBA1 mutation and the effects of immunosuppressive treatments. Infections are a leading cause of morbidity and mortality, particularly affecting the respiratory tract and skin. Prevention should be a central pillar of care, based on vaccination, targeted anti‑infective prophylaxis, and risk assessment prior to any immunosuppression. These data support an integrated, multidisciplinary, and proactive approach to improve survival and quality of life for people living with VEXAS.

Figure 1: Distribution of infection sites and pathogens across studies

Le syndrome VEXAS et le risque d’infections.pdf

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