VEXAS syndrome is a haemato-inflammatory disease caused by somatic UBA1 mutations and characterized by cytoplasmic vacuoles in myeloid and erythroid precursor cells. Although there is currently no standard treatment algorithm for VEXAS, patients are generally treated with anti-inflammatory therapies focused on symptom management, with only partial effectiveness. Hypomethylating agents (HMA) have shown promise in VEXAS patients with concomitant myelodysplastic syndrome (MDS), while the efficacy of HMA in VEXAS patients without MDS is largely unknown. Furthermore, the usefulness of monitoring the variant allele frequency (VAF) of UBA1 or vacuolization in precursor cells over the course of treatment has not been extensively investigated. We have evaluated the efficacy of HMA in four VEXAS patients without MDS and performed longitudinal analyses of the VAF of UBA1 and vacuolization during treatment. HMA treatment led to overall clinical improvement, a dramatic reduction in the VAF of UBA1, normalization of haematological and inflammatory markers and a quantifiable decrease in vacuolization, leading us to speculate that unlike anti-inflammatory therapies, HMA may well act as a disease-modifying treatment. If these findings are confirmed in further studies, it could lead to the early use of HMA in the treatment of all VEXAS patients—with or without MDS.

CONFLICT OF INTEREST STATEMENT

MDB.: consultant or advisory role, travel grants or speaker (Bristol Myers Squibb, Abbvie, Astellas, JazzPharma, Takeda, Novartis). JIA: speaker honoraria (Novartis, SOBI). JE: consultancy-honoraria (Abbvie, Novartis, Astellas, Jazz Pharmaceuticals, BMS-Celgene, Pfizer, Daiichi-Sankyo), research grants (Novartis, Jazz Pharmaceuticals). These organizations had no role in the design of the study; in the collection, analysis or interpretation of data; in the writing of the manuscript; or in the decision to publish the results. The remaining authors declare no competing interests.

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DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

Supporting Information

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Volume206, Issue2

February 2025

Pages 565-575

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Hypomethylating agents for patients with VEXAS without myelodysplastic syndrome: Clinical outcome and longitudinal follow-up of vacuolization and UBA1 clonal dynamics

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Hypomethylating agents for patients with VEXAS without myelodysplastic syndrome: Clinical outcome and longitudinal follow-up of vacuolization and UBA1 clonal dynamics

Summary

CONFLICT OF INTEREST STATEMENT

Open Research

DATA AVAILABILITY STATEMENT

Supporting Information

REFERENCES

Citing Literature

References

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