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

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.