VEXAS syndrome: complete molecular remission after hypomethylating therapy

Abstract

The VEXAS syndrome, a genetically defined autoimmune disease, associated with various hematological neoplasms has been attracting growing attention since its initial description in 2020. While various therapeutic strategies have been explored in case studies, the optimal treatment strategy is still under investigation and allogeneic cell transplantation is considered the only curative treatment. Here, we describe 2 patients who achieved complete molecular remission of the underlying UBA1 mutant clone outside the context of allogeneic HCT. Both patients received treatment with the hypomethylating agent azacitidine, and deep molecular remission triggered treatment de-escalation and even cessation with sustained molecular remission in one of them. Prospective studies are necessary to clarify which VEXAS patients will benefit most from hypomethylating therapy and to understand the variability in the response to different treatment strategies.

Keywords: Azacitidine; Hypomethylating therapy; Molecular remission; VEXAS.

Fig. 1

Variant allele frequencies (VAF) of the UBA1 mutation during azacitidine treatment. Left: UBA1 VAF in CD34-selected peripheral blood (pB) during the first 6 treatment cycles. Right: UBA1 VAF in unsorted BM cells. Ultradeep NGS with a detection limit of 0.1%⁹ was used for longitudinal molecular follow-up. Patient 1 (yellow) achieved complete eradication of the UBA1 clone 6 months after azacitidine start.  Follow-up assessments in patient 2 (blue) identified complete molecular remission at month 21 after treatment start