Hypomethylating Therapy in VEXAS Syndrome: Disease Modification Beyond Bridging to Transplant

Abstract

I read with great interest the article by Fathima et al. reporting comparative outcomes of allogeneic hematopoietic stem cell transplantation (alloHSCT) and hypomethylating agents (HMA) in VEXAS syndrome [1]. The authors are to be commended for addressing a clinically important question in this rare disorder.

I would like to offer an additional perspective on the interpretation of the favorable outcomes associated with alloHSCT, particularly in light of the disease-modifying potential of hypomethylating therapy and inherent limitations of retrospective analyses. VEXAS is driven by somatic mutations in the UBA1 gene, most commonly affecting codon Met41, and thus represents a clonal hematopoietic disorder amenable to therapies targeting the malignant clone [2, 3]. In this context, accumulating evidence including data from the present study indicates that azacitidine can reduce the variant allele fraction (VAF) of UBA1 mutations and induce molecular remissions in a subset of patients [4-6]. The 22% molecular remission rate observed in the HMA cohort supports prior findings that hypomethylating agents can meaningfully impact clonal burden [4, 6].

While alloHSCT was associated with higher rates of molecular remission and superior overall survival, this association warrants careful interpretation. Response to HMA therapy appears heterogeneous, and the attenuation of survival differences among patients able to complete prolonged HMA treatment suggests that a subset may achieve durable clinical benefit when therapy is tolerated [4, 6]. In this setting, the intention-to-treat framework, combined with a high rate of early HMA discontinuation, may underestimate the therapeutic potential of HMAs in selected patients.

A central challenge is residual confounding from selection and survivor effects [7]. Patients undergoing alloHSCT must necessarily survive the interval from diagnosis to transplantation and maintain sufficient fitness to proceed, introducing a survivor effect not fully captured by analyses anchored at treatment initiation. The authors thoughtfully addressed this through 1:1 matching on age and Charlson Comorbidity Index and propensity score based inverse probability treatment weighting, with the association favoring alloHSCT persisting across both analyses. Such adjustments may still leave residual confounding that could contribute to an overestimation of the survival advantage associated with alloHSCT [7, 8]. While these biases are difficult to eliminate entirely in retrospective studies, definitive comparisons between hypomethylating agents and alloHSCT will require prospective evaluation. The interpretation of HMA efficacy in VEXAS remains challenging because of the limitations of the available evidence. The FRENVEX cohort, which is frequently cited as a benchmark for azacitidine activity, was also retrospective and therefore susceptible to referral and selection biases that may partly explain the differences in response rates compared with the present US cohort [1, 6]. Although azacitidine can reduce UBA1 variant allele frequency, the durability of these molecular remissions after treatment discontinuation remains uncertain. Indeed, the FRENVEX study reported frequent relapse among responders who stopped therapy, as well as a substantial proportion of treatment discontinuations due to toxicity or treatment failure. By contrast, alloHSCT achieved molecular remission in all evaluable patients, with no reported re-emergence of the UBA1 clone at the last follow-up, supporting its potential as a curative approach. However, the evidence for alloHSCT in VEXAS remains limited to retrospective series and requires confirmation in larger studies with longer follow-up. Notably, outcomes reported by Fathima et al. compared favorably with those of the multicenter EBMT experience [9], possibly reflecting the consistent use of reduced-intensity conditioning, frequent incorporation of post-transplant cyclophosphamide, and avoidance of donor lymphocyte infusions for mixed chimerism, which may increase the risk of GVHD without clearly improving outcomes in VEXAS. In my view, these data support alloHSCT as an effective and potentially curative option in carefully selected patients, rather than establishing it as the preferred strategy across all eligible individuals. Hypomethylating agents may represent not only a bridge to transplantation but also, in a subset of patients, a disease-modifying approach capable of inducing meaningful remissions, although their durability after discontinuation remains uncertain. A prospective randomized trial comparing alloHSCT and azacitidine would be invaluable to define the optimal therapeutic strategy in VEXAS syndrome.

The author has nothing to report.

This article is a commentary and does not contain original data involving human participants or animals; therefore, ethical approval was not required.

No individual patient data are reported; therefore, patient consent was not required.

The author declares no conflicts of interest.

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.