Azacitidine as therapy for VEXAS syndrome Free

How should patients with VEXAS (an acronym for vacuoles [in myeloid and erythroid precursors], E1 enzyme, X-linked, autoinflammatory, somatic) syndrome be treated? Until now, we have only had case reports and small series to guide us. In this issue of Blood, Jachiet and colleagues from the French VEXAS group FRENVEX retrospectively describe their experience with azacitidine therapy in 88 patients with genetically confirmed VEXAS syndrome.¹ Improvements in inflammatory signs and symptoms, blood counts, or both disease markers were observed in more than 60% of patients, and the median duration of treatment response was longer than 5 years. There was also an association between reduction in the size of the mutant hematopoietic clone and clinical response.

Sometimes a new observation resolves a long-standing clinical mystery, a sensation similar to a blurred camera image springing into sharp focus. Over the years, we cared for a number of patients diagnosed with myelodysplastic syndromes (MDS) who also had peculiar nonhematological autoimmune and inflammatory disorders that started shortly before or at the same time as their cytopenias.² These manifestations included skin rashes---especially neutrophilic dermatosis, erythema nodosum, or leukocytoclastic vasculitis---as well as chondritis, joint inflammation, lung infiltrates or pleural effusions, ocular disorders, epididymitis or orchitis, and other rare and seemingly bizarre conditions like colitis or myocarditis. Perhaps you have cared for some of these puzzling patients, too, and wondered if the scattered stars of their condition would ever form themselves into a coherent pattern, a recognizable constellation.

Autoimmune diseases tend to be more common in women, so it also seemed peculiar that so many of these “MDS plus” patients were men. Occasionally the nonhematologic conditions improved with treatment of their presumed MDS, suggesting these associated disorders were not coincidental and were perhaps paraneoplastic. One of our patients experienced a 3-year-long remission with decitabine, and when he relapsed, it was the autoimmune manifestations (perichondritis and olecranon bursitis in his case) that returned first, shortly before the cytopenias. Other patients responded well to systemic glucocorticoids, but it was difficult to taper them off the steroid. A few patients did poorly, no matter how we tried to help them (see table).³ 

The 2020 report of a new syndrome that its describers at the National Institutes of Health and in the United Kingdom termed VEXAS was an “aha!” moment.⁸ Suddenly there was a unifying diagnosis for some of the previously perplexing patients. VEXAS syndrome is driven by acquired mutations in UBA1, which encodes a key regulator of ubiquitin-proteasome-mediated protein degradation. Since UBA1 is X-linked, mostly biological males are affected by VEXAS syndrome. Because UBA1 was not a part of most myeloid-focused next-generation sequencing (NGS) panels, and MDS-associated driver mutations other than DNMT3A and TET2 are uncommon in VEXAS syndrome, this association had remained opaque even after NGS testing in suspected MDS became routine more than a decade ago. Some patients had no cytopenias, some presented without inflammatory features (eg, those with Ser56Phe UBA1 variants), while others had concomitant monoclonal gammopathies, expanding the phenotype.

Hematologists have found VEXAS syndrome fascinating, as have clinicians specializing in rheumatology, dermatology (where many patients with VEXAS syndrome start their medical journey), and pulmonary medicine.⁹ VEXAS syndrome was included in both the 2022 World Health Organization and International Consensus Classification disease classifications of hematological neoplasms. Although some publications reporting VEXAS clinical data have had more authors than patients, this reflects the level of interest and enthusiasm across the community, and the syndrome is also likely underrecognized and underdiagnosed. Curiously, PubMed still tries to correct “VEXAS syndrome” to “Texas syndrome” (ie, partial paralysis of finger extensors, leading to a hand gesture resembling the horns of longhorn cattle), but when properly guided, the search engine returns more than 450 publications as of this writing. Most of these publications describe clinical and biological manifestations of VEXAS syndrome rather than therapeutic outcomes.

Even though VEXAS syndrome was first described in 2020, the FRENVEX series reported in this issue of Blood extends back to 2009. DNA sequencing of archival samples allowed the investigators to readjudicate patients with MDS diagnoses and include them if they had characteristic UBA1 mutations and clinical features consistent with VEXAS syndrome, and had received azacitidine. Common adverse effects in this series included infection (likely contributed to by prior and concomitant use of glucocorticoids or other immunosuppressants) and cytopenias, as expected for azacitidine therapy. Opportunistic infections have been a major cause of morbidity and mortality in VEXAS syndrome, both from the disease itself and as an effect of therapy.

Although there are International Working Group (IWG) response criteria for MDS that are widely used, there are no validated consensus criteria yet for measuring response in VEXAS syndrome. The FRENVEX group used the MDS IWG criteria to assess hematological response and developed a reasonable set of inflammatory response criteria including 3 parameters: clinical inflammatory symptoms; C-reactive protein level (≤10 mg/L for complete response, ≥50% reduction from pretreatment values for partial response) in the absence of infection; and ability to lower glucocorticoid dose (prednisone-equivalent dose of ≤10 mg/d for complete response, ≥50% dose reduction for partial response). The high rate of response and durability of improvement in all of these parameters with azacitidine are encouraging.

In the absence of sizable prospective clinical trials, these new data on azacitidine therapy will help inform clinicians, and azacitidine represents an attractive approach to VEXAS syndrome. Key questions remain, such as when azacitidine should be used as a bridge to allogeneic hematopoietic cell transplant (HCT), which is often curative.^7,10 Several prospective studies of other approaches are ongoing, including 2 trials with pacritinib (NCT06782373 and NCT06538181) and a National Cancer Institute/National Institutes of Health intramural study of allogeneic HCT (NCT05027945). But most patients will be treated outside the context of a clinical trial, so reports like the FRENVEX series are helpful.

Conflict-of-interest disclosure: D.P.S. declares employment with Ajax Therapeutics (no active or planned programs in VEXAS syndrome). M.M.P. declares no competing financial interests.