Bone marrow vexations

In this issue of Blood, Sirenko et al¹ report the prevalence of UBA1 mutations in 2 cohorts of patients with myelodysplastic syndrome (MDS) and demonstrate their enrichment in males with MDS who lacked disease-defining genetic aberrations. Their findings provide the rationale for the routine inclusion of UBA1 in somatic panels applied for workup of suspected MDS; however, this recommendation occurs in the setting of a need for more data and prospective studies to better understand and categorize the relevant diseases, natural history, and clinical implications of UBA1 mutations.

Since the first description of VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome by Beck et al in 2020,² there has been a striking interest in this multifaceted disease, with >300 published articles on the topic. It has captured the attention of both benign and malignant hematologists alike, along with our rheumatology, dermatology, and pulmonology colleagues. Notwithstanding a memorable label, this syndrome has garnered the attention of the many hematologists who have grappled with patients with MDS presenting difficult to manage inflammatory symptoms and signs of unclear cause. Similarly, the description of VEXAS syndrome and its associated molecular marker UBA1 has permitted rheumatologists to succinctly convey a unifying diagnosis for myriad inflammatory features, including fever, chondritis, and associated rheumatological diagnoses, such as Sweet syndrome and relapsing polychondritis, several of which may frequently occur concurrently in patients with VEXAS syndrome and which are reflective of the significant morbidity of this disease.³ The severe and multisystem nature of VEXAS syndrome, now often relatively easily diagnosed with a bone marrow biopsy and somatic genetic test, has spurred considerable and widespread physician interest in only a few years.

VEXAS syndrome occurs as the result of somatic mutations arising in hematopoietic stem and progenitor cells in the gene encoding UBA1, the major E1 enzyme required for ubiquitination, with resultant triggering of activation of inflammatory pathways.² VEXAS syndrome thus has its origins in the hematological compartment, but it remains difficult to accurately describe and characterize the spectrum of hematological diseases that may arise in patients with VEXAS syndrome. A large proportion (25%-55%) of patients with VEXAS syndrome are reported to have “MDS,” yet progression to acute myeloid leukemia is infrequent.^1,4-6 Concurrently, it is noted that most patients with VEXAS syndrome have macrocytosis, progressive anemia, and other cytopenia, and the distinction between malignant and nonmalignant causes of cytopenia can be difficult to discern in the setting of severe systemic inflammation and associated medications and the detrimental effects these may have on both cell counts and bone marrow morphology even in the absence of myeloid malignancy.^7,8 It has recently been demonstrated that when ineffective hematopoiesis was factored into MDS diagnosis, the prevalence of MDS in a cohort of patients with VEXAS syndrome was 18%, lower than previously reported.⁴ 

Although there have been advancements in understanding the proportion of patients with VEXAS syndrome reported to have MDS, little is understood about the prevalence of both UBA1 mutations and VEXAS syndrome features in the broader patient population with MDS. In this study, Sirenko et al identified UBA1 mutations deemed “pathogenic” in 1% of patients with MDS. Mutations were enriched in male patients lacking MDS-defining mutations or established World Health Organization disease classification, raising the possibility that this is a population with VEXAS syndrome diagnosed as having MDS but lacking cardinal genomic and clinical MDS features, and which therefore may represent a distinct UBA1 mutated MDS entity. Retrospective review of marrow morphology demonstrated vacuoles in 71% of patients with pathogenic UBA1 mutations, with 83% of patients having inflammatory clinical presentations determined. The authors acknowledge the significant limitation of ascertainment of the cohort with MDS before the first description of VEXAS syndrome with resultant challenges in uniform inflammation manifestation assessment.

Overall, the findings of Sirenko et al further highlight the challenges in distinguishing MDS from VEXAS syndrome and in diagnosing concurrent MDS and VEXAS syndrome, and provide an argument for routine UBA1 assessment in workup of patients with suspected MDS and those with severe inflammatory conditions. These data are needed to inform diagnostic criteria that may be applied to “VEXAS-associated MDS”⁴ or “VEXAS/MDS overlap syndrome,”¹ possibly reflecting multiple distinct entities and which will enhance understanding of clinical implications, including prognosis. Meanwhile, undertaking systematic screening of UBA1 must be done recognizing (1) the lack of a current established approach to curation of non-M41 UBA1 variants, (2) the need to expand data sets examining the prevalence of UBA1 mutations in unbiased cohorts,⁹ and (3) the need to clearly define which patient groups should be systematically screened. In turn, these data will help inform optimal therapeutic strategies in a syndrome in which patients frequently experience poor outcomes.

Conflict-of-interest disclosure: L.C.F. declares no competing financial interests.