During the recent workshop "Focus on Allogeneic HSCT in Myelodysplastic Syndromes," Professor Fabio Ciceri (IRCCS San Raffaele Scientific Institute / Vita-Salute San Raffaele University), Chair of the EBMT Scientific Council and the Acute Leukemia Working Party (ALWP), provided a comprehensive overview of "Contemporary Approaches to VEXAS." He systematically detailed the genetic foundations, clinical progression, and multidimensional therapeutic landscape of this complex disease. 01 Molecular Definition: UBA1 Somatic Mutations as the Driver of Autoinflammation
VEXAS syndrome (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) was first identified and defined in late 2020. Professor Ciceri noted that the central pathogenic mechanism involves a somatic mutation in the UBA1 gene. As this gene is located on the X chromosome, the disease primarily affects men, typically over the age of 50.
Mutations in UBA1 lead to functional defects in the E1 ubiquitin-activating enzyme, triggering a profound systemic autoinflammatory state. This chronic inflammation results in severe hematologic consequences, positioning VEXAS as a critical bridge between rheumatologic autoimmune conditions and hematologic malignancies.
02 Clinical Phenotype: Morphological Vacuoles and Multisystem Involvement
The diagnosis of VEXAS syndrome relies on distinct morphological hallmarks. Professor Ciceri emphasized that the presence of vacuoles in bone marrow cells—specifically within myeloid and erythroid precursors—is a recurrent and significant diagnostic observation.
Clinically, patients present with systemic inflammatory manifestations, including recurrent fever, significantly elevated C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR), skin infiltration, pulmonary inflammation, and relapsing polychondritis. Due to the high heterogeneity of symptoms, these patients are often managed by rheumatologists or internal medicine specialists before a hematologic diagnosis is confirmed.
03 Hematologic Clonal Evolution: From Clonal Hematopoiesis to MDS/AML
Hematologic involvement and clonal evolution are primary determinants of prognosis in VEXAS. Professor Ciceri described how progressive cytopenias often emerge as the disease evolves.
Next-generation sequencing (NGS) has revealed that VEXAS patients frequently harbor additional mutations associated with clonal hematopoiesis, such as DNMT3A and TET2, and occasionally KRAS or TP53. Two evolutionary patterns have been elucidated: one where clonal hematopoiesis pre-exists the UBA1 mutation, and a second, more frequent pattern where the UBA1-driven inflammatory environment promotes the emergence and dominance of additional clones. While evolution into Myelodysplastic Syndrome (MDS) is common, progression to Acute Myeloid Leukemia (AML) is observed less frequently.
04 Targeted Anti-inflammatory Therapy and Clonal Control
The immediate therapeutic goal in VEXAS is to control systemic inflammation while implementing steroid-sparing strategies to reduce morbidity.
- JAK Inhibitors: Agents such as ruxolitinib and pacritinib have shown promise in managing the inflammatory response by blocking cytokine signaling pathways.
- Cytokine Blockade: Targeted therapies against IL-1 and IL-6 have been utilized to alleviate systemic symptoms.
- Hypomethylating Agents (HMAs): Azacitidine has demonstrated significant efficacy. In specific patient series, response rates reached 70%–100%, characterized by the resolution of inflammatory symptoms and a reduction in the UBA1 mutant clone burden. However, response rates may be lower in patients who have already progressed to morphological MDS.
05 Curative Approaches: The Role of Allogeneic HSCT
For patients with high-risk hematologic features or refractory inflammation, allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the only curative option.
Professor Ciceri highlighted that allo-HSCT is increasingly considered based on the patient’s MDS-like profile and the severity of their autoinflammatory symptoms. While the transplant can successfully eradicate the UBA1 clone and reset the immune system, the high burden of comorbidities—stemming from chronic steroid use and organ damage—requires careful patient selection. Professor Ciceri referenced emerging registry data and international recommendations suggesting that transplant should be prioritized before the accumulation of excessive treatment-related morbidities.
Conclusion and Outlook
VEXAS syndrome provides a unique model for studying how inflammation drives hematopoietic damage and clonal dominance. Professor Ciceri concluded that management has moved from clinical observation to precise molecular monitoring (NGS, dPCR). The upcoming International VEXAS Workshop (September 24–25, 2026) will further address these challenges, focusing on optimizing the transition from anti-inflammatory therapy to definitive transplantation.
