Trisomy 8 clonal expansion during disease progression and azacitidine resistance in VEXAS syndrome: a case report

Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome is an adult-onset autoinflammatory disorder driven by clonal hematopoiesis with somatic UBA1 mutations. Azacitidine can reduce the mutant clonal burden and improve inflammatory manifestations. However, the clonal basis of treatment resistance remains poorly understood.

A 61-year-old man presented with predominant gastrointestinal symptoms, macrocytic anemia, thrombocytopenia, and systemic inflammation. A bone marrow examination revealed cytoplasmic vacuoles in myeloid precursors and trisomy 8. Retrospective genetic testing identified a somatic UBA1 p.Met41Val variant, thus establishing the diagnosis of VEXAS syndrome in this patient. At the time of referral and during immunosuppressive therapy with prednisolone and cyclosporine, the UBA1 variant allele frequency was consistently higher than the trisomy 8 burden, although relapse coincided with an expansion of trisomy 8. Azacitidine reduced the clonal burdens of both the UBA1 mutation and trisomy 8. However, both persisted at similar levels, and after 21 cycles, the disease progressed to myelodysplastic syndrome with increased blasts-2, accompanied by concordant re-expansion of UBA1-mutated and trisomy 8 clones. These findings suggest that a trisomy 8 subclone likely emerged within a UBA1-mutated founder clone and expanded during treatment, whereas the disomy 8 fraction of the UBA1-mutated clone was preferentially eliminated by azacitidine. Urgent cord blood transplantation resulted in sustained clinical and molecular remission.

This case suggests that trisomy 8 may contribute to disease progression and azacitidine resistance in VEXAS syndrome.