Prevalence and outcome of VEXAS syndrome in unrelated hematopoietic cell transplantation for bone marrow failure.

VEXAS syndrome (vacuoles, E1 enzyme, X-linked, autoinflammatory, and somatic) is a recently identified clonal disorder caused by somatic UBA1 mutations in hematopoietic stem cells, leading to bone marrow failure (BMF) and systemic inflammation. We screened 1771 patients with BMF who underwent unrelated hematopoietic cell transplantation in Japan between 1995 and 2020 using multitarget real-time PCR. The diagnoses included myelodysplastic syndrome (MDS, n = 1139), myeloproliferative neoplasms (n = 125), plasma cell neoplasms (n = 23), acquired BMF (n = 395), and congenital BMF (n = 89). Pathogenic UBA1 mutations were detected in two male patients with MDS (aged 48 and 63 years), corresponding to a prevalence of 0.11% in the overall cohort and 0.18% in MDS cases; an additional 70-year-old male was diagnosed outside of the cohort. All three underwent unrelated bone marrow transplantation following fludarabine and busulfan-based conditioning. The first and third patients died of idiopathic pneumonia syndrome 5 and 28 months after transplantation. In the third patient, UBA1-mutant cells persisted at low frequency in skin graft-versus-host disease tissue despite clearance from his blood. The second patient survived without relapse or graft-versus-host disease at 28 months. Although VEXAS syndrome is rare among unrelated HCT recipients with malignant and non-malignant BMF in the historical cohort, HCT is positioned as a potentially curative, yet high-risk strategy. Additional studies are essential to refine patient selection, optimize transplant timing, and improve management strategies to mitigate risk and enhance survival. Therefore, the role of tissue-residual UBA1-mutant clones in post-transplant complications warrants further investigation.