Prevalence Of Vexas Syndrome In Mds/Cmml Patients With Systemic Inflammatory And Auto-Immune Disease

Context: Systemic inflammatory and auto-immune diseases (SIAD) are observed in 25% of patients with MDS or CMML, who harbor a high frequency of mutations in TET2, IDH1/2 and SRSF2 as we previously reported (Zhao et al, Leukemia 2021). Recently, the identification of mutations in UBA1 in patients with autoinflammatory disorders, some of whom have dysplastic bone marrow, defined novel disease called VEXAS syndrome (Beck et al, NEJM 2020). Objective: To explore the prevalence of UBA1 mutations in our initial cohort of MDS/CMML patients with SIAD (n=85) (Zhao et al, Leukemia 2021). Design and Patients: All male patients for whom material was available (n=33) were analyzed for the presence of UBA1 mutations. Primary Outcome: UBA1 mutations screening with Sanger sequencing. Results: Four out of 33 (12%) patients had UBA1 mutations. All of them had MDS without excess of blasts. Cytomorphologic review of bone marrow smears showed numerous vacuoles in precursors in all 4 cases. Karyotype was normal in 3/4 patients, and one patient had deletion 9q. One patient also had somatic mutations in DNMT3A (VAF 11%) and TP53 (VAF 2%), and another patient had a mutation of TET2 (VAF 18%). Three patients in our MDS/CMML SIAD cohort had relapsing polychondritis, and 2 of them had UBA1 mutations, while 6 patients from our initial SIAD cohort had a diagnosis of Sweet syndrome, including 2 with UBA1 mutations. Three out of 4mut patients had steroid refractory SIAD and were heavily treated with other immunosuppressive therapies including methotrexate, azathioprine or cytokine targeting agents. At last follow-up, none of the 4 patients with UBA1 mutations had MDS progression, and one of them had died from a stroke, 2.4 years after MDS diagnosis. Conclusions: Our retrospective study represents the first assessment of VEXAS syndrome among patients with myeloid malignancies associated with SIAD. The low prevalence of UBA1 mutations in our cohort suggests that other pathological mechanisms may drive inflammation in the large majority of MDS/CMML patients with associated SIAD, likely in relation with mutations in epigenetic regulators TET2/IDH and SRSF2 as we previously proposed.