P778: a cartography of uba1 gene testing, epidemiology and clinical-genomic characteristics: the vexas italian experience

Topic: 12. Bone marrow failure syndromes incl. PNH - Clinical Background: VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory and somatic) is a prototypic hemato-inflammatory disease juxtaposing for the first time rheumatologic and hematologic disorders under the aegis of a molecularly defined nosologic entity. Given its multifaceted clinical presentations, VEXAS represents a challenging masquerade syndrome and has elicited a wide medical interest. Indeed, this disorder lies at the interface between bone marrow failure syndromes, inflamm-aging and clonal hematopoiesis, displaying a tetrad of somatic mutations, morphologic features, inflammatory pathways and immune overshooting. UBA1 mutations constitute the genomic underpinnings of VEXAS, which oftentimes presents in association with MDS. Aims: Herein, we wanted to screenshot the current UBA1 diagnostic capabilities and clinical-genomic features of VEXAS in Italy, after 2 years from its discovery. Methods: This study was performed through a national survey, under the patronage of the Italian societies of experimental hematology (SIES) and rheumatology (SIR), mostly involved in the clinical management of VEXAS patients. Results: Overall, 13 out of 26 participating centers had available UBA1 genomic testing (Fig.1A). This consisted of either Sanger sequencing (50%), next-generation sequencing (NGS, 14%) or Droplet Digital PCR (ddPCR, 7%), whereas a combination of these was in use in 29% of the centers (Fig.1B). Over a median time of 13.7 months from UBA1 testing availability, the positivity rate achieved 11.5% (n=39 out of 337 total requests). Majority (72%) of VEXAS cases harbored threonine substitutions at the Met41 hotspot, followed by leucine and valine (14% each; Fig.1C). A complete set of information was available for 31 patients, all males. Median age at VEXAS diagnosis was 67 years (IQR=63-72). All patients had anemia (median hemoglobin 9.1 gr/dL, IQR=8.3-10.5) and macrocytosis (median MCV 106 fL, IQR=102-109.3). Bone marrow vacuoles were observed in myeloid (24%) and erythroid (4%) precursors, or both (72%) in all patients (Fig.1D). Recurrent polychondritis was the most common rheumatologic association, accounting for 52% of cases. Notably, 35% of patients also showed MGUS at serum protein electrophoresis evaluation. A concomitant MDS was registered in 68% of our patients, all falling into lower IPSS-R (scores <3.5) categories. When re-stratified according to IPSS-M, only 1 case was upstaged to the moderate high risk group while the others remained into lower-risk categories (negative IPSS-M values). Cytogenetics was normal in all patients apart from 3 MDS cases showing delY, t(12;16)(q13;q24) and trisomy8. DNMT3A was the most recurrently mutated gene (n=8), followed by TET2 (n=3) with a 34.9% median VAF (IQR, 25.75-38.5). At a median follow up of 8.8 months, 5 patients died because of infectious complications and 2 progressed to AML. Remarkably, one patient with ASXL1/SF3B1-mutant MDS evolved to AML upon acquisition of a RUNX1 mutation and is currently undergoing allogeneic HSCT after achievement of complete remission, whereas another underwent transplant with subsequent clinical and molecular reversion of VEXAS.Summary/Conclusion: We present here the first multidisciplinary Italian cartography of VEXAS, detailing genomic testing capabilities and peculiar features of this newly defined condition. Acute clinical acumen and multidisciplinary interactions are essential to identify VEXAS, which must be judiciously considered in male patients above 50 years of age presenting with a history of macrocytic anemia (with/without MDS) and autoinflammatory manifestations. Keywords: Somatic mutation, Bone marrow failure, MDS, VEXAS syndrome