Diagnostic capabilities, clinical features, and longitudinal <scp><i>UBA1</i></scp> clonal dynamics of a nationwide <scp>VEXAS</scp> cohort
Carmelo Gurnari, Maria Rosaria Pascale, Antonio Vitale, Elisa Diral, Alessandro Tomelleri, Elisa Galossi, Giulia Falconi, Alessandro Bruno, Francesca Crisafulli, Micol Frassi, Chiara Cattaneo, Diego Bertoli, Massimo Bernardi, Annalisa Condorelli, Erika Morsia, Antonella Poloni, Elena Crisà, Daniela Caravelli, Paola Triggianese, Luisa Brussino, Giorgia Battipaglia, Sara Bindoli, Paolo Sfriso, Federico Caroni, Matteo Dragani, Flavia Mallegni, Federica Pilo, Davide Firinu, Antonio Curti, Cristina Papayannidis, Attilio Olivieri, Shahram Kordasti, Francesco Albano, Fabrizio Pane, Pellegrino Musto, Monica Bocchia, Elisabetta Lugli, Massimo Breccia, Marco Frigeni, Lorenzo Dagna, Raffaella Greco, Franco Franceschini, Corrado Campochiaro, Luca Cantarini, Maria Teresa Voso
Abstract
VEXAS is a prototypic hemato-inflammatory disease combining rheumatologic and hematologic disorders in a molecularly defined nosological entity. In this nationwide study, we aimed at screenshotting the current diagnostic capabilities and clinical-genomic features of VEXAS, and tracked UBA1 longitudinal clonal dynamics upon different therapeutics, including allogeneic hematopoietic cell transplant. We leveraged a collaboration between the Italian Society of Experimental Hematology and of Rheumatology and disseminated a national survey to collect clinical and molecular patient information. Overall, 13/29 centers performed UBA1 genomic testing locally, including Sanger sequencing (46%), next-generation sequencing (23%), droplet digital polymerase chain reaction (8%), or combination (23%). A total of 41 male patients were identified, majority (51%) with threonine substitutions at Met41 hotspot, followed by valine and leucine (27% and 8%). Median age at VEXAS diagnosis was 67 years. All patients displayed anemia (median hemoglobin 9.1 g/dL), with macrocytosis. Bone marrow vacuoles were observed in most cases (89%). The most common rheumatologic association was polychondritis (49%). A concomitant myelodysplastic neoplasm/syndrome (MDS) was diagnosed in 71% of patients (n = 28), chiefly exhibiting lower Revised International Prognostic Scoring System risk profiles. Karyotype was normal in all patients, except three MDS cases showing -Y, t(12;16)(q13;q24), and +8. The most frequently mutated gene was DNMT3A (n = 10), followed by TET2 (n = 3). At last follow-up, five patients died and two patients progressed to acute leukemia. Longitudinal UBA1 clonal dynamics demonstrated mutational clearance following transplant. We collected a nationwide interdisciplinary VEXAS patient cohort, characterized by heterogeneous rheumatologic manifestations and treatments used. MDS was diagnosed in 71% of cases. Patients exhibited various longitudinal UBA1 clonal dynamics.