Diagnostic capabilities, clinical features, and longitudinal UBA1 clonal dynamics of a nationwide VEXAS cohort

Gurnari, Carmelo;Pascale, Maria Rosaria;Vitale, Antonio;Diral, Elisa;Tomelleri, Alessandro;Galossi, Elisa;Falconi, Giulia;Bruno, Alessandro;Crisafulli, Francesca;Frassi, Micol;Cattaneo, Chiara;Bertoli, Diego;Bernardi, Massimo;Condorelli, Annalisa;Morsia, Erika;Poloni, Antonella;Crisà, Elena;Caravelli, Daniela;Triggianese, Paola;Brussino, Luisa;Battipaglia, Giorgia;Bindoli, Sara;Sfriso, Paolo;Caroni, Federico;Dragani, Matteo;Mallegni, Flavia;Pilo, Federica;Firinu, Davide;Curti, Antonio;Papayannidis, Cristina;Olivieri, Attilio;Kordasti, Sharham;Albano, Francesco;Pane, Fabrizio;Musto, Pellegrino;Bocchia, Monica;Lugli, Elisabetta;Breccia, Massimo;Frigeni, Marco;Dagna, Lorenzo;Greco, Raffaella;Franceschini, Franco;Campochiaro, Corrado;Cantarini, Luca;Voso, Maria Teresa

2023-01-01

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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.