Benign and malignant hematologic manifestations in patients with VEXAS syndrome due to somatic mutations in UBA1

Abstract

Somatic mutations in UBA1 involving hematopoietic stem and myeloid cells have been reported in patients with the newly defined VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome. Here, we report clinical hematologic manifestations and unique bone marrow (BM) features in 16 patients with VEXAS. All patients were male and had a history of severe autoinflammatory and rheumatologic manifestations and a somatic UBA1 mutation (p.Met41). Ten patients had hematologic disorders: myelodysplastic syndrome (MDS; 6 of 16), multiple myeloma (2 of 16), monoclonal gammopathy of undetermined significance (2 of 16), and monoclonal B-cell lymphocytosis (2 of 16), and a few of those patients had 2 co-existing clonal processes. Although macrocytic anemia (100%) and lymphopenia (80%) were prevalent in all patients with VEXAS, thrombocytopenia and neutropenia were more common in patients with progression to MDS. All BMs in VEXAS patients had prominent cytoplasmic vacuoles in myeloid and erythroid precursors. In addition, most BMs were hypercellular with myeloid hyperplasia, erythroid hypoplasia, and varying degrees of dysplasia. All patients diagnosed with MDS were lower risk (low blast count, very good to intermediate cytogenetics) according to standard prognostic scoring with no known progression to leukemia. In addition, 10 of 16 patients had thrombotic events, including venous thromboembolism and arterial stroke. Although VEXAS presents symptomatically as a rheumatologic disease, morbidity and mortality are associated with progression to hematologic disease. Given the increased risk of developing MDS and multiple myeloma, surveillance for disease progression is important.

Thrombosis in VEXAS syndrome

“…Beck et al [1] reported the presence of lupus anticoagulant (LA) in 12 (48%) of 25 patients with VEXAS syndrome. Obiorah et al [4] also reported that 7 (44%) of 16 patients had persistently positive LA and 5 (55.5%) out of 9 patients with VTE had positive LA. One patient also had weakly positive IgM anticardiolipin antibodies.…”

“…The recently published and largest case series by Georgin-Lavialle et al [3] described the rate of unprovoked VTE at 35.3% (41 out of 116 patients). Obiorah et al [4] reported an even higher VTE rate at 56.25% (9 out of 16 patients), with 60% of thrombotic events occurring within the first 2 years of disease onset. 7 patients were observed to have recurrent VTE with a median of 2 events per patient, with 3 patients were noted to have recurrent VTEs despite being on therapeutic anticoagulation.…”

“…7 patients were observed to have recurrent VTE with a median of 2 events per patient, with 3 patients were noted to have recurrent VTEs despite being on therapeutic anticoagulation. Apart from VTE, there were also arterial thrombotic events reported including transient ischaemic attack (TIA), ischaemic stroke, and myocardial infarction [4,5]. A rapid literature review showed that the incidence of VTE (36.4%) is markedly higher than arterial thrombosis (1.6%).…”

“…Data on the aetiology and management of VTE was heterogenous, with most studies lacking discussion on these aspects. Obiorah et al [4] found out of 9 patients with VTE, 2 patients had high factor VIII levels and 1 patient had a high factor IX level, where elevated factor VIII levels are associated with increased risk of venous thrombosis via enhanced thrombin formation. 2 studies evaluated the presence of antiphospholipid antibodies.…”

“…VEXAS (Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome [1] is described as a late-onset autoinflammatory syndrome exhibiting a spectrum of systemic inflammatory manifestations as well as significant haematologic abnormalities such as macrocytic anaemia, marrow dysplasia, vacuolisation in myeloid cells [2] and thrombosis. Several published case series [1,[3][4][5][6][7][8][9][10] have observed a high prevalence of venous thromboembolism (VTE) in patients with VEXAS syndrome of between 10% and 56%, with a significant mortality rate (27%-50%). We report a case of VEXAS syndrome complicated by unprovoked venous thromboembolism, followed by a rapid review of available literature.…”