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.

Graphical abstract

Figure 1.

Thrombocytopenia and the risk for MDS in patients with VEXAS. (A) PB counts (from the same timepoint) are compared between patients with MDS diagnosis on BM biopsy and those without MDS diagnosis (at either the last BM biopsy performed or the biopsy before treatment for patients with MM). Median platelet counts at the time of MDS diagnosis were significantly lower (P value 0.0030) compared with those of patients whose BM was not diagnostic of MDS (this included 2 patients with MM). The 2 groups were compared using nonparametric Student t test. The error bars represent the range and middle horizontal bars mark the median. (B) Serial blood counts and BM evaluations for UPN-14 are used as an example to show disease progression. Macrocytic anemia was seen at the onset of inflammatory disease, which progressed over the next 5 years to RBC transfusion dependence. After 5 years, there was steady decline in platelet counts to <50 × 10³/µL 1 year later, when the BM biopsy revealed diagnosis of MDS-SLD. Previous BM evaluations did not reveal a diagnosis. ALC, absolute lymphocyte count; AMC, absolute monocyte count; ARC, absolute reticulocyte count.

Figure 2.

PB and BM features of VEXAS. All patients studied had (A) macrocytic anemia demonstrated by RBCs greater in size than the nuclei of small lymphocytes. (B) Circulating hyposegmented pelgeroid neutrophils and (C) vacuolated neutrophils are common. Bone BM aspirates show striking vacuolization of (D) myeloid and erythroid precursors including (E) blasts, (F) erythroid pronormoblasts, (G) monoblasts, (H-I) promyelocytes, (J) myelocytes, (K) eosinophilic myelocytes, (L) promonocytes, and less commonly (M) megakaryocytes. (N) Core biopsies typically demonstrate hypercellular BM with myeloid hyperplasia (hematoxylin and eosin (H&E) stain; original magnification ×200). (A-M) Wright-Giemsa stained smears; original magnification ×1000.

Figure 3.

MDS in patients with VEXAS. MDS in patients with VEXAS is associated with hypercellular BM (panel A: H&E stain; original magnification ×500) with dysplastic megakaryocytes, including micromegakaryocytes highlighted by CD61 immunohistochemistry (IHC) on the core biopsy (panel B: original magnification ×500). Dysmegakaryopoiesis can be seen on aspirate smears, including (C) micromegakaryocytes, (D) megakaryocytes with vacuoles, and (E) megakaryocytes with separated nuclear lobes. Dyserythropoiesis including (F-G) binucleation and multinucleation, megaloblastic changes, and nuclear budding are common. Dysmyelopoiesis can be striking with abnormal maturation including (G) binucleation and maturation asynchrony, (H) binucleated eosinophilic myelocytes, (I) hypogranular forms, and (J) myeloid cells with abnormal morphology and vacuoles. All aspirate images show Wright-Giemsa–stained smears; original magnification ×1000.

Figure 4.

MM in patients with VEXAS. Extensive BM infiltration by markedly atypical plasma cells on core biopsy (panel A: H&E stain; original magnification ×500, inset ×1000 ), highlighted by CD138 IHC (panel B: original magnification ×500). Marrow aspirate showed myeloid precursors with vacuoles and increased scattered plasma cells (panel C: Wright-Giemsa stain; original magnification ×1000). The plasma cells expressed lambda light chains by in situ hybridization on core biopsy (panel D; original magnification ×500) and aberrant expression of cyclin D1 by IHC (panel E: original magnification ×500).