Venous and Arterial Thrombosis in Patients with VEXAS Syndrome.

VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) syndrome, caused by somatic mutations in UBA1, is an autoinflammatory disorder with diverse systemic manifestations. Thrombosis is a prominent clinical feature of VEXAS. The risks factors and frequency of thrombosis in VEXAS are not well described, due to the disease's new discovery and paucity of large databases. We evaluated 119 VEXAS patients for venous and arterial thrombosis and correlated their presence with clinical outcomes and survival. Thrombosis occurred in 49% of patients, mostly venous thromboembolism (VTE; 41%). Almost two thirds of VTE were unprovoked, 41% were recurrent, and 20% occurred despite anticoagulation. The cumulative incidence (CI) of VTE was 17% at 1 year from symptom onset and 40% by 5 years. Cardiac and pulmonary inflammatory manifestations were associated with time to VTE. M41L was positively associated specifically with pulmonary embolism (PE) by univariate (OR: 4.58, CI 1.28-16.21; p=0.02) and multivariate (OR: 16.94, CI 1.99-144.3; p=0.01) logistic regression. The cumulative incidence of arterial thrombosis was 6% at 1 year and 11% at 5 years. The overall survival (OS) of the entire patient cohort at median follow up time of 4.8 years was 88% and there was no difference in survival between patients with or without thrombosis (p=0.8). Patients with VEXAS syndrome are at high risk of VTE; thromboprophylaxis should administered be in high-risk settings unless strongly contraindicated.

Comprehensive morphologic characterization of bone marrow biopsy findings in a large cohort of patients with VEXAS syndrome: A single-institution longitudinal study of 111 bone marrow samples from 52 patients.

OBJECTIVES: VEXAS syndrome is an adult-onset autoinflammatory disease caused by a somatic pathogenic mutation in the UBA1 (ubiquitin-like modifier activating enzyme 1) gene. Patients present with rheumatologic manifestations and cytopenias and may have an increased predisposition to myelodysplastic syndrome (MDS) and plasma cell neoplasms. Prior studies have reported on the peripheral blood and bone marrow findings in patients with VEXAS syndrome. Due to the protean clinical presentation and lack of specificity of morphologic features (eg, vacuoles in early erythroid and granulocytic precursors), an optimal screening methodology to identify these patients in a timely fashion is desirable. METHODS: To further evaluate and describe the salient diagnostic morphologic features in VEXAS syndrome, we carried out a comprehensive study of the largest single-institution cohort to date. Diagnostic and follow-up bone marrow biopsy specimens from 52 male patients with molecularly identified VEXAS syndrome underwent central review. RESULTS: Cytopenias were common in all cases, primarily macrocytic anemia, monocytopenia, and thrombocytopenia. Bone marrow aspirate and biopsy were often hypercellular, with an increased myeloid/erythroid ratio, granulocytic hyperplasia with left shift, erythroid left shift, and megakaryocyte hyperplasia, which exhibited a range of striking morphologic findings. Distinctly vacuolated myeloid and erythroid precursors were seen in more than 95% of cases. CONCLUSIONS: Our data reveal potential novel diagnostic features, such as a high incidence of monocytopenia and distinct patterns of atypical megakaryopoiesis, that appear different from dysmegakaryopoiesis typically associated with MDS. In our experience, those findings are suggestive of VEXAS, in the appropriate clinical context.

Granularity in disease classification impacts survival prediction in advanced systemic mastocytosis: A single institution study of 329 informative cases.

The World Health Organization (WHO) classification system categorizes advanced systemic mastocytosis (SM-Adv) into aggressive SM (ASM), mast cell leukemia (MCL), and SM with associated hematological neoplasm (SM-AHN). By contrast, the International Consensus Classification (ICC) requires "immature" MC cytomorphology for the diagnosis of MCL and limits SM-AHN to myeloid neoplasms (SM-AMN). The current study includes 329 patients with SM-Adv (median age 65 years, range 18-88; males 58%): WHO subcategories SM-AHN (N = 212; 64%), ASM (N = 99; 30%), and MCL (N = 18; 6%); ICC subcategories SM-AMN (N = 190; 64%), ASM (N = 99; 33%), and MCL (N = 9; 3%); WHO-defined MCL with "mature" MC cytomorphology and SM-AHN associated with lymphoid neoplasms were operationally labeled as "MCL-mature" (N = 9) and SM-ALN (N = 22), respectively, and distinguished from ICC-defined MCL and SM-AMN. Multivariable analysis that included the Mayo alliance risk factors for survival in SM (age >60 years, anemia, thrombocytopenia, increased alkaline phosphatase) revealed more accurate survival prediction with the ICC versus WHO classification order: (i) survival was significantly worse with MCL-immature versus MCL-mature (hazard ratio [HR] 15; p < .01), (ii) prognostic distinction between MCL and SM-AHN/AMN was confirmed in the context of ICC (HR 9.3; p < .01) but not WHO classification order (p = .99), (iii) survival was similar between MCL-mature and SM-AMN (p = .18), and (iv) SM-AMN (HR 1.7; p < .01) but not SM-ALN (p = .37) was prognostically distinct from ASM. The current study provides evidence for the independent prognostic contribution of both the ICC system for SM-Adv and the Mayo alliance risk factors for survival in SM.

VEXAS syndrome: Clinical, hematologic features and a practical approach to diagnosis and management.

VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) syndrome is a newly identified disease caused by somatic alterations in UBA1 which produce a recalcitrant inflammatory state along with hematologic disturbances. Patients with VEXAS can have a wide spectrum of clinical symptoms and providers should be familiar with the heterogeneity of associated clinical features. While hematologic parameters may be generally non-specific, peripheral blood features of macrocytosis, monocytopenia, and/or thrombocytopenia coupled with bone marrow vacuolization of erythroid or myeloid precursors should raise suspicion for this condition. Due to an increased mortality, prompt recognition and accurate diagnosis is paramount. Access to testing for confirmation of UBA1 variants is not yet universally available but clinicians should understand the current available options for genetic confirmation of this disease. Treatment options are limited due to lack of prospective clinical trials but cytokine directed therapies such as interleukin-6 inhibitors and JAK-STAT inhibitors as well as hypomethylating agents such as azacitidine have shown evidence of partial effect. Though cases are limited, allogeneic stem cell transplantation holds promise for durable response and potential cure. The intent of this review is to outline the pathophysiology of VEXAS syndrome and to provide a practical approach to diagnosis and treatment.

Reappraisal of mast cell leukemia based on a single institution review of 16 cases: Mast cell morphology determines clinical outcome.

Cytologic abnormalities of atypical mast cells in mastocytosis. The mature mast cells have oval-shaped nuclei, cytoplasmic hypogranulation and spindle-shaped cytology. or well-differentiated displaying a round nucleus with condensed chromatin, and abundant dense cytoplasmic granulations. Immature mast cells include promastocytes and metachromatic blast-like forms.

TP53 variant allele frequency and therapy-related setting independently predict survival in myelodysplastic syndromes with del(5q).

Among 210 patients with myelodysplastic syndromes (MDSs) with del(5q), molecular information was available at diagnosis or at least 3 months before leukaemic transformation in 146 cases. Multivariate analysis identified therapy-related setting (p = 0.02; HR 2.3) and TP53 variant allele frequency (VAF) ≥22% (p < 0.01; HR 2.8), but not SF3B1 mutation (p = 0.65), as independent risk factors for survival. Median survival was 11.7 versus 4 years (5/10-year survival 73%/52% vs. 42%/14%) in the absence (N = 112) versus presence (N = 34) of ≥1 risk factors; leukaemia-free survival was affected by TP53 VAF ≥22% (p < 0.01). Such information might inform treatment decision-making in MDS-del(5q) regarding allogeneic stem cell transplant.

Real-world experience with ponatinib therapy in chronic phase chronic myeloid leukemia: impact of depth of response on survival and prior exposure to nilotinib on arterial occlusive events.

We surveyed the performance of ponatinib, as salvage therapy, in a real-world setting of chronic phase chronic myeloid leukemia (CML-CP). Among 55 consecutive patients (median age 49 years) with relapsed/refractory CML-CP, 35 (64%) had failed ≥3 tyrosine kinase inhibitors (TKIs), 35 (64%) were pre-treated with nilotinib, and 14 (28%) harbored ABL1T315I. At start of ponatinib (median dose 30 mg/day), 40 patients were already in complete hematologic (CHR), 4 in complete cytogenetic (CCyR), 3 in major molecular (MMR) remission, while 8 had not achieved CHR (NR). Ponatinib improved the depth of response in 13 (33%), 3 (75%), 2 (66%), and 4 (50%) patients with CHR, CCyR, MMR, and NR, respectively (p = 0.02). At a median follow-up of 42 months, 13 (23%) deaths, 5 (9%) blast transformations, and 25 (45%) allogeneic transplants were recorded. Five/10-year post-ponatinib survival was 77%/58% with no significant difference when patients were stratified by allogeneic transplant (p = 0.94), ponatinib-induced deeper response (p = 0.28), or a post-ponatinib ≥CCyR vs CHR remission state (p = 0.25). ABL1T315I was detrimental to survival (p = 0.04) but did not appear to affect response. Prior exposure to nilotinib was associated with higher risk of arterial occlusive events (AOEs; 11% vs 0%; age-adjusted p = 0.04). Ponatinib starting/maintenance dose (45 vs 15 mg/day) did not influence either treatment response or AOEs. Our observations support the use of a lower starting/maintenance dose for ponatinib in relapsed/refractory CML-CP but a survival advantage for deeper responses was not apparent and treatment might not overcome the detrimental impact of ABL1T315I on survival. The association between prior exposure to nilotinib and a higher risk of post-ponatinib AOEs requires further validation.

Targeted testing of bone marrow specimens with cytoplasmic vacuolization to identify previously undiagnosed cases of VEXAS syndrome.

OBJECTIVE: To retrospectively identify patients with VEXAS syndrome (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic syndrome) among male patients with bone marrow vacuolization using a clinically applicable, targeted-screening approach. METHODS: Bone marrow reports from 1 May 2014 through 18 February 2022 were reviewed for documentation of cytoplasmic vacuolization. Patients with acute leukaemia, lymphoma, metastatic solid tumour, amyloidosis or POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes) syndrome were excluded, as were those without clinical records available for direct chart review. Cases were rated for suspicion of VEXAS syndrome using a 5-point scale based on the presence of laboratory findings, clinical features and treatment response. Patients with available DNA material and moderate (three patients) or high (four to five patients) suspicion were tested for somatic UBA1 variants associated with VEXAS syndrome. RESULTS: A total of 315 reports from 292 unique patients included documentation of vacuolization. Following exclusion criteria, 64 patients underwent direct medical chart review to assess likelihood of VEXAS syndrome, for which 21 patients met moderate to high suspicion. Available DNA was present in eight patients, seven (87.5%) of whom had a pathogenic somatic UBA1 variant consistent with VEXAS syndrome. The distribution of cytoplasmic vacuolization in the bone marrow biopsy reports among patients with VEXAS syndrome were erythroid and myeloid precursors (6/7), erythroid precursors only (1/7) and myeloid precursors only (0/7). CONCLUSION: In this study, the utilization of a clinically applicable targeted-screening approach to test bone marrow specimens (with vacuolization) for the presence of previously undiagnosed VEXAS syndrome resulted in a positive detection rate of 87.5%.

Pulmonary manifestations in VEXAS syndrome.

BACKGROUND: Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome is a recently recognized multisystem disorder caused by somatic mutations in the UBA1 gene. METHODS: A retrospective cohort study was conducted on all patients with VEXAS syndrome evaluated at our institution from June 2020 through May 2022. Medical records and chest imaging studies were reviewed. RESULTS: We identified 45 subjects with median age of 68 years (range, 57-89), all men. Prior to VEXAS diagnosis, most patients had been diagnosed with various hematologic, rheumatologic, and dermatologic disorders. Most patients (84%) demonstrated canonical UBA1 methionine-41 (p.Met41) somatic mutations in hematopoietic cells. Fever (82%), skin lesions (91%), and respiratory symptoms (93%) were common presenting features. Chest CT manifested abnormalities in 91% of patients including parenchymal opacities in 25 (74%), most commonly ground-glass opacities (47%), along with mediastinal lymphadenopathy (29%), airway abnormalities (29%), and pleural effusion (24%). Pulmonary function test results available in 18 (40%) patients demonstrated mild restrictive impairment or normal results. Bronchoalveolar lavage and lung biopsy performed in a minority of patients demonstrated neutrophilic alveolitis and parenchymal inflammation, respectively. All patients received glucocorticoid therapy with at least partial response, but relapses were common and other immunosuppressive agents were employed in most patients. Pulmonary involvement appeared to improve in patients who received tocilizumab and JAK inhibitors. CONCLUSION: The pulmonary manifestations in VEXAS are relatively nonspecific and nonsevere, occur in the context of systemic inflammation and are responsive to escalation in glucocorticoid dosing.

Updates on eosinophilic disorders.

This review addresses changes and updates in eosinophilic disorders under the International Consensus Classification (ICC). The previous category of myeloid/lymphoid neoplasm with eosinophilia (M/LN-eo) and a specific gene rearrangement is changed to M/LN-eo with tyrosine kinase gene fusions to reflect the underlying genetic lesions. Two new members, M/LN-eo with ETV6::ABL1 fusion and M/LN-eo with various FLT3 fusions, have been added to the category; and M/LN-eo with PCM1::JAK2 and its genetic variants ETV6::JAK2 and BCR::JAK2 are recognized as a formal entity from their former provisional status. The updated understanding of the clinical and molecular genetic features of PDGFRA, PDGFRB and FGFR1 neoplasms is summarized. Clear guidance as to how to distinguish these fusion gene-associated disorders from the overlapping entities of Ph-like B-acute lymphoblastic leukemia (ALL), de novo T-ALL, and systemic mastocytosis is provided. Bone marrow morphology now constitutes one of the diagnostic criteria of chronic eosinophilic leukemia, NOS (CEL, NOS), and idiopathic hypereosinophilia/hypereosinophilic syndrome (HE/HES), facilitating the separation of a true myeloid neoplasm with characteristic eosinophilic proliferation from those of unknown etiology and not attributable to a myeloid neoplasm.

Pure (acute) erythroid leukemia: morphology, immunophenotype, cytogenetics, mutations, treatment details, and survival data among 41 Mayo Clinic cases.

Pure erythroid leukemia (PEL), also known as acute erythroid leukemia (AEL), is recognized as a distinct morphologic entity by both the 2016 and 2022 World Health Organization (WHO) classification system. By contrast, the 2022 International Consensus Classification (ICC) includes PEL under a broader category of "acute myeloid leukemia with mutated TP53". We identified 41 Mayo Clinic cases of PEL (mean age 66 years, range 27-86; 71% males) and provide a comprehensive account of bone marrow morphology, immunophenotype, cytogenetic and mutation profiles. PEL was primary in 14 cases, therapy-related in 14, secondary in 12, and undetermined in one. All cases expressed biallelic TP53 alterations, including TP53 deletion/single TP53 mutation (68%), two TP53 mutations (29%) or two TP53 deletions (3%); additional mutations were infrequent. Karyotype was complex in all cases and monosomal in 90%. Treatment details were available in 29 patients: hypomethylating agent (HMA) alone (n = 5), HMA + venetoclax (n = 12), intensive chemotherapy (n = 4), supportive care/other (n = 8); no responses or allogeneic stem cell transplants were documented, and all patients died at a median 1.8 months (range 0.2-9.3). The current study highlights a consistent and reproducible set of morphologic and genetic characteristics that identify PEL as a distinct AML variant whose dismal prognosis requires urgent attention.