Reichard, Kaaren K.

Background Absolute basophil count (ABC) might be increased in patients with myeloproliferative neoplasms and has been associated with poor prognosis in chronic myeloid leukemia (CML) and, possibly, primary myelofibrosis (PMF, Front. Oncol 2019;9:872). In a Mayo Clinic survey of 382 patients with BCR::ABL1-negative leukocytosis and ABC ≥0.09 x 109/L, 191 (50%) were associated with myeloid neoplasms, including 104 (27%) with CML, 23 (6%) essential thrombocythemia, 21 (6%) polycythemia vera (PV), and 18 (5%) PMF (AJH 2020;95:E216). Herein, we tapped into a well-characterized cohort of patients with PV, in order to describe the prevalence of basophilia, at specific ABC thresholds, and corresponding clinical, molecular, and prognostic correlates. Methods Study patients were retrospectively recruited from Mayo Clinic (USA) databases, after approval from IRB. Diagnostic criteria were according to the International Consensus Classification (Blood 2022;140:1200). Study inclusion criteria included the availability of information on ABC and absolute eosinophil count (AEC). Mayo Clinic institutional reference range for ABC was 0.01 to 0.08 x 109/L and for AEC 0.03 to 0.48 x 109/L. “Eosinophilia” was defined as an AEC of ≥0.6 x 109/L. Basophilia was evaluated both at an ABC of ≥0.1 x 109/L and ABC of ≥0.3 x 109/L, the latter representing 3 x the upper limit of the normal reference range. Cytogenetic information obtained within one year of diagnosis was available in 270 patients. Next-generation sequencing information collected before disease transformation was available in 99 patients. Conventional statistical methods were employed for comparisons of groups and survival analysis (JMP Pro 17.0.0 software SAS Institute, Cary, NC, USA). Results Information on ABC and AEC, obtained within one year of diagnosis, was available in 478 patients (median age 66 years; males 51%). Median values at presentation were 10.6 x 109/L for leukocyte count, 453 x 109/L platelet count, and 17.3 g/dL hemoglobin level. Presenting symptoms included palpable splenomegaly 24%, pruritus 31%, arterial thrombosis 12%, and venous thrombosis 17%. Median and range values for ABC and AEC were 0.12 x 109/L (0-3.2) and 0.27 x 109/L (0-6.5), respectively. ABC was ≥0.3 x 109/L in 80 (17%) patients and ≥0.1 x 109/L in 315 (66%). AEC was ≥0.6 x 109/L in 68 (14.6%) patients. ABC≥0.3 x 109/L was associated with AEC ≥0.6 x 109/L (p<0.01), leukocytosis (p<0.01), and palpable splenomegaly (p=0.02), but not platelet count, pruritus, smoking history, diabetes, or arterial or venous thrombosis; in multivariable analysis, the association with leukocytosis, but not that with splenomegaly, was confirmed. At a median follow-up of 5.7 years (range 0.03-32.8), 132 (28%) deaths, 17 (3.6%) leukemic and 40 (8.4%) fibrotic progressions were documented. Post-diagnosis events also included arterial (7%) and venous (9%) thrombosis. In univariate analysis, neither ABC (p=0.8, 0.7, and 0.96) nor AEC (p=0.7, 0.6, and 0.8), evaluated as continuous variables, affected overall (OS), leukemia-free (LFS), or myelofibrosis-free (MFFS) survival, respectively. Similarly, eosinophilia at AEC ≥0.6 x 109/L did not appear to influence OS (p=0.99), LFS (p=0.6) or MFFS (p=0.5). On the other hand, although basophilia at ABC≥0.3 x 109/L did not affect OS (p=0.27), it was significantly associated with inferior LFS (HR 6.5, 95% CI 2.3-18.0; p<0.01) and MFFS (HR 2.3, 95% CI 1.2-4.5; p=0.01); the corresponding p values for ABC≥0.1 x 109/L were 0.7, 0.1, and 0.17. The detrimental impact of basophilia (ABC≥0.3 x 109/L) on LFS was confirmed (P<0.01) with multivariable analysis that included other clinical variables, including leukocytosis (NS), platelet count (NS), basophil percentage (NS), age (p<0.01), and palpable splenomegaly (p<0.01). Results were similar during multivariable analysis for MFFS with palpable splenomegaly (p<0.01), ABC≥0.3 x 109/L (p=0.03), and age (p=0.05) sustaining independent predictive value. The number of informative cases was too small to evaluate prognostic interaction with mutations and karyotype. Conclusions: Basophilia in PV is associated with palpable splenomegaly and leukocytosis and independently predicts leukemic and myelofibrotic transformation. Additional studies are needed to confirm these observations and examine prognostic interaction with mutations and karyotype.

Abstract Objectives To define the prevalence, distribution and characteristics of patients with VEXAS (vacuoles, E1-enzyme, X-linked, autoinflammation, somatic) syndrome who have confirmed vasculitis. Methods Patients with VEXAS syndrome, verified by positive UBA1 mutation, were included. Chart review was performed to identify patient characteristics and outcomes. Vasculitis diagnosis was based on either histopathology showing vascular inflammation or non-invasive angiography findings. Summary statistics were calculated. Results Eighty-nine patients met inclusion criteria. All were male with a median age of onset of 66.9 years (interquartile range 60.1, 72.7). Median (interquartile range) follow-up was 3.8 (2.2–5.5) years, during which 21 patients (23.6%) had evidence of vasculitis. Vasculitis subtypes included small vessel vasculitis (19.1%), cutaneous medium vessel vasculitis (2.2%) and large vessel vasculitis (2.2%). No patient had more than one vessel size involved. Histopathology in small vessel vasculitis patients was consistent with cutaneous leukocytoclastic vasculitis in the majority, though one patient had leukocytoclastic peritubular capillaritis on renal biopsy. Cranial symptoms (headache, vision changes or jaw pain) were noted in 18.0%. Two additional patients not experiencing cranial symptoms exhibited large vessel involvement with confirmed carotid thickening on non-invasive angiography; one of these had a positive temporal artery biopsy. Conclusion VEXAS syndrome manifests as a variable vessel vasculitis in a quarter of patients, with cutaneous small and medium vessel involvement being particularly common. Some patients may have positive ANCA serologies or even renal vasculitis leading to misdiagnosis. Cranial symptoms are common and may mimic GCA, though documented large vessel inflammation is rare.

Abstract This phase 2 trial assessed high-dose IV ascorbic acid in TET2 mutant clonal cytopenia. Eight of 10 patients were eligible for response assessment, with no responses at week 20 by International Working Group Myelodysplasia Syndromes/Neoplasms criteria. This trial was registered at www.clinicaltrials.gov as #NCT03418038.

AbstractThe current study was inspired by observations from exploratory analyses of an institutional cohort with chronic myelomonocytic leukemia (CMML; N = 398) that revealed no instances of blast transformation in the seven patients with plant homeodomain finger protein 6 (PHF6) mutation (PHF6MUT). A subsequent Mayo Clinic enterprise‐wide database search identified 28 more cases with PHF6MUT. Compared with their wild‐type PHF6 counterparts (PHF6WT; N = 391), PHF6MUT cases (N = 35) were more likely to co‐express TET2 (89% vs. 45%; p < .01), RUNX1 (29% vs. 14%; p = .03), CBL (14% vs. 2%; p < .01), and U2AF1 (17% vs. 6%; p = .04) and less likely SRSF2 (23% vs. 45%; p < .01) mutation. They were also more likely to display loss of Y chromosome (LoY; 21% vs. 2%; p < .01) and platelets <100 × 109/L (83% vs. 51%; p < .01). Multivariable analysis identified PHF6MUT (HR 0.28, 95% CI 0.15–0.50) and DNMT3AMUT (HR 5.8, 95% CI 3.3–10.5) as the strongest molecular predictors of overall survival. The same was true for blast transformation‐free survival with corresponding HR (95% CI) of 0.08 (0.01–0.6) and 9.5 (3.8–23.5). At median 20 months follow‐up, blast transformation was documented in none of the 33 patients with PHF6MUT/DNMT3AWT but in 6 (32%) of 19 with DNMT3AMUT and 74 (20%) of 374 with PHF6WT/DNMT3AWT (p < .01). The specific molecular signatures sustained their significant predictive performance in the context of the CMML‐specific molecular prognostic model (CPSS‐mol). PHF6MUT identifies a unique subset of patients with CMML characterized by thrombocytopenia, higher prevalence of LoY, and superior prognosis.

Abstract Objectives Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic (VEXAS) syndrome is an autoinflammatory disease caused by somatic mutation of UBA1 and affects multiple organ systems. Involvement of the kidneys is not well characterized. We aimed to investigate the incidence, risk factors and histopathologic features of acute kidney injury (AKI) in VEXAS syndrome. Methods Patients with genetically confirmed UBA1 mutation consistent with VEXAS were included. Charts were manually reviewed. Cox regression analysis was used to identify variables associated with time-to-first AKI event. For patients with a kidney biopsy, histopathologic findings were reviewed. Results Eighty-one patients were included, all white men, with a mean age of 66.3 ± 8.6 years. Median (IQR) follow up was 3.5 (2.1–5.2) years during which 20 (25%) developed AKI and 22% died. AKI relapsed in 90% of cases for a median of 6 times during the follow up period. Cumulative incidence estimates (95% CI) for AKI at 1, 3 and 5 years were 6.2% (0.80–11.3%), 16.7% (7.5–25.0%) and 27.9% (14.9–38.9%), respectively. Age and baseline C-reactive protein (CRP) were significantly associated with time-to-first AKI event. Six patients underwent a kidney biopsy. Findings included, plasma cell-rich interstitial nephritis (n = 3), neutrophilic-rich interstitial inflammation (n = 1), leukocytoclastic peritubular capillaritis (n = 1) and acute tubular injury (n = 1). AKI responded well to treatment with glucocorticoids but had relapse upon tapering. Conclusion AKI is an underrecognized feature of VEXAS occurring in 25% of patients in this cohort. Age at diagnosis and CRP were associated with time to first AKI event during follow up. Plasma cell-rich interstitial nephritis was the most common histopathologic finding.

DDX41 -associated cytopenia(s)/myeloid neoplasms ( DDX41 -C/MNs) are an emerging pathologic entity. We examined the hematopathologic findings in DDX41 -C/MNs with both a germline and somatic DDX41 mutation ( DDX41 -C/MNs-GS). We reviewed the peripheral blood and bone marrow (BM) findings from treatment-naive patients with DDX41 -C/MNs-GS. Thirty cases were identified: 10% (3/30) were classified as clonal cytopenia(s) of unknown significance (CCUS), 17% (5/30) as myelodysplastic neoplasm/syndrome (MDS) with <5% blasts, 20% (6/30) as MDS with 5% to 9% blasts, 20% (6/30) as MDS with 10% to 19% blasts, and 33% (10/30) as acute myeloid leukemia (AML). All patients were cytopenic; circulating blasts were rare (23%, 7/30). 63% (19/30) showed dysmegakaryopoiesis. Dyserythropoiesis and dysgranulopoiesis were uncommon; seen in 20% (6/30) and 7% (2/30), respectively. Sixty-six percent (19/29) of cases were normocellular; 43% (13/30) showed erythroid predominance. Flow cytometry revealed an unremarkable blast myeloid phenotype. Blasts were intermediate sized with round nuclei, distinct nucleoli, and light blue cytoplasm with azurophilic granules. The karyotype was predominantly normal (93%, 26/28). All germline mutations were deleterious: 53% (16/30) truncating and 47% (14/30) missense. The most common somatic variant was the R525H mutation in 70% (21/30). The BM diagnostic spectrum in DDX41- C/MNs that harbor both a germline and somatic DDX41 mutation is broad—ranging from CCUS to AML. We describe consistent hematopathologic findings that pathologists may expect in these cases.

SummaryWe describe the clinical phenotype, management strategies and outcomes of 22 patients with autoimmune myelofibrosis (AIMF); median age: 45 years; 77% females; 83% with autoimmune disease, pancytopenia in 32% and transfusion‐requiring anaemia in 59%. All informative cases were negative for JAK2 (n = 18) and CALR/MPL mutations (n = 12). Fourteen of nineteen (74%) evaluable patients achieved complete response (CR) based on the resolution of cytopenias. First‐line treatments included steroids +/− immunosuppressive agents, cyclosporin and mycophenolate with CR in 7 of 13 (54%), 1 of 2 (50%) and 1 of 2 (50%) respectively. Rituximab salvage therapy yielded CR in 4 of 5 (80%) cases. The current study provides information on steroid‐sparing treatments for AIMF.

Abstract 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 syndrome. The risk factors and frequency of thrombosis in VEXAS syndrome are not well described, due to the disease’s recent discovery and the paucity of large databases. We evaluated 119 patients with VEXAS syndrome 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 VTEs were unprovoked, 41% were recurrent, and 20% occurred despite anticoagulation. The cumulative incidence 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 by univariate (odds ratio [OR]: 4.58, confidence interval [CI] 1.28-16.21, P = .02) and multivariate (OR: 16.94, CI 1.99-144.3, P = .01) logistic regression. The cumulative incidence of arterial thrombosis was 6% at 1 year and 11% at 5 years. The overall survival 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 = .8). Patients with VEXAS syndrome are at high risk of VTE; thromboprophylaxis should administered be in high-risk settings unless strongly contraindicated.