Citations

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 TET2 mutations (mTET2) are common genetic events in myeloid malignancies and clonal hematopoiesis. These mutations arise in the founding clone and are implicated in many clinical sequelae associated with oncogenic feedforward inflammatory circuits. However, the direct downstream effector of mTET2 responsible for the potentiation of these inflammatory circuits is unknown. To address this, we performed scRNA-seq and scATAC-seq in patients with COVID-19 with and without TET2-mutated clonal hematopoiesis reasoning that inflammation from COVID-19 may highlight critical downstream transcriptional targets of mTET2. Using this approach, we identified metastasis-associated lung adenoma transcript 1 (MALAT1), a therapeutically tractable lncRNA, as a central downstream effector of mTET2 that is both necessary and sufficient to induce the oncogenic proinflammatory features of mTET2 in vivo. We also elucidate the mechanism by which mTET2 upregulate MALAT1 and describe an interaction between MALAT1 and p65, which leads to RNA “shielding” from protein phosphatase 2A dephosphorylation, thus preventing resolution of inflammatory signaling. Significance: This work identifies MALAT1 as a requisite downstream effector of oncogenic feedforward inflammatory circuits necessary for the development of TET2-mutated CH and fulminant myeloid malignancy. We elucidate a novel mechanism by which MALAT1 “shields” p65 from dephosphorylation to potentiate this circuit and nominate MALAT1 inhibition as a future therapeutic strategy.

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.

Abstract The ZRSR2 gene is a member of the spliceosome gene family which are frequently mutated in myeloid neoplasms. ZRSR2 mutations (ZRSR2m) occur in less than 5% of MDS, CMML, and AML. Our study included 164 ZRSR2m patients (98.8% males) and 98 ZRSR2wt MDS control cohort. In the ZRSR2m group, there were 53 MDS (32%), 39 CCUS (24%), 33 MPN (20%), 23 MDS/MPN overlap (14%), 15 AML (9%), and 1 MPAL (0.6%). Most MDS patients were the low blast subtype (n=37, 70%). Twenty-seven MDS patients (51%), and 23 CCUS patients (59%) had absolute monocyte count ≥0.5 x109/L and 18 of 23 MDS/MPN overlap were CMML (78%). Mutations in ZRSR2 were spread across the entire gene. The median number of co-mutations was 2, with TET2 (51%) and ASXL1 (32%) being the most common. U2AF1 and SRSF2, previously described as mutually exclusive with ZRSR2, were found in 10.4% of patients. Median overall survival (OS) was 51 months, and significantly varied among MNs (p=0.004). ZRSR2m MDS patients had better mOS than the MDS control cohort with ZRSR2wt (35 vs 22 months, p=0.013). ZRSR2m patients with isolated TET2 co-mutation and higher hemoglobin showed improved survival, while patients with RUNX1m, higher WBC count showed worse OS.

Abstract Clonal cytopenia of undetermined significance (CCUS) represents a distinct disease entity characterized by myeloid-related somatic mutations with a variant allele fraction of ≥2% in individuals with unexplained cytopenia(s) but without a myeloid neoplasm (MN). Notably, CCUS carries a risk of progressing to MN, particularly in cases featuring high-risk mutations. Understanding CCUS requires dedicated studies to elucidate its risk factors and natural history. Our analysis of 357 patients with CCUS investigated the interplay between clonality, cytopenia, and prognosis. Multivariate analysis identified 3 key adverse prognostic factors: the presence of splicing mutation(s) (score = 2 points), platelet count of &lt;100 × 109/L (score = 2.5), and ≥2 mutations (score = 3). Variable scores were based on the coefficients from the Cox proportional hazards model. This led to the development of the clonal cytopenia risk score (CCRS), which stratified patients into low- (score of &lt;2.5 points), intermediate- (score of 2.5 to &lt;5), and high-risk (score of ≥5) groups. The CCRS effectively predicted 2-year cumulative incidence of MN for low- (6.4%), intermediate- (14.1%), and high-risk (37.2%) groups, respectively, by the Gray test (P &lt; .0001). We further validated the CCRS by applying it to an independent CCUS cohort of 104 patients, demonstrating a c-index of 0.64 (P = .005) in stratifying the cumulative incidence of MN. Our study underscores the importance of integrating clinical and molecular data to assess the risk of CCUS progression, making the CCRS a valuable tool that is practical and easily calculable. These findings are clinically relevant, shaping the management strategies for CCUS and informing future clinical trial designs.

PURPOSE Thrombocytopenia is a relatively common dose-limiting toxicity during peptide receptor radionuclide therapy (PRRT) in patients with NET. Although uncommon, some patients develop persistent cytopenia and eventually therapy-related myeloid neoplasm (t-MN), which has a dismal prognosis. As the indications for PRRT are expanding, it is important to investigate factors that may predict cytopenias during/after PRRT. We prospectively evaluated the prevalence of clonal hematopoiesis (CH) and cytopenia in patients with NET undergoing PRRT. MATERIALS AND METHODS Patients with metastatic NET with plan to receive four cycles of lutetium-177 were enrolled. CH was evaluated before PRRT using a panel of 220 genes with a targeted depth of ≥1,000×. Patients were followed during PRRT and every 3 months thereafter. RESULTS Of 37 patients enrolled, the median age was 68 years and 51.4% were male. Previous treatment exposures included alkylating agents in 30%, platinum agents in 8%, and external radiation in 13%. CH was detected in 35.1% using a variant allele frequency (VAF) cutoff of ≥2% and 45.9% with a VAF of ≥1%. The most common mutations were in age-related genes ( DNMT3A, TET2). CH was not associated with anemia or neutropenia; however, it was associated with lower platelet count at baseline and more time spent in a thrombocytopenic state during/after PRRT. Five patients had bone marrow biopsies (BMBs) because of sustained hematologic dysfunction post-PRRT, and of those, diagnoses included clonal cytopenia of undetermined significance (CCUS) in three and idiopathic cytopenia of undetermined significance (ICUS) in two. CONCLUSION CH is present in 35.1% of patients with NET and is associated with thrombocytopenia risk during PRRT. Future studies with long-term follow-up will delineate whether CH might be a predictor for higher risk of t-MN after PRRT.