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BACKGROUND: Organomegaly, including splenomegaly, hepatomegaly, and/or lymphadenopathy, are important diagnostic and prognostic features in patients with cutaneous mastocytosis (CM) or systemic mastocytosis (SM). OBJECTIVES: To investigate the prevalence and prognostic impact of 1 or more organomegalies on clinical course and survival in patients with CM/SM. METHODS: Therefore, 3155 patients with CM (n = 1002 [32%]) or SM (n = 2153 [68%]) enrolled within the registry of the European Competence Network on Mastocytosis were analyzed. RESULTS: Overall survival (OS) was adversely affected by the number of organomegalies (OS: #0 vs #1 hazard ratio [HR], 4.9; 95% CI, 3.4-7.1, P < .001; #1 vs #2 HR, 2.1, 95% CI, 1.4-3.1, P < .001; #2 vs #3 HR, 1.7, 95% CI, 1.2-2.5, P = .004). Lymphadenopathy was frequently detected in patients with smoldering SM (SSM, 18 of 60 [30%]) or advanced SM (AdvSM, 137 of 344 [40%]). Its presence confered an inferior outcome in patients with AdvSM compared with patients with AdvSM without lymphadenopathy (median OS, 3.8 vs 2.6 years; HR, 1.6; 95% CI, 1.2-2.2; P = .003). OS was not different between patients having organomegaly with either ISM or SSM (median, 25.5 years vs not reached; P = .435). At time of disease progression, a new occurrence of any organomegaly was observed in 17 of 40 (43%) patients with ISM, 4 of 10 (40%) patients with SSM, and 33 of 86 (38%) patients with AdvSM, respectively. CONCLUSIONS: Organomegalies including lymphadenopathy are often found in SSM and AdvSM. ISM with organomegaly has a similar course and prognosis compared with SSM. The number of organomegalies is adversely associated with OS. A new occurrence of organomegaly in all variants of SM may indicate disease progression. (c) 2022 American Academy of Allergy, Asthma & Immunology

Background: Hypertension management in older patients represents a challenge, particularly when hospitalized. Objective: The objective of this study is to investigate the determinants and related outcomes of antihypertensive drug prescription in a cohort of older hospitalized patients. Methods: A total of 5671 patients from REPOSI (a prospective multicentre observational register of older Italian in-patients from internal medicine or geriatric wards) were considered; 4377 (77.2%) were hypertensive. Minimum treatment (MT) for hypertension was defined according to the 2018 ESC guidelines [an angiotensin-converting-enzyme-inhibitor (ACE-I) or an angiotensin-receptor-blocker (ARB) with a calcium-channel-blocker (CCB) and/or a thiazide diuretic; if >80 years old, an ACE-I or ARB or CCB or thiazide diuretic]. Determinants of MT discontinuation at discharge were assessed. Study outcomes were any cause rehospitalization/all cause death, all-cause death, cardiovascular (CV) hospitalization/death, CV death, non-CV death, evaluated according to the presence of MT at discharge. Results: Hypertensive patients were older than normotensives, with a more impaired functional status, higher burden of comorbidity and polypharmacy. A total of 2233 patients were on MT at admission, 1766 were on MT at discharge. Discontinuation of MT was associated with the presence of comorbidities (lower odds for diabetes, higher odds for chronic kidney disease and dementia). An adjusted multivariable logistic regression analysis showed that MT for hypertension at discharge was associated with lower risk of all-cause death, all-cause death/hospitalization, CV death, CV death/hospitalization and non-CV death. Conclusions: Guidelines-suggested MT for hypertension at discharge is associated with a lower risk of adverse clinical outcomes. Nevertheless, changes in antihypertensive treatment still occur in a significant proportion of older hospitalized patients.

The proprotein convertase subtilisin/kexin type 9 (PCSK9) is emerging as a novel cardiovascular risk factor. Levels of PCSK9 in thrombotic primary antiphospholipid syndrome (PAPS) have never been investigated.Cross sectional comparison of baseline characteristics of 91 PAPS patients enrolled in the multicenter prospective ATHERO-APS cohort study. PCSK9 levels were categorized into tertiles and the association with arterial and recurrent thrombosis were assessed by univariable and multivariable logistic regression analysis.Median age was 51 years and 71.4% (n = 65) were women. Overall, 33% (n = 30) experienced an arterial event while 31% (n = 28) had recurrent thrombotic events. Median PCSK9 levels were 1243 (1100-1650) pg/ml. Patients in the third PCSK9 tertile (1458 pg/ml) showed a higher prevalence of dyslipidemia, lupus anticoagulant positivity and a history of previous arterial and recurrent thrombosis than patients in the first and second tertile. PCSK9 levels were higher in arterial than venous thrombosis (1502 vs. 1180 pg/ml, p = 0.002), and in patients with recurrent vs isolated thrombosis (1680 vs. 1150 pg/m, p 0.001). High plasma PCSK9 levels were associated with a 4-fold increase risk for arterial events and with a 10-fold increase risk for recurrent thrombosis after adjustment for confounding factors.These preliminary data suggest that PCSK9 levels are increased in PAPS patients with arterial and recurrent thrombosis. Its role as a possible therapeutic target in PAPS needs further studies.

In the current classification of the World Health Organization (WHO), bone marrow mastocytosis (BMM) is a provisional variant of indolent systemic mastocytosis (ISM) defined by bone marrow involvement and absence of skin lesions. However, no additional diagnostic criteria for BMM have been proposed. Within the registry dataset of the European Competence Network on Mastocytosis, we compared characteristics and outcomes of 390 patients with BMM and 1175 patients with typical ISM. BMM patients were significantly older, predominantly male, had lower tryptase and lower burden of neoplastic mast cells, and displayed a higher frequency of allergic reactions, mainly triggered by Hymenoptera, than patients with typical ISM. The estimated 10-year progression-free survival of BMM and typical ISM was 95.9% and 92.6%, respectively. In BMM patients defined by WHO-based criteria, the presence of one B-Finding and tryptase level ≥125 ng/mL were identified as risk factors for progression in multivariate analyses. BMM patients without any of these risk factors were found to have better progression-free survival (p < 0.05) and better overall survival (p < 0.05) than other ISM patients. These data support the proposal to define BMM as a separate SM variant characterized by SM criteria, absence of skin lesions, absence of B-Findings, and tryptase levels

Systemic mastocytosis (SM) encompasses a heterogeneous group of clonal disorders characterized by abnormal expansion of mast cells (MCs). Beyond KIT and other genes recurrently mutated in myeloid neoplasms, several genetic variants have been described as predisposing to the development of the disease and influencing its clinical phenotype. Increased copy number variants of the TPSAB1 gene were identified as a cause of nonclonal elevated tryptasemia and defined as hereditary α-tryptasemia (HαT). Moreover, HαT is enriched in patients with SM, where it can affect the incidence of mediator-related symptoms.In a multicenter data set of 444 patients with MC disorders, we aimed to investigate the clinical correlates of germline TPSAB1 copy number gains.Droplet digital PCR was performed in all cases to ascertain the presence of HαT. Clinical history along with blood values and bone marrow examination were analyzed.We confirmed a higher incidence of HαTThese findings on a large patient series support and extend previous data, and suggest that knowledge of HαT status may be useful for personalized management of patients with SM.

Introduction Hereditary alpha-Tryptasemia (HαT) is a group of genetically defined traits that share increased copy number of TPSAB1 gene encoding for both the α- and β-alleles (Lyons et al 2018). Increased copy number (CN) of the α-tryptase coding sequence in TPSAB1 on one or both alleles represents the genetic base of HαT (Lyons et al 2016). HαT is characterized by mild elevation in serum tryptase levels and a variety of mast cell (MC) activation symptoms, including recurrent anaphylaxis. Prevalence in the general population is up to 5%, that increases up to 20% in systemic mastocytosis (SM); it has been suggested that HαT might be a germline variant predisposing to SM development. In SM, HαT correlated with higher incidence of mediator-related symptoms (Greiner G et al, Blood 2021). Due to its complexity, the assay for TPSAB1 CN is performed in few centers and the actual prevalence of HαT in selected subsets is still to be elucidated. To this end, we screened for HαT 2 groups of subjects, the first with MC activation symptoms and no evidence of SM, the second with diagnosis of SM according to WHO-2016. Methods Droplet digital PCR (ddPCR) was used to measure CN variation (CNV) in TPSAB1 by adapting standard CNV ddPCR protocol to genotype for both TPSAB1 and TPSB2 (Fig.1A). The high homology between α and β encoding isoforms and the presence of paralogous genes in a single locus makes TPSAB1 CNV detection very challenging. ddPCR was performed on genomic DNA with/without BamHI, using the PrimePCR ddPCR Copy Number reference AP3B1 (BioRad). Accuracy and precision of the ddPCR protocol was assessed by analyzing 10 samples in triplicate in 3 separate experiments. Data robustness and repeatability can be appreciated in Fig 1B. Results We studied 41 subjects with mediator-related symptoms and augmented basal serum tryptase (BST) (cohort 1) and 150 patients with ascertained diagnosis of mastocytosis (cohort 2). The BST threshold established for cohort 1 was equal or higher than 11 mcg/L. Median age was 64.7 yr, males 54%; median BST levels was 15.3 (range 12.3-21 mcg/L); 29% of the pts had history of anaphylaxis. In cohort 2, 134/150 (89.3%) pts had a diagnosis of SM, whereas 13/150 (8,6%) were Cutaneous Mastocytosis (CM). Among SM patients, 113(84.3%) presented with non-advanced SM variants. Advanced forms including aggressive SM (ASM) and SM with an associated hematological neoplasm (SM-AHN) were diagnosed in 6 (4.5%) and 8 (6%) respectively. In 3 pts, SM subtype was not available. Median age was 49 yr, males 55%; 41.7% of the pts had history of anaphylaxis. HαT was documented in 27 (65.9%) subjects in cohort 1, and 14 (9.3%) in cohort 2. In cohort 1, 3 α-tryptase (3α) copy number was observed more frequently (59.2% of HαT+ pts); conversely 3α and 2α-tryptase copy number were observed at a similar rate (42,8%) in cohort 2. HαT+ pts in cohort 1 presented significantly higher BST (17.1 vs 12.05 mgc/L, P In cohort 2, BST levels were similar in HαT+ and HαT wt pts (24.6 and 24.3 mcg/L), as were anaphylaxis episodes (50% and 41%, respectively). A trend for lower MC burden in HαT+ as assessed by flow cytometry was demonstrated (% of bone marrow MC: 0.01% in HαT+ vs 0.07%) whereas no meaningful differences emerged regarding the symptom burden. In addition, a lower prevalence of KIT 816V mutation was observed in HαT+ (71.4% vs 89.5%; p=0.073). Conclusions In our study HαT+ was observed in around 10% of patients with SM, a prevalence lower than previously reported (Greiner et al, Blood 2021) and remarkably lower than in a selected cohort of subjects with raised BTL and history of mediator-released symptoms (66%). ddPCR represents a suitable method to investigate the presence of CNV in the α-tryptase coding sequence. Genetic testing for HαT+ should be considered in the diagnostic workout of patients presenting with anaphylaxis or MC mediator-related symptoms and no suspicion/evidence of SM. The clinical correlates of HαT in SM remain to be fully ascertained. Supported by IMH no.GR-2016-02362631 and AIRC, Mynerva project no21267 Figure 1 Figure 1. Disclosures Elena: CELGENE: Other: funding for meeting participation; PFIZER: Membership on an entity's Board of Directors or advisory committees; NOVARTIS: Membership on an entity's Board of Directors or advisory committees; GILEAD: Membership on an entity's Board of Directors or advisory committees. Vannucchi: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees.