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Background Sex is a major source of diversity among patients and a sex-informed approach is becoming a new paradigm in precision medicine. We aimed to describe sex diversity in myelodysplastic syndromes in terms of disease genotype, phenotype, and clinical outcome. Moreover, we sought to incorporate sex information into the clinical decision-making process as a fundamental component of patient individuality. Methods In this multicentre, observational cohort study, we retrospectively analysed 13 284 patients aged 18 years or older with a diagnosis of myelodysplastic syndrome according to 2016 WHO criteria included in the EuroMDS network (n=2025), International Working Group for Prognosis in MDS (IWG-PM; n=2387), the Spanish Group of Myelodysplastic Syndromes registry (GESMD; n=7687), or the Dusseldorf MDS registry (n=1185). Recruitment periods for these cohorts were between 1990 and 2016. The correlation between sex and genomic features was analysed in the EuroMDS cohort and validated in the IWG-PM cohort. The effect of sex on clinical outcome, with overall survival as the main endpoint, was analysed in the EuroMDS population and validated in the other three cohorts. Finally, novel prognostic models incorporating sex and genomic information were built and validated, and compared to the widely used revised International Prognostic Scoring System (IPSS-R). This study is registered with ClinicalTrials.gov, NCT04889729. Findings The study included 7792 (58middot7%) men and 5492 (41middot3%) women. 10 906 (82middot1%) patients were White, and race was not reported for 2378 (17middot9%) patients. Sex biases were observed at the single-gene level with mutations in seven genes enriched in men (ASXL1, SRSF2, and ZRSR2 p

PURPOSE Myelodysplastic syndromes (MDS) are heterogeneous myeloid neoplasms in which a risk-adapted treatment strategy is needed. Recently, a new clinical-molecular prognostic model, the Molecular International Prognostic Scoring System (IPSS-M) was proposed to improve the prediction of clinical outcome of the currently available tool (Revised International Prognostic Scoring System [IPSS-R]). We aimed to provide an extensive validation of IPSS-M. METHODS A total of 2,876 patients with primary MDS from the GenoMed4All consortium were retrospectively analyzed. RESULTS IPSS-M improved prognostic discrimination across all clinical end points with respect to IPSS-R (concordance was 0.81 v 0.74 for overall survival and 0.89 v 0.76 for leukemia-free survival, respectively). This was true even in those patients without detectable gene mutations. Compared with the IPSS-R based stratification, the IPSS-M risk group changed in 46% of patients (23.6% and 22.4% of subjects were upstaged and downstaged, respectively). In patients treated with hematopoietic stem cell transplantation (HSCT), IPSS-M significantly improved the prediction of the risk of disease relapse and the probability of post-transplantation survival versus IPSS-R (concordance was 0.76 v 0.60 for overall survival and 0.89 v 0.70 for probability of relapse, respectively). In high-risk patients treated with hypomethylating agents (HMA), IPSS-M failed to stratify individual probability of response; response duration and probability of survival were inversely related to IPSS-M risk. Finally, we tested the accuracy in predicting IPSS-M when molecular information was missed and we defined a minimum set of 15 relevant genes associated with high performance of the score. CONCLUSION IPSS-M improves MDS prognostication and might result in a more effective selection of candidates to HSCT. Additional factors other than gene mutations can be involved in determining HMA sensitivity. The definition of a minimum set of relevant genes may facilitate the clinical implementation of the score.

The West‐Svalbard continental slope represents one of the northernmost gas hydrate provinces in the world. It is located on the western Svalbard margin in the eastern Fram Strait at ~79°N, north of the Knipovich Ridge and Molloy transform fault, situated on a hot and relatively young oceanic crust. The project Advancing Knowledge of Methane in the Arctic (AKMA), funded by the Norwegian Research Council, explores Arctic methane sources, processes, ecosystems and geological history in part of this province. During a dedicated research expedition (CAGE21-1-AKMA) a spectacular pinnacle-like structure has been identified at 914 m of water depth in the area of the north Kniponich Ridge, during the exploration by remotely operated vehicle. The structure is located at the base of a small-scale escarpment, typified by the presence of carbonate slabs. It is more than 1 m in height, has a diameter of at least 50 cm, and appears isolated on a flat seafloor with muddy-dominated heterogeneous sediment. From the video, the structure was apparently composed of dead bivalves cemented in a substrate of finer particles. Many bivalves were still articulated and with their valves closed, although no sign of living bivalves could be detected. Living regular echinoids, one large crinoid, several sponges and a few soft corals colonized the surface at the time of observation. Small samples have been collected from the surface of this fossil bivalve pinnacle. These samples supported the video-based interpretation of a fossil structure composed of cemented and carbonate-encrusted dead valves, among which the most abundant and the largest specimens belong to Thyasira cf capitanea, both juvenile and adult. The valves, either articulated or disarticulated, are often cemented by a white thick (3 mm) authigenic carbonate crust that binds together the mollusk shells, but also encrusts some of them internally. This means that these crusts continued to grow also after the death of the mollusks, when some of the valves were open. Additional interesting benthic fauna recognized in the cement includes small gastropods and foraminifers. The genus Thyasira has already been described as a typically chemosymbiotic group of species and as such, it has been reported from active cold seeps in the Arctic, as well as in other geographic areas and in the geologic record. We interpret the pinnacle as fossil evidence of a site of past methane emission, possibly exhumed by recent erosional or gravity-driven resedimentation processes.

To evaluate the health-related quality of life (HRQoL), disease activity, treatment adherence, and work ability in the real-world setting in patients with axial spondyloarthritis (axSpA).QUASAR was a prospective 12-month, observational study involving 23 rheumatology centres across Italy, including adult patients with axSpA according to the Assessment of SpondyloArthritis International Society (ASAS) criteria. Patients were followed at baseline, 3, 6, and 12 months for disease activity and health-related QoL (HRQoL), treatment adherence and work ability. Regression analysis was used to assess the association between treatment and outcome variables.413 (80.7%) out of axSpA 512 patients were diagnosed with ankylosing spondylitis (AS) and 99 (19.3%) with non-radiographic axSpA (nr-axSpA). Nr-axSpA and AS patients had similar baseline disease activity and HRQoL. Biologic disease-modifying anti-rheumatic drugs (bDMARDs) were the most frequent medication (n=426, 83.2%). Over the 1-year follow-up, disease activity measures (joint pain and swelling, CRP, global assessment, BASDAI, ASDAS), HRQoL and work ability significantly improved, while few differences emerged between nr-axSpA and AS patients. Treatment satisfaction and adherence questionnaires improved over the 12 months. Patients treated with bDMARDs showed improved outcomes for disease activity measures and HRQoL variables, greater benefit observed in patients with AS.We found clinical and HRQoL improvement over 1 year in a large, real-world population of nr-axSpA and AS patients treated with bDMARDs or conventional synthetic DMARDs.

© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ., Objectives: To determine factors associated with COVID-19-related death in people with rheumatic diseases. Methods: Physician-reported registry of adults with rheumatic disease and confirmed or presumptive COVID-19 (from 24 March to 1 July 2020). The primary outcome was COVID-19-related death. Age, sex, smoking status, comorbidities, rheumatic disease diagnosis, disease activity and medications were included as covariates in multivariable logistic regression models. Analyses were further stratified according to rheumatic disease category. Results: Of 3729 patients (mean age 57 years, 68% female), 390 (10.5%) died. Independent factors associated with COVID-19-related death were age (66-75 years: OR 3.00, 95% CI 2.13 to 4.22; >75 years: 6.18, 4.47 to 8.53; both vs ≤65 years), male sex (1.46, 1.11 to 1.91), hypertension combined with cardiovascular disease (1.89, 1.31 to 2.73), chronic lung disease (1.68, 1.26 to 2.25) and prednisolone-equivalent dosage >10 mg/day (1.69, 1.18 to 2.41; vs no glucocorticoid intake). Moderate/high disease activity (vs remission/low disease activity) was associated with higher odds of death (1.87, 1.27 to 2.77). Rituximab (4.04, 2.32 to 7.03), sulfasalazine (3.60, 1.66 to 7.78), immunosuppressants (azathioprine, cyclophosphamide, ciclosporin, mycophenolate or tacrolimus: 2.22, 1.43 to 3.46) and not receiving any disease-modifying anti-rheumatic drug (DMARD) (2.11, 1.48 to 3.01) were associated with higher odds of death, compared with methotrexate monotherapy. Other synthetic/biological DMARDs were not associated with COVID-19-related death. Conclusion: Among people with rheumatic disease, COVID-19-related death was associated with known general factors (older age, male sex and specific comorbidities) and disease-specific factors (disease activity and specific medications). The association with moderate/high disease activity highlights the importance of adequate disease control with DMARDs, preferably without increasing glucocorticoid dosages. Caution may be required with rituximab, sulfasalazine and some immunosuppressants.

Despite widespread use of decitabine to treat acute myeloid leukaemia (AML), data on its effectiveness and safety in the real-world setting are scanty. Thus, to analyze the performance of decitabine in clinical practice, we pooled together patient-level data of three multicentric observational studies conducted since 2013 throughout Italy, including 306 elderly AML patients (median age 75 years), unfit for intensive chemotherapy, treated with first-line decitabine therapy at the registered schedule of 20 mg/m2 /iv daily for 5 days every 4 weeks. Overall response rate (ORR), overall survival (OS) curves, and multivariate hazard ratios (HRs) of all-cause mortality were computed. Overall, 1940 cycles of therapy were administered (median, 5 cycles/patient). A total of 148 subjects were responders and, therefore, ORR was 48.4%. Seventy-one patients (23.2%) had complete remission, 32 (10.5%) had partial remission, and 45 (14.7%) had haematologic improvement. Median OS was 11.6 months for patients with favourable-intermediate cytogenetic risk and 7.9 months for those with adverse cytogenetic risk. Median relapse-free survival after CR was 10.9 months (95% confidence interval [CI]: 8.7-16.0). In multivariate analysis, mortality was higher in patients with adverse cytogenetic risk (HR=1.58; 95% CI: 1.13-2.21) and increased continuously with white blood cell (WBC) count (HR=1.12; 95% CI: 1.06-1.18). A total of 183 infectious adverse events occurred in 136 patients mainly (>90%) within the first five cycles of therapy. This pooled analysis of clinical care studies confirmed, outside of clinical trials, the effectiveness of decitabine as first-line therapy for AML in elderly patients unfit for intensive chemotherapy. An adverse cytogenetic profile and a higher WBC count at diagnosis were, in this real life setting, unfavourable predictors of survival.

PURPOSE Recurrently mutated genes and chromosomal abnormalities have been identified in myelodysplastic syndromes (MDS). We aim to integrate these genomic features into disease classification and prognostication. METHODS We retrospectively enrolled 2,043 patients. Using Bayesian networks and Dirichlet processes, we combined mutations in 47 genes with cytogenetic abnormalities to identify genetic associations and subgroups. Random-effects Cox proportional hazards multistate modeling was used for developing prognostic models. An independent validation on 318 cases was performed. RESULTS We identify eight MDS groups (clusters) according to specific genomic features. In five groups, dominant genomic features include splicing gene mutations ( SF3B1, SRSF2, and U2AF1) that occur early in disease history, determine specific phenotypes, and drive disease evolution. These groups display different prognosis (groups with SF3B1 mutations being associated with better survival). Specific co-mutation patterns account for clinical heterogeneity within SF3B1- and SRSF2-related MDS. MDS with complex karyotype and/or TP53 gene abnormalities and MDS with acute leukemia–like mutations show poorest prognosis. MDS with 5q deletion are clustered into two distinct groups according to the number of mutated genes and/or presence of TP53 mutations. By integrating 63 clinical and genomic variables, we define a novel prognostic model that generates personally tailored predictions of survival. The predicted and observed outcomes correlate well in internal cross-validation and in an independent external cohort. This model substantially improves predictive accuracy of currently available prognostic tools. We have created a Web portal that allows outcome predictions to be generated for user-defined constellations of genomic and clinical features. CONCLUSION Genomic landscape in MDS reveals distinct subgroups associated with specific clinical features and discrete patterns of evolution, providing a proof of concept for next-generation disease classification and prognosis.

Introduction: The first-line therapy for patients with low-risk myelodysplastic syndromes (MDSs) commonly consists of erythropoietin stimulating agents (ESAs), with a response rate ranging from 34 to 62%. For nonresponder patients, outside clinical trials, blood transfusions are the most frequent therapeutic option, with detrimental effect on the quality of life and with risks of iron-overload. Since no studies have been yet conducted on this topic, we investigated the potential predictive role of bone marrow (BM) histological evaluation in patients treated with ESAs. Materials and Methods: We performed a morphological and immunohistochemical retrospective analysis of BM biopsies of 96 patients with low-risk MDSs subsequently treated with ESAs. Results: In our series, substantial morphological overlap was found between responder and nonresponder patients. On the contrary, patients with a percentage of CD34-positive blasts >3% or with p53 protein expression Conclusions: Our study reinforces the role of BM biopsy as diagnostic tool in MDSs, being also able to supply information related to response to ESAs and to its loss over time.

OBJECTIVES: Italy was one of the first countries significantly affected by the coronavirus disease 2019 (COVID-19) epidemic. The Italian Society for Rheumatology promptly launched a retrospective and anonymised data collection to monitor COVID-19 in patients with rheumatic and musculoskeletal diseases (RMDs), the CONTROL-19 surveillance database, which is part of the COVID-19 Global Rheumatology Alliance. METHODS: CONTROL-19 includes patients with RMDs and proven severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) updated until May 3rd 2020. In this analysis, only molecular diagnoses were included. The data collection covered demographic data, medical history (general and RMD-related), treatments and COVID-19 related features, treatments, and outcome. In this paper, we report the first descriptive data from the CONTROL-19 registry. RESULTS: The population of the first 232 patients (36% males) consisted mainly of elderly patients (mean age 62.2 years), who used corticosteroids (51.7%), and suffered from multi-morbidity (median comorbidities 2). Rheumatoid arthritis was the most frequent disease (34.1%), followed by spondyloarthritis (26.3%), connective tissue disease (21.1%) and vasculitis (11.2%). Most cases had an active disease (69.4%). Clinical presentation of COVID-19 was typical, with systemic symptoms (fever and asthenia) and respiratory symptoms. The overall outcome was severe, with high frequencies of hospitalisation (69.8%), respiratory support oxygen (55.7%), non-invasive ventilation (20.9%) or mechanical ventilation (7.5%), and 19% of deaths. Male patients typically manifested a worse prognosis. Immunomodulatory treatments were not significantly associated with an increased risk of intensive care unit admission/mechanical ventilation/death. CONCLUSIONS: Although the report mainly includes the most severe cases, its temporal and spatial trend supports the validity of the national surveillance system. More complete data are being acquired in order to both test the hypothesis that RMD patients may have a different outcome from that of the general population and determine the safety of immunomodulatory treatments.

Introduction: Rheumatoid arthritis (RA) represents a risk of non-fatal and cardiovascular events. The aim of the present study was to evaluate simultaneously left and right atrial and ventricular function, as well as arterial stiffness, in RA patients. Methods: This cross-sectional study included 55 consecutive RA patients and 55 healthy age and gender-matched controls. Blood pressure and arterial stiffness were assessed in all participants, who also underwent a complete echocardiographic examination. Results: RA patients were treated with steroid therapy (52.7%), methotrexate (66.6%) and biological therapy (54.5%). Disease activity score revealed low average RA activity. Augmentation index was significantly higher in RA patients (32.2 ± 8.6 vs. 28.4 ± 8.9%, P = 0.02). Left atrial volume was also higher among RA patients (23.1 ± 8.2 vs. 20.1 ± 7.1 ml/m2, P = 0.04), whereas mitral and tricuspid E/A ratios were significantly lower in RA individuals (0.90 ± 0.24 vs. 1.03 ± 0.35, P = 0.02; 1.07 ± 0.31 vs. 1.27 ± 0.35, P = 0.003, respectively). Tissue Doppler systolic and diastolic velocities were similar between the observed groups. Arterial stiffness index showed significant correlation with disease duration (r = 0.29; P = 0.03). Tissue Doppler-derived transmitral late diastolic velocity (A′) showed significant correlation with index of disease activity in the RA patients. Conclusions: Our results showed that left and right ventricular diastolic function and arterial stiffness were significantly deteriorated in the RA patients comparing with controls. The assessment of left and right ventricular diastolic function, as well as vascular function, should be an essential part of clinical evaluation in the RA patients.

Background Low risk Myelodysplastic syndromes (LR MDS) are a heterogeneous group of clonal disorders of the hematopoietic stem cell characterized by ineffective hematopoiesis, peripheral cytopenias and relative increase of bone marrow blasts [List 2004]. The most common cytopenia is anemia, which occurs in 85-90% of cases (isolated in 35% of cases) [Fenaux 2013], and ranges from mild/asymptomatic to transfusion dependent. The standard of care for anemia remains supportive care and about 70% of cases benefits from erythropoiesis-stimulating agents (ESAs). According to the FAB classification, a low-risk group of MDS characterized by the presence of ring sideroblasts (RS) was recognized. In the 2017 WHO classification, the nosologic entities of MDS uni-linear and multi-linear dysplasia with RS (MDS-UD-RS, MDS-MD-RS) were established, to emphasize the importance of identifying forms with a potential therapeutic target [Arber 2016]. Luspatercept is a recombinant fusion protein consisting of the modified extracellular domain of human activin receptor type IIB (ActRIIB) linked to a domain of human immunoglobulin Fc G1. The drug showed efficacy in re-establishing erythropoiesis and was recently approved for the treatment of adult patients with very low- to intermediate-risk MDS-RS failing ESAs[Platzbecker 2017; Fenaux 2020]. Aims To retrospectively assess the efficacy and/or clinical benefit (defined as a reduction in red blood cells transfusions [RBCT] or increase in hemoglobin levels) of luspatercept in patients with LR MDS with RS in a real-life setting. Safety issues were also addressed and clinical and hematological predictors of outcome analyzed. Methods We considered all IPSS-R lower-risk MDS with RS patients with unsatisfactory response or unsuitable for ESAs, treated with luspatercept as monotherapy through an expanded access program since November 2020, in 2 tertiary hematologic centers in Milan, Italy. Luspatercept was administered according to the published schedule: starting dose 1,0 mg/kg every three weeks, with the possibility to increase up to 1,33 mg/kg and 1,75 mg/kg if patients did not reach transfusion independence or decreased transfusion burden after two consecutive infusions. Response to luspatercept was evaluated according to IWG 2018 criteria: Hb increase by > 1.5 g/dL and/or relevant reduction of units of RBC transfusions by an absolute number of at least 4 RBC transfusions/8 wk compared with the pretreatment transfusion number in the previous 8 wk. Results We included a total of 17 pts (70% males, 30% females), with a median age of 68 years (range 45-89). The median follow-up from the start of the Luspatercept was 4 months (range 3-6).According to WHO 2017 we included 13 MLD (76%) and 4 ULD (24%); in all of them SF3B1 mutations was confirmed. Moreover, According to IPSS-R classification: 5 (27%)cases were intermediate and 12 (73%) low risk. All patients received at least three doses of luspatercept. Nine patients (53%) needed a dose escalation to 1,33 mg/kg, and 7 (41%) required the maximal dose of 1,75 mg/kg. Interestingly, not all patients received a dose escalation, and 8 (47%) obtained prolonged efficacy with 1 mg/kg dose. Hemoglobin levels increased in 9 pts (53%): 4 (24%), 3 (18%) and 2 (12%) cases at 1 mg/Kg, 1,33 mg/kg and 1,75 mg/dl, respectively. Medina increase was 1,5 g/dl (range 0,2 - 2,2) and these levels were maintained for a median of 4 months (range 3-6). In addition, considering transfusion burden, the independence was reached in 3 pts (18%), after a median time of 6 weeks from treatment start. Importantly, off the 14 patients remaining transfusion-dependent, 6 (35%) reduced the transfusion burden. The most prominent toxicity was increased blood pressure (grade 2) occurring in 3 pts (18%), and dizziness (grade 2) in 2 pts (12%); though the drug was generally well tolerated. No serious adverse events (SAEs) were reported. Therefore, patients were treated as outpatients in all cases. At the last follow up, all patients are alive and free from leukemic evolution. Conclusions: Our real-world experience confirms the efficacy of luspatercept in improving erythropoiesis and decreasing transfusion dependency in very low, low or intermediate risk MDS with RS, with an acceptable toxicity profile. Disclosures Fattizzo: Amgen: Honoraria, Speakers Bureau; Apellis: Speakers Bureau; Annexon: Consultancy; Momenta: Honoraria, Speakers Bureau; Novartis: Speakers Bureau; Alexion: Speakers Bureau; Kira: Speakers Bureau. Barcellini: Agios: Honoraria, Research Funding; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Alexion Pharmaceuticals: Honoraria; Novartis: Honoraria.

Background: In myelodysplastic syndromes (MDS), thrombocytopenia is an adverse risk factor. Treatments in this setting are scarce. In a randomized international phase 2 trial (EQoL-MDS, EudraCT number 2010-022890-33), we reported effecacy and safety of eltrombopag for the treatment of thrombocytopenia in the first 90 patients with lower-risk MDS with a platelet (PLT) count < 30 Gi/L (Oliva et al. Lancet Hem 2017). However, there are concerns of regulatory agencies regarding the use of thrombopoetin rececptor agonists in MDS due to previous reports signalling disease progression in clinical trials with the use of romiplostim and of eltrombopag, the latter in high risk MDS. Objective: We are further evaluating safety by conducting a comprehensive analysis of mutations in a panel of major driver or candidate driver genes in cases enrolled in the EQoL-MDS trial using targeted-capture sequencing. Methods: Serial (every 3 months) sequencing was performed using the SureSelect custom kit (Agilent Technologies), for which 350 genes were selected from known oncogenes or tumour suppressor genes in haematological malignancies. Relevant somatic mutation data with (i) VAF > 0.05; (ii) depth > 100; (iii) P value for EBCall < 0.0001, were filtered by exclusion based on (i) synonymous SNVs; (ii) variants present only in unidirectional reads; (iii) variants occurring in repetitive genomic regions; (iv) missense SNVs with VAF of 0.4-0.6 or Results: We present preliminary results of the first 21 cases (13 eltrombopag, 9 placebo) enrolled in the trial and with biological samples. Mean age was 62 (± 15) and 13 patients were male. According to the WHO 2016 classification, 11 patients had MDS with single lineage dysplasia (SLD), 7 had multi lineage dysplasia (MLD), 1 placebo case had excess blasts-1, and 1 placebo case had unclassifiable. IPSS-R risk was very low, low and intermediate in 4, 8 and 1 eltrombopag cases, respectively, and 5, 2 and 1 placebo cases, respectively. Karyotype was normal in 16 cases, del(20q) was detected in 4 cases and +14 in 1 case. At study entry, in total 49 genes were mutated (Figure), where one or more of the 49 driver genes were mutated in all but 1 placebo patient (Table). The table shows characteristics and events of patients according to treatment arm. Noteworthy, in the eltrombopag arm, two cases experienced a loss of gene mutations, one obtaining International Working Group defined complete remission of MDS, while 1 MDS EB-1 case had a gain in ZRSR2. Two placebo cases experienced a gain in mutations Conclusions: Treatment with eltrombopag in lower risk MDS is effective and safe. Preliminary analyses do not suggest that eltombopag induces disease progression neither at a clinical, nor a molecular level. Loss of mutations may occur during eltrombopag treatment with complete remission. Figure 1 Figure 1. Disclosures Oliva: Novartis: Other: Advisory Board; Celgene BMS: Consultancy, Other: Advisory Board, Patents & Royalties; Alexion: Other: Advisory Board; Argenx: Other: Advisory Board; Daiichi: Other: Advisory Board; Amgen: Other: Advisory Board. Nannya: Otsuka Pharmaceutical Co., Ltd.: Consultancy, Speakers Bureau; Astellas: Speakers Bureau. Kulasekararaj: Alexion, AstraZeneca Rare Disease Inc.: Consultancy, Honoraria, Other: Travel support; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; Ra Pharma: Consultancy, Honoraria, Speakers Bureau; Alexion: Consultancy, Honoraria, Speakers Bureau; Achilleon: Consultancy, Honoraria, Speakers Bureau; Biocryst: Consultancy, Honoraria, Speakers Bureau; Akari: Consultancy, Honoraria, Speakers Bureau; Apellis: Consultancy; F. Hoffmann-La Roche Ltd.: Consultancy, Honoraria, Speakers Bureau. Latagliata: Novartis: Honoraria; Pfizer: Honoraria; BMS Cellgene: Honoraria. Santini: Astex: Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Geron: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Menarini: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Ogawa: Eisai Co., Ltd.: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Research Funding; Kan Research Laboratory, Inc.: Consultancy, Research Funding; Dainippon-Sumitomo Pharmaceutical, Inc.: Research Funding; ChordiaTherapeutics, Inc.: Consultancy, Research Funding; Ashahi Genomics: Current holder of individual stocks in a privately-held company. OffLabel Disclosure: Eltrombopag (Revolade) is indicated for chronic immune (idiopathic) thrombocytopenic purpura (ITP) patients aged 1 year and above who are refractory to other treatments (e.g. corticosteroids, immunoglobulins).Revolade is indicated in adult patients with chronic hepatitis C virus (HCV) infection for the treatment of thrombocytopenia, where the degree of thrombocytopenia is the main factor preventing the initiation or limiting the ability to maintain optimal interferon-based therapy.Revolade is indicated in adult patients with acquired severe aplastic anaemia (SAA) who were either refractory to prior immunosuppressive therapy or heavily pretreated and are unsuitable for haematopoietic stem cell transplantation.

Background: The treatment for relapsed or refractory acute myeloid leukemia (R/R AML) has minimal chances and a low impact on improving survival. One of the most important goal is to treat unfit patients who are often intolerant to intensive chemotherapy and are not eligible for allogeneic stem cell transplantation. Most patients with AML, including nearly all patients older than 60 years, present multiple, sequentially acquired, somatic mutations. Isocitrate dehydrogenase 2 (IDH2) mutations are present in approximately 8-19% of cases (Buege MJ, Cancers 2018). IDH2 mutations occur early in the leukemogenesis and accumulate an oncogenic product (R-2-hydroxyglutarate) that arrests the histone demethylation pathway, thereby stopping haematopoietic differentiation (Rakheja D, Hum Pathol. 2012). Enasidenib (ENA) is a selective, powerful oral inhibitor of the oncogenic activity of the IDH2 mutant enzyme, that decreases R-2-hydroxyglutarate levels in vitro and in vivo. Interestingly, phase I/II trials showed an overall response rate (ORR) of 40.3% in R/R disease, with 19.3% of complete remission (CR) and with 6.8 % of CR with incomplete haematological recovery (CRi). Moreover, the reported median overall survival was 9.3 months, with 19.7 months (mo) for patients who achieved CR (Stein E, Blood 2017). Aims: To study retrospectively the efficacy and safety of ENA, as single agent, in improving overall survival (OS) and progression-free survival (PFS) in IDH2 mutated R/R AML patients (pts), unfit for intensive chemotherapy. Furthermore, to compare outcomes with a cohort of patients with R/R AML IDH2 wild-type (wt). Methods: Since 2018 we have retrospectively collected and analyzed data of unfit IDH2 mutated R/R AML patients, treated with ENA, thanks to the expanded access program of this drug. The dose was 100 mg/day for all pts. PFS and OS were estimated using the Kaplan-Meier product limit method. Therefore, we considered, as historical comparison, a sample of 28 pts with R/R IDH2 wt AML, treated with the best available therapy at our Institution in the same time frame and matched for clinical features. OS and PFS were compared using the log-rank test. Results: Nine IDH2 mutated pts were considered for analysis: 4 (44%) cases were de novo AML, while 5 (56%) were secondary (1 myelodysplasia and 4 myeloproliferative neoplasms). Median age at relapse was 71 years (range 47-79). Median number of previous therapies was 2 (range 1-3). All pts completed at least one cycle of ENA with a median number of 5 cycles (range 1-16). Median OS from AML diagnosis and from the beginning of ENA was 28 mo (range 3-65), and 15 mo (range 1-27) respectively; median PFS was 13 mo (range 1-14). Among the 28 patients of the control group, with a median age at relapse of 74 years (range 65-86) we recorded a median OS of 14 mo (range 7-62) and an OS from the last relapse of 2 mo (range 0,5-26). The ENA pts group showed a significantly better OS than the control population (p = 0,0419) (Figure 1). The most prominent toxicities were hyperbilirubinemia in 2 pts (22,2%) and IDH-differentiation syndrome (IDH-DS) in 3 (33,3%); though the drug was generally well tolerated. Therefore, patients were treated as outpatients in most cases. Conclusions: In the era of precision medicine, molecular target therapy is the most promising strategy to increase the probability of treatment success with limited side effects. Our experience confirms the efficacy of the IDH2 inhibitor ENA to treat unfit patients with R/R AML in the real life, showing significantly better outcome in terms of survival for the pts treated with target therapy, compared to pts treated with standard therapy. Disclosures Veronese: Janssen Cilag:Honoraria;Bayer:Honoraria;Novartis:Other: Travel Expenses;AstraZeneca:Other: Travel Expenses.

Background: Baricitinib is an oral selective JAK1/2 inhibitor recently approved in the EU for the treatment of rheumatoid arthritis (RA). No real-life data are available about its efficacy and safety. Objectives: To investigate the efficacy and safety profiles of baricitinib in a real-life setting. Methods: We performed a multicenter prospective observational study on adult RA patients starting JAK inhibitors between 12/2017 and 12/2018. Demographic and clinical data as well as laboratory values and adverse events were collected at baseline and after 12 and 24 weeks. Disease activity was measured by DAS28-CRP at baseline, after 12 and 24 weeks. Results: We obtained data from 150 patients with RA (women 116 – 77.3%; median age 60 years, inter-quartile range IQR 54-68; median disease duration 10 years, IQR 4-18) treated with baricitinib 2 or 4 mg QD, however only 2/150 (1.3%) at the reduced dosage. At the time of database lock 95/150 (63%) patients have completed the 12 weeks follow-up, 38/150 (25%) patients have completed the 24 weeks follow-up. Baricitinib was started after at least one conventional synthetic DMARD in all 148/150 cases (99%), being in all of cases methotrexate, while was started prior to a biologic DMARD in 57 (38%) patients. It was prescribed as a second line in 17/93 (18%) patients, third in 27 (29%), fourth or higher in 49 (53%). Baricitinib was prescribed as monotherapy in 57/150 (38%) patients, while combined with methotrexate in 65/150 (43%), at a median dosage of 15 mg/week. Oral corticosteroids were used by 105/150 (70%) patients, at a median dosage of 5 mg/day. Mean DAS28-CRP at baseline was 4.92 (standard deviation 1.22), with 65 (43.3%) patients having a DAS28-CRP>5.1. At both 12 and 24 weeks, a significant reduction of disease activity scores was observed (DAS28-CRP mean 3.07, SD 1.36, and 2.85, SD 1.35, respectively; p values Conclusion: In our real-world dataset, baricitinib is effective in reducing RA disease activity, after 12 weeks, being generally well-tolerated with few severe adverse events. Disclosure of Interests: Giacomo Maria Guidelli: None declared, Elena Generali: None declared, Chiara Bazzani: None declared, Roberto Gorla: None declared, Garifallia Sakellariou: None declared, Massimiliano Limonta: None declared, Maria Sole Chimenti: None declared, Roberto Perricone: None declared, Edoardo Conticini: None declared, Bruno Frediani: None declared, nicola boffini: None declared, Lorenzo Dagna Consultant for: Prof Lorenzo Dagna received consultation honoraria from Abbvie, Amgen, Biogen, Bristol-Myers Squibb, Celltrion, Novartis, Pfizer, Sanofi-Genzyme, and SOBI., Marta Riva: None declared, Maria Rosa Pozzi: None declared, Rosa Daniela Grembiale Grant/research support from: BMS, Consultant for: JANSSEN, CELGENE, Speakers bureau: PFIZER, JANSSEN, BMS, NOVARTIS, Teodora Serban: None declared, Gerolamo Bianchi Consultant for: Alfa-Sigma, Amgen, BMS, Celgene, Medac, UCB, Speakers bureau: Abbvie, Abiogen, Alfa-Sigma, Amgen, BMS, Celgene, Carlo Selmi Grant/research support from: Abbvie, Janssen, MSD, Novartis, Pfizer, Consultant for: Abbvie, Alfa-Sigma, Biogen, BMS, Celgene, Eli-Lilly, GSK, Janssen, Merck Sharp and Dohme, Novartis, Pfizer, Roche, Sanofi-Genzyme, YCB, Speakers bureau: Abbvie, Alfa-Sigma, Biogen, BMS, Celgene, Eli-Lilly, GSK, Janssen, Merck Sharp and Dohme, Novartis, Pfizer, Roche, Sanofi-Genzyme, YCB

Scanty information is available on the effects of combination drug treatment based on an ACE inhibitor and a calcium channel blocker on the neurometabolic alterations characterizing obesity-related hypertension (OHT). After 2-week run-in with enalapril (20 mg), 36 OHTs were randomized according to a double-blind crossover design to a combination therapy with either lercanidipine 10 mg (L) or felodipine extended release 5 mg (F), each lasting 8 weeks. Measurements included clinic and ambulatory blood pressure (BP) and heart rate, homeostasis model assessment index, plasma norepinephrine, and muscle sympathetic nerve activity. Patients with uncontrolled BP were then uptitrated to 20 mg/d (L) and 10 mg/d (F) combined with enalapril 20 mg, respectively, for further 8 weeks. For similar BP reductions, enalapril-lercanidipine (EL) caused norepinephrine and MSNA increases significantly less pronounced than those seen with enalapril-felodipine, the lesser sympathoexcitation observed with EL being coupled with a significant improvement in homeostasis model assessment index. This was the case also when L and F were uptitrated in the combination. In OHT, at variance from enalapril-felodipine, EL combination is almost entirely devoid of any major sympathoexcitatory effect and is associated with an improvement in insulin sensitivity.

Azacitidine (AZA) treatment is effective treatment for patients with myeloid disorders, and factors predictive of treatment outcome are under investigation. Little is known about the effect of bone marrow fibrosis on response to AZA therapy. We, retrospectively, evaluated clinical predictors of overall survival (OS) and overall response rate (ORR) for patients treated with AZA in a real-life cohort. We evaluated 94 consecutive patients treated with AZA outside of clinical trials (75mg/m2/day for 7 days every 28 days; 5 + 2 + 2 schedule), from June 2009 to February 2016. Ninety-three patients were evaluated for response. After a median of 6 cycles, ORR-complete response (CR; including marrow CR) + partial response (PR) + hematological improvement (HI)-was 41.9% (CR = 18.3%; PR = 11.8%; HI = 11.8%). Stable disease was observed in 21.5%, and failure in 36.5%. Pre-AZA bone marrow blast percentage, International Prognostic Scoring System (IPSS) or IPSS-R category, and time from diagnosis to AZA had no effect on response. Median OS from start of therapy was 18.5 months, and was significantly related to higher IPSS category (P = .01), poor cytogenetics according to the IPSS (P = .01), poor and very poor cytogenetics according to the IPSS-R (P = .02), and lower ORR (P = .006). Patients with MF-0 pre-AZA demonstrated significantly higher ORR, (CR + PR + HI) and stable disease, and lower failure rates than those with any grade of fibrosis. Indeed, cases with pre-AZA fibrosis > MF-1 had shorter OS (P = .005). Achievement of HI before 4 cycles of treatment negatively impacted OS (P = .009).

Objective The medullar blast count is a milestone in the prognostic assessment in myelodysplastic syndromes (MDS). The optical microscopy (OM) may sometimes be inaccurate in this disease. The aim of this work is to test the flow immunocytometric (FCM) determinations of medullar immature cells (CD45±) and the expression, among them, of CD33, CD34, and CD117 markers, for their prognostic relevance. Methods In a retrospective analysis of 98 patients affected by MDS, the IPSS was re-calculated by means of the FCM determination of blasts. Survival of patients at low or intermediate-1 IPSS risk was compared with the survival of patients at intermediate-2 or high IPSS risk. In the 64 cases with OM blast count lower than 5%, the survival of patients with the FCM count of medullar blasts ≤2% was compared with that of patients with FCM count >2%. Results Each single marker had a prognostic weight comparable to the optical blast count. The FCM blast count was particularly efficient in distinguishing the risk of having up to 2% or more than 2% of blasts in patients without OM excess of blasts. Conclusion This method is interesting as prognostic tool, especially in patients without excess of blast.

Background The elevated cardiovascular burden of rheumatoid arthritis is well known and the recent update of EULAR recommendations for cardiovascular disease management (1) establish as overarching principle that the rheumatologist is responsible for CVD risk management in patients with RA. They highlight the need of optimal disease activity control, regular CVD risk assessment, lifestyle counseling, appropriate prescription of NSAIDS,corticosteroids,antihypertensives and statins. Screening for asymptomatic atherosclerotic plaques by use of carotid ultrasound is also suggested: the presence of carotid plaques is associated with poor CVD-free survival and is strongly linked to future acute coronary syndrome in RA patients. Objectives We performed an overall cardiovascular assessment to evaluate the presence of end-organ damage in a group of RA patients. Methods We carried out non-invasive 24 hours ambulatory blood pressure monitoring, echocardiography, carotid doppler ultrasound and pulse wave velocity (PWV) in a group of RA patients to optimize non-DMARDs therapy and to evaluate end organ damage. Results 55 RA patients, 76.4% female, mean age 62.8±9 yrs were examined. The median disease duration was 12 yrs. 84% were RF +, 80% ACPA + and 51% had erosions. Mean DAS 28 CRP was 2.82±1.23 and HAQ 0.54±0.6. All pts were treated with cDMARDs and/or bDMARDs (54%) and Pd mean dosage was ≤5 mg/day. Only 3 patients had previous CV event. 49% were hypertensive, 25% had high cholesterol, 13% diabetes and 16% were smokers: median BMI was 25. MAP monitoring revealed that 43/55 (78%) pts were hypertensive: 13 of them had unknown or not/under treated hypertension: 63% had dipper profile and only 12% were reverse dipper. We did not find increased left ventricular mass and wall thickness, but left ventricular diastolic dysfunction grade I-II was found in 26/55 pts, not related to hypertension nor to RA activity. The IMT median value was 655 mm; only in 3 pts was >900 mm: no relation with disease activity was found. In 11 pts carotid plaques were present and related with age, BMI and ambulatory mean pressure values, but not with RA activity or duration. In one patient the plaque required carotid endarterectomy. The PWV median value was >10m/s in 16 pts, all hypertensive. Conclusions The accurate evaluation of cardiovascular involvement of this small group of RA patients shows that hypertension is frequent and often not appropriately treated and seems to be the main cause of the increased PWV. Low grade LV diastolic dysfunction was found in half of patients, with no relation with hypertension or RA features, except for CCP presence, but the small numbers do not allow any speculation. Carotid artery involvement was present in 20% of pts, but only in 1 was clinically significant. Once again no relation with RA features was found: the small number of patients, the low disease activity and the tight and overall clinical control could be partial explanations. The clinical tight control of patients with RA is an unique opportunity to fulfill EULAR reccomendations. References Agca R, et al. Ann Rheum Dis 2016. Disclosure of Interest None declared

Rationale: Granulomatosis with polyangiitis (GPA) is an antineutrophil cytoplasmatic antibodies (ANCA)-associated vasculitis affecting small- and medium-sized blood vessels, mostly involving lung and kidney. Patient concerns: We report the case of a 33-year-old man that presented with acute respiratory distress syndrome caused by alveolar hemorrhage. Diagnoses: Aggressive GPA presenting with diffuse alveolar hemorrhage and multiorgan involvement. Inteventions: Immunosuppressive therapy, plasma exchange, extracorporeal membrane oxygenation (ECMO). Outcomes: Relapse occurred very early, despite immunosuppressive treatment, with a rare involvement of genital system (epididymitis) and rapidly progressive glomerulonephritis difficult to treat. Lessons: GPA is a challenging, multifaceted disease that can require aggressive supportive therapy and is associated with a high rate of relapse that may present with uncommon site of involvement.

Invasive fungal infections (IFIs) seem to be a relevant cause of morbidity and mortality in patients with chronic lymphoproliferative disorders. We studied retrospectively the epidemiology, clinical manifestations and outcome of invasive fungal infections in 42 patients with lymphoproliferative diseases, treated between January 2004 and February 2012 for probable or proven IFI. In our entire population (1355 patients) of chronic lymphoproliferative malignancies, the incidence of probable/proven IFI was 3% (molds 2.3%, yeasts 0.5%, mixed infections 0.2%). Eight patients developed a yeast infection documented by blood cultures in seven cases and by the microscopic observation of Candida spp. in the vitreum after vitrectomy in one case. Among molds we diagnosed three proven infections by histologic evidence of Aspergillus spp. (n = 2) and Mucor (n = 1) in the lung and 28 probable mycoses. Three mixed infections from both molds and yeasts were also observed. Twenty-two cases showed positivity of galactomannan antigen in the serum (n = 16), in bronchoalveolar lavage (BAL) fluid (n = 4) or in both (n = 2). Cultures were positive in 11 cases. The overall rate of response to therapy was 64%. Fungal-attributable mortality rate was 17%, with a significant difference between molds and yeasts (16% vs. 25%, p = 0.03). At univariate analysis, the only risk factors related to mortality were severe and prolonged neutropenia (p = 0.003) and age (p = 0.03). Among molds, the rapid start of antifungals was probably partially responsible, together with new drugs, for the reduction of mortality, despite the severe immunosuppression of these patients.

Background: In myelodysplastic syndromes (MDS), thrombocytopenia is associated with mortality and treatments in this setting are scarce. We tested whether eltrombopag, a thrombopoietin receptor agonist, be effective in improving outcomes in lower-risk MDS with severe thrombocytopenia within a multicentre clinical trial (EQoL-MDS). Initial interim results of short-term efficacy and safety have been published (Oliva et al. Lancet Hem 2017) in the first 90 subjects. We present interim results of the second phase for long-term results in the initial 90 of 174 subjects. Methods: In a single-blind, randomised, controlled, phase 2 trial of adult patients with International Prognostic Scoring System (IPSS) low- or intermediate-1-risk MDS and severe thrombocytopenia. Adult patients with a stable platelet (PLT) count Results: The first 90 subjects were enrolled between 2011 and 2016. Characteristics of patients have been previously published (Lancet Hem 2017). PLT responses occurred in 28 (47.5%) of 59 patients in the eltrombopag group versus 1 (3.2%) of 31 patients in the placebo group (odds ratio 27.1 [95% CI 3.5-211.9], p=0.002) in median time 14 days (95% CI 7-40 days). Severe bleeding (WHO bleeding score ≥2) occurred in 19 patients, with a significantly higher incidence in the placebo (11 [35.3%] of 31 patients) than in the eltrombopag arm (8 [13.6%] of 59 patients; p=0.015). Sixty-eight grade 3-4 adverse events occurred in 30 of 59 (50.8%) eltrombopag patients versus 10 events in 6 of 31 placebo cases (19.4%;χ2=8,4, p=0.004, stopping rule not reached). The outcomes acute myeloid leukemia (AML) evolution, progression and death occurred in 5 (8.5%), 4 (6.8%), and 5 (8.5%), respectively of 59 eltrombopag cases versus 2 (6.5%), 3 (9.7%), 2 (6.5%), respectively of 31 placebo cases (P ranging from 0.69 to 1.00). Median LFS, combined outcome (AML, disease progression and death) and OS were not reached in the whole group. Differences in LFS, combined outcome and OS at 2 and 5 years by study arms were adjusted for baseline bone marrow blasts since the proportion of patients with >2% blasts (i.e. the median value of the whole study cohort) tended to be higher (P=0.06) in Eltrombopag (59.3%) than in placebo treated (38.7%) patients and resulted to be a strong predictor of study outcomes at both 2 and 5 years (P Conclusion. Eltrombopag is well-tolerated in patients with lower-risk MDS and severe thrombocytopenia and is clinically effective in raising PLT count and reducing bleeding events. QoL improves with response to treatment. The assessment of long-term safety and efficacy of eltrombopag and its effect on survival (phase 2 part of study) is still ongoing. Disclosures Oliva: Novartis: Consultancy, Speakers Bureau; Apellis: Consultancy; Celgene Corporation: Consultancy, Honoraria, Speakers Bureau. Alati:Pfizer: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Santini:Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Honoraria; Acceleron: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Menarini: Membership on an entity's Board of Directors or advisory committees. Giai:Pfizer: Honoraria; BMS: Honoraria; Novartis: Honoraria. Balleari:Celgene: Membership on an entity's Board of Directors or advisory committees. Ferrero:Novartis: Honoraria. Germing:Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria; Amgen: Honoraria. Fenaux:Aprea: Research Funding; Jazz: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding; Astex: Honoraria, Research Funding. Palumbo:Amgen: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Novartis: Honoraria; Teva: Honoraria; Hospira: Honoraria. Liberati:Novartis: Other: Clinical trial support; Janssen: Honoraria; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Clinical trial support; Roche: Other: Clinical trial support; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Clinical trial support; Celgene: Honoraria, Other: Clinical trial support; Bristol-Myers Squibb: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy. Molteni:Celgene: Membership on an entity's Board of Directors or advisory committees. Buccisano:Astellas: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Bocchia:Novartis: Honoraria; Incyte: Honoraria; BMS: Honoraria. Candoni:Merck SD: Honoraria, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Celgene: Honoraria; Pfizer: Honoraria; Janssen: Honoraria. Martino:Bristol myers squibb: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees. Latagliata:Janssen: Honoraria; Novartis: Honoraria; Pfizer: Honoraria; Celgene: Honoraria. OffLabel Disclosure: Eltrombopag is indicated for: 1. the treatment of patients aged 1 year and above with primary immunethrombocytopenia (ITP) lasting 6 months or longer from diagnosis and who are refractory to other treatments; 2. in adult patients with chronic hepatitis C virus (HCV) infection for the treatment of thrombocytopenia, where the degree of thrombocytopenia is the main factor preventing the initiation or limiting the ability to maintain optimal interferon-based therapy; 3. in adult patients with acquired severe aplastic anaemia who were either refractory to prior immunosuppressive therapy or heavily pretreated and are unsuitable for hematopoietic stem cell transplantation

Background Most MDS patients require regular packed red blood cells (RBC) transfusions and finally most become transfusion dependent. One of the unavoidable consequences of transfusion therapy is iron overload which has been found to be deleterious for different categories of patients including MDS patients. So far tissue and organ damage have been directly and strictly connected to the amount of tissue iron deposition (i.e. a "bulky" disease). All the studies performed in the last years have linked survival to markers of iron accumulation (mainly indirect markers) such as serum ferritin (PLoS One 2017;12: e0179016 17). Recent data support the notion that iron disease is not only a "bulky" disease exclusively secondary to iron accumulation but rather it is a toxic disease in which tissue damage is due to toxic iron forms (Non-Transferrin-Bound-Iron, NTBI, and Labile Plasma Iron, LPI) (Free Radic Biol Med 2014; 72: 23-40). These tissue reactive iron species are present in plasma since early phase of transfusion therapy or even before (Hematology 2017; 22: 9-15. Clin Biochem 2017 Nov;50: 911-7). NTBI and LPI emerge in the serum only once iron binding capacity is saturated in a rate over 60-70% (Haematologica 2016; 101: 38-45). Notably these iron fractions are chelatable and can be removed from circulation by a chelator (Blood. 2003; 102: 2670-7). The scientific rationale for this study (ClinicalTrials.gov: NCT03920657; CICL670AIT17T) is the notion that iron-induced tissue damage is not only a process of progressive organs bulking through high-volumes iron deposition, but also a reactive iron species related "toxic" damage. Therefore, a timely early initiation of iron chelation may be of benefit before overt iron overload is seen. Our hypothesis is that early and low dose Deferasirox film coated tablets (DFX-FCT) is well tolerated and is able to prevent iron accumulation, oxidative stress and related tissue damage, by consistently suppressing iron reactive oxygen species (NTBI and LPI). Study design and Methods. For inclusion, patients must be affected by Myelodysplastic Syndrome (MDS), aged ≥ 18 years, with very low, low and intermediate revised IPSS stage. They must have a limited history of transfusions (5-20 RBC units) and be chelation naïve. Additional inclusion criteria are serum ferritin levels >350 ng/mL and transferrin saturation >60%. In a recruitment period of 1 years, 60 patients from 10 Italian centers will be included in the study. DFX-FCT will be administered at the fixed dose of 3.5 mg/kg/day for the entire study year. The primary efficacy objective and end point is to evaluate impact on of iron burden in one-year treatment in early phase of transfusion requirement by low dose DFX-FCT acting as prevention of iron accumulation as demonstrated by hepatic iron concentration determined by liver MRI (end of study versus baseline). Most relevant secondary objectives and endpoints are 1) Definition of iron overload and oxidative stress in MDS at beginning of transfusion history. 2) demonstrating presence and quantitative changes of toxic serum iron forms and oxidative stress under low dose DFX-FCT therapy by regular NTBI, LPI and serum Malonildialdehyde (MDA) monitoring. 3) Verify if regular suppression of the "free iron forms" prevent tissue iron accumulation by absolute change in hepatic iron concentration end of study versus baseline 4) Evaluate the overall safety of low DFX-FCT dose in patients with lower risk MDS at the beginning of their transfusion history 5) hemopoietic response Conclusions This prospective multicenter study has been designed to investigate the clinical benefit and safety of early chelation therapy with DFX-FCT in patients with MDS at the beginning of their transfusion history to verify the possibility to continually suppress tissue NTBI, LPI and Oxidative stress thus preventing iron accumulation and tissue damage. Disclosures Angelucci: Roche: Other: Local advisory board; Vertex Pharmaceuticals Incorporated, and CRISPR Therapeutics: Other: Partecipation in DMC; Jazz Pharmaceuticals: Other: Local advisory board; Novartis: Honoraria, Other: Chair Steering Committee TELESTO protocol; Celgene: Honoraria, Other: Partecipation in DMC; BlueBirdBio: Other: Local advisory board. Forni:Novartis, Iron chelation: Research Funding; Roche, Erithropoiesis Stimulation: Research Funding; BlueBirdBio: Consultancy; Celgene, Erithropoiesis Stimulation: Research Funding. Girelli:Vifor Pharma: Other: honoraria for lectures; Silence Therapeutics: Membership on an entity's Board of Directors or advisory committees; La Jolla Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy. Oliva:Novartis: Consultancy, Speakers Bureau; Celgene Corporation: Consultancy, Honoraria, Speakers Bureau; Apellis: Consultancy. Pilo:Novartis: Other: Advisory board. Cilloni:Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Crisà:Jannsen: Honoraria. Santini:Menarini: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Honoraria; Acceleron: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees.

A large amount of research is currently being conducted on wine pH because of its effect on the formation of turbidity in unfined white wines. The haze-forming tendency and the protein profile of an Italian white wine (Erbaluce di Caluso D.O.C.G.), as affected by pH ranging from 3.00 to 3.60, a common pH range in wine, were analysed. The results indicated increased heat stability of the wine at lower pH, which was revealed by a lack of haze formation even above 70 °C. The pH increase was accompanied by a progressive shift in the haze formation temperature from 50–60 °C to 70–80 °C. The electrophoretic protein pattern of the wine was characterised, and proteins derived from both yeast and grape tissues were identified. The statistical analysis of band intensities revealed that the solubility of five yeast and grape protein bands was modified by the pH shift. Most of the proteins involved were determined to be glycosylated, a feature that has been speculated to have an influence on the differential solubility of wine proteins in response to pH.