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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.

There are few data regarding the association of autoimmune and inflammatory diseases (AID) with Philadelphia negative myeloproliferative neoplasms (MPN). In this retrospective study, we describe the prevalence, clinical and biological features and outcome of AID association in MPN. A total of 1541 MPN patients were included, encompassing 95 (6%) patients with AID. Female patients were predominant within the AID group (65% versus 54%, p=0.03). A total of 103 AID diagnoses were reported in 95 patients, including 48 organ-specific AID, 13 inflammatory arthritis, 9 connective tissue diseases, 9 dermatosis, 6 systemic vasculitis and 18 unclassified AID. The prevalence of TET2 mutations was higher in the AID cohort (32% versus 22%), although not statistically significant (p=0.08). In subgroup analysis of patients with myelofibrosis, TET2 mutations were more prevalent in AID group (p=0.025). The prevalence of driver and other additional mutations did not differ between the 2 groups. The association with AID did not impact overall survival (p=0.67), transformation-free survival (p=0.37) or secondary myelofibrosis-free survival (p=0.91). Our data suggest that the prevalence of AID is similar in MPN patients to that of the general population. TET2 mutations are highly prevalent in MPN patients with AID potentially suggesting a shared physiopathology.

Systemic inflammatory and autoimmune diseases (SIADs) occur in 10-20% of patients with myelodysplastic syndrome (MDS). Recently identified VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) syndrome, associated with somatic mutations in UBA1 (Ubiquitin-like modifier-activating enzyme 1), encompasses a range of severe inflammatory conditions along with hematological abnormalities, including MDS. The pathophysiological mechanisms underlying the association between MDS and SIADs remain largely unknown, especially the roles of different myeloid immune cell subsets. The aim of this study was to quantitatively evaluate peripheral blood myeloid immune cells (dendritic cells (DC) and monocytes) by flow cytometry in MDS patients with associated SIAD (n = 14, most often including relapsing polychondritis or neutrophilic dermatoses) and to compare their distribution in MDS patients without SIAD (n = 23) and healthy controls (n = 7). Most MDS and MDS/SIAD patients had low-risk MDS. Eight of 14 (57%) MDS/SIAD patients carried UBA1 somatic mutations, defining VEXAS syndrome.Compared with MDS patients, most DC and monocyte subsets were significantly decreased in MDS/SIAD patients, especially in MDS patients with VEXAS syndrome. Our study provides the first overview of the peripheral blood immune myeloid cell distribution in MDS patients with associated SIADs and raises several hypotheses: possible redistribution to inflammation sites, increased apoptosis, or impaired development in the bone marrow.

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A 45-year-old female patient receiving rituximab for B cell non-Hodgkin follicular lymphoma presented unexplained recurrent fever, abdominal discomfort, and pollakiuria. We performed shotgun metagenomic sequencing from peri-kidney collection that identified a co-infection with Mycoplasma hominis and Ureaplasma urealyticum. The patient recovered with sequelae after appropriate antibiotic treatment was given.

Applying next-generation sequencing to paired skin and marrow biopsies, Delaleu et al describe an entity they term “myelodysplasia cutis,” comprising histologic features of histiocytoid Sweet syndrome in the skin and a clonally related myelodysplasia in the bone marrow. This can be distinguished from forms of histiocytoid Sweet syndrome not associated with myelodysplastic syndromes, as well as classical neutrophilic Sweet syndrome associated with various malignant and nonmalignant diseases and leukemia cutis where the infiltrating cells are myeloblasts.

Introduction Les maladies auto-immunes et inflammatoires (MAI) sont associees a un sur-risque de survenue de neoplasies myeloproliferatives (NMP) [1] . Chez les patients presentant un syndrome myelodysplasique (SMD) ou une leucemie myelomonocytaire chronique (LMMC), les mutations des regulateurs epigenetiques TET2 et IDH1/2 etaient significativement plus frequentes chez les patients porteurs de MAI comparativement a une cohorte temoin de patients SMD/LMMC sans MAI [2] . Dans le contexte des NMP, le phenotype des MAI associees et leur statut mutationnel ont ete peu decrits. Les objectifs de notre etude etaient de decrire les caracteristiques cliniques et genetiques des patients presentant une NMP avec une MAI et d’evaluer leur impact pronostique. Patients et Methodes Dans notre centre, 1541 patients ont ete diagnostiques d’une NMP selon les criteres OMS, entre janvier 2011 et janvier 2021. Des analyses moleculaires par sequencage haut debit (NGS) ciblant un panel de 36 genes mutes dans les NMP ont ete realisees pour 998 d’entre eux, au diagnostic ou durant le suivi. Tous les cas de MAI ont ete revus par un interniste et les diagnostics evalues selon les criteres internationaux correspondants. Les diagnostics de MAI post-interferon ont ete exclues. Resultats Notre cohorte comprenait 522 (34 %) polyglobulie de Vaquez (PV), 709 (46 %) thrombocytemie essentielle (TE) et 229 (15 %) myelofibrose primitive (MFP). Cent (6.6 %) patients presentaient une MAI associee et les 1441 patients restants ont constitue notre population temoin. L’âge median de nos patients dans la cohorte globale etait de 54 ans [IQR 40.4–63.2] et il y avait une predominance de femmes dans le groupe avec MAI associee (66 (66 %) versus 769 (53 %), p = 0.019). Il n’y avait pas de difference significative entre les 2 groupes concernant les sous-types de NMP, les mutations « driver » (JAK2, MPL et CALR) ou encore l’hemogramme au diagnostic des NMP. L’incidence d’episodes thrombotiques ou hemorragiques etait aussi similaire dans les 2 groupes (44 (44 %) versus 564 (39 %), p = 0.356). Le diagnostic de MAI etait anterieur a celui de NMP dans 34 % des cas, concomitant dans 12 % et ulterieur dans 31 %. Sur les 100 MAI, 45 etait des maladies auto-immunes specifiques d’organe, principalement des thyroidites auto-immunes, 13 rhumatismes inflammatoires chroniques, 9 connectivites, 8 dermatoses inflammatoires, 7 vascularites et 18 inclasses. Au total, 70 % des maladies auto-immunes remplissaient leurs criteres de classification. Parmi les patients ayant beneficie d’une analyse moleculaire, 62 % avaient une mutation additionnelle a la mutation « driver ». Les mutations de TET2 etaient plus frequemment retrouvees chez les patients avec une MAI associee (24 (34 %) versus 205 (22 %), OR = 1.84 95 %CI [1.08–3.07], p = 0.028), mais elle n’etait pas associee a un sous-type de MAI particulier. Il existait une tendance a une surrepresentation des mutations IDH1/2 dans le groupe MAI (4 (6 %) versus 27 (3 %), OR = 2.02 95 %CI[0.74–5.51], p = 0.27), bien que non statistiquement significatif. Nous n’avons pas retrouve d’autres mutations de facteurs epigenetiques, de transcription, d’epissage ou de mutation a haut risque moleculaire, associees preferentiellement au groupe NMP avec MAI associee. Apres un suivi median de 8.3 ans dans la cohorte globale, la presence d’une MAI n’avait pas d’impact defavorable sur la survie globale (p = 0.82), ni sur la survenue de myelofibrose secondaire (p = 0.98), ou la survenue de transformation en SMD/LAM (p = 0.53). Conclusion Au sein de cette large cohorte retrospective de NMP decrite sur le plan clinique et moleculaire, la prevalence de MAI est de 6.6 %, similaire a celle de la population generale. Une sur-prevalence de la mutation de TET2 a ete mise en evidence dans le groupe de patients presentant une MAI associee. Nos resultats suggerent une susceptibilite genetique commune, secondaire a la mutation de regulateur epigenetique comme TET2, potentiellement responsable des phenotypes inflammatoire et hematologique.

Context: Systemic inflammatory and auto-immune diseases (SIAD) are observed in 25% of patients with MDS or CMML, who harbor a high frequency of mutations in TET2, IDH1/2 and SRSF2 as we previously reported (Zhao et al, Leukemia 2021). Recently, the identification of mutations in UBA1 in patients with autoinflammatory disorders, some of whom have dysplastic bone marrow, defined novel disease called VEXAS syndrome (Beck et al, NEJM 2020). Objective: To explore the prevalence of UBA1 mutations in our initial cohort of MDS/CMML patients with SIAD (n=85) (Zhao et al, Leukemia 2021). Design and Patients: All male patients for whom material was available (n=33) were analyzed for the presence of UBA1 mutations. Primary Outcome: UBA1 mutations screening with Sanger sequencing. Results: Four out of 33 (12%) patients had UBA1 mutations. All of them had MDS without excess of blasts. Cytomorphologic review of bone marrow smears showed numerous vacuoles in precursors in all 4 cases. Karyotype was normal in 3/4 patients, and one patient had deletion 9q. One patient also had somatic mutations in DNMT3A (VAF 11%) and TP53 (VAF 2%), and another patient had a mutation of TET2 (VAF 18%). Three patients in our MDS/CMML SIAD cohort had relapsing polychondritis, and 2 of them had UBA1 mutations, while 6 patients from our initial SIAD cohort had a diagnosis of Sweet syndrome, including 2 with UBA1 mutations. Three out of 4mut patients had steroid refractory SIAD and were heavily treated with other immunosuppressive therapies including methotrexate, azathioprine or cytokine targeting agents. At last follow-up, none of the 4 patients with UBA1 mutations had MDS progression, and one of them had died from a stroke, 2.4 years after MDS diagnosis. Conclusions: Our retrospective study represents the first assessment of VEXAS syndrome among patients with myeloid malignancies associated with SIAD. The low prevalence of UBA1 mutations in our cohort suggests that other pathological mechanisms may drive inflammation in the large majority of MDS/CMML patients with associated SIAD, likely in relation with mutations in epigenetic regulators TET2/IDH and SRSF2 as we previously proposed.

Background: Systemic autoimmune and inflammatory diseases (SAIDs) occur in 10-15% of MDS or CMML patients. They are often severe, difficult to treat and steroid resistant/dependent disorders. In a retrospective report of 22 patients with steroid-dependent MDS/CMML associated SAID, we observed promising results with azacytidine (AZA) on the SAID component (Fraison et al, Leuk Res, 2016). In this prospective French nationwide trial, we aimed at confirming this effect prospectively. Patients and Methods: This open-label, single-arm multicenter, phase II study included MDS/CMML patients with IPSS/CPSS int 2 or high, or lower IPSS/CPSS but with significant cytopenias, especially ESA resistant anemia (or, for CMML, proliferative features) and SAID with steroid dependence and/or resistance. The primary endpoint was response rate (RR, including CR and PR) of SAID after 6 cycles of AZA. Secondary endpoints included RRof SAID after 3 cycles of AZA, response of MDS, time to MDS progression (including to AML), overall survival (OS) and safety. AZA was used at 75 mg/m²/d x 7 days, every 4 weeks for a minimum of 6 cycles (unless overt disease progression occurred before). At the onset of AZA, prednisone (PRED) was administered at 1 mg/kg during 1 month and then decreased progressively over 6 months. Results: 30 patients were included between July 2017 and June 2020 , 29 of whom received AZA and were considered evaluable: median age 72 [range 68-78], 69% males; WHO: MDS ML (n=11; 41%), CMML (n=11, 41%), MDS-RS (n=2, 7%), EB-1 (n=1) and EB-2 (n=1), unclassified (n=3); IPSS-R : good (n=15, 54%), very good (n=3; 11%, each), intermediate (n=7; 25%) and very poor profile (n=3; 11%) (all CMML had WBC 19 patients (65.5%, IC95% [45.7.82.1]) obtained a SAID response after 6 cycles (including 8 CR and 11 PR), while 17 (58.6% (IC95% [38.9; 76.5]) patients achieved an IWG 2006 hematological response (7 CR, 9 SD with HI and 1 marrow CR). All the 13 patients who received 12 cycles of AZA achieved SAID CR or PR at 12 months, and 10 of them had a hematological response (6 CR, 1PR, 2 HI, 1 marrow CR). The SAID response rate at 12 month was at 72.4% (IC95% : [51.3;85.6]). SAIDs complete/partial response occurred in 3/9 (33%) UBAI-positive versus 8/19 (42%) non-mutated cases. No significant prognostic factor of SAID response after 6 cycles, including sex, age, WHO classification, IPSS-R, UBA1 and TET-2 mutation status was found. With a median follow-up of 18.5 months [11.8; 24.3], 9 (31%) patients had died, with a 1-year OS of 82.3% (IC95% [69.4; 97.7]. At least one SAE occurred in 23 patients, with a median of 2 events/patient [1.5; 5.5]. Death was due to infection (n=5, two of them in patients with good IPSS-R, but severe steroid dependent SAID), MDS progression (n=2), or unrelated causes (n=2). Conclusion We confirmed prospectively an effect of AZA on the autoimmune/inflammatory component in two thirds of MDS/CMML patients with steroid dependent / refractory concomitant systemic autoimmune/inflammatory disease. No significant difference in AZA response was noted between UBA1 mutated and unmutated MDS patients. The adverse events and mortality rates, often from infectious origin, appear to be those expected in such an MDS population, potentially worsened by the associated SAID and background of immunosuppressive treatment (especially steroids) Disclosures Terriou: Alexion, AstraZeneca Rare Disease: Consultancy, Membership on an entity's Board of Directors or advisory committees. Vey: Amgen: Honoraria; BMS: Honoraria; BIOKINESIS: Consultancy, Research Funding; NOVARTIS: Consultancy, Honoraria, Research Funding; SERVIER: Consultancy; JAZZ PHARMACEUTICALS: Honoraria; JANSSEN: Consultancy. Ades: ABBVIE: Honoraria; TAKEDA: Honoraria; CELGENE/BMS: Honoraria; NOVARTIS: Honoraria; JAZZ: Honoraria, Research Funding; CELGENE: Research Funding. Fenaux: Abbvie: Honoraria, Research Funding; JAZZ: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Celgene/BMS: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Syros Pharmaceuticals: Honoraria.

Introduction: Although myeloproliferative neoplasms (MPN) are driven by three mutually exclusive driver mutations (JAK2, CALR and MPL), targeted deep sequencing studies identified multiple additional somatic mutations potentially impacting MPN evolution. Presence of a high molecular risk (HMR: ASXL1, EZH2, SRSF2 and IDH1/2) or a TP53 mutations has been associated with adverse prognosis. However, to date, the effect of clonal evolution (CEv) on MPN patients' outcome has not been evaluated, as most of the studies assessed mutational-based prognosis stratification from single baseline molecular genotyping. The objective of our study was to describe the clinical and molecular characteristics of patients with CEv in a large cohort of MPN patients and analyze its impact on patients' outcome. Methods: A total of 1538 consecutive patients were diagnosed with MPN according to WHO criteria and followed in our hospital between January 2011 and January 2021. From this large retrospective cohort, we included in this study 446 patients who had at least 2 molecular analyses during the chronic phase of MPN, performed at diagnosis and/or during follow-up using next generation sequencing (NGS), targeting a panel of 36 genes involved in myeloid malignancies. Significant variants were retained with a sensitivity of 1%. CEv was defined as the acquisition of a new additional non-driver mutation between baseline and subsequent NGS evaluation. Statistical analyses were performed using the STATA software (STATA 17.0 for Mac Corporation, College Station, TX). Results: The median age at MPN diagnosis in our whole cohort was 51 years [IQR 41 - 60]. Our cohort included 167 (37%), 205 (46%) and 64 (14%) patients with polycythemia vera, essential thrombocythemia and primary myelofibrosis (MF) respectively. With a median interval of 1.6 years [IQR 1.0 - 2.8] between the first and the second NGS analysis in the whole cohort, CEv occurred in 128 patients (29%). Patients with CEv were significantly older compared to patients without CEv (n=318) (p=0.03). MPN diagnosis, the type of driver mutation and complete blood counts at MPN diagnosis did not differ between the 2 groups. Eighty-one (63%) and 198 (62%) patients with or without CEv respectively had at least one additional non-driver mutation at baseline NGS (p=0.59), while the rate of HMR (n=25 (20%) versus n=79 (25%)) or TP53 (n=7 (5%) versus n=20 (6%)) mutations at baseline NGS did not differ between the 2 groups. Thirty six out of 128 (28%) of patients with CEv had more than 1 acquired mutation. Most recurrently acquired mutations involved the epigenetic regulators TET2 and DNMT3A that were mutated in respectively 33% and 25% of patients with CEv (Figure 1A). Moreover, 38% of CEv patients acquired HMR (ASXL1 (14%), EZH2 (6%), SRSF2 (3%), IDH1/2 (2%)) or TP53 (13%) mutations. After a median follow up of 10.8 years [IQR 6.6 - 17.2] in the whole cohort representing a total of 5635 patient years, 32 (7%) patients died, and 11 (2.5%) and 11 (2.5%) patients with at least 2 NGS performed during MPN chronic phase transformed respectively into secondary MF or myelodysplastic syndrome / acute myeloid leukemia (MDS/AML). Interestingly, CEv (HR 11.27, 95%CI [5.09; 24.96], p Conclusion: Our study on a large retrospective clinically and biologically annotated real-life cohort of MPN patients with long-term follow up shows that CEv independently adversely impacts OS, MDS/AML and secondary MF free survivals. CEv occurred in a clinically relevant proportion of MPN patients (28%) and was associated with patients' age. Acquired mutations mainly involved epigenetic regulators, HMR and TP53 genes. These results suggest that serial molecular monitoring using NGS could be routinely implemented in MPN patients follow up, to assess more accurately disease evolution and potentially update therapeutic management. Figure 1 Figure 1. Disclosures Raffoux: PFIZER: Consultancy; CELGENE/BMS: Consultancy; ABBVIE: Consultancy; ASTELLAS: Consultancy. Kiladjian: Novartis: Membership on an entity's Board of Directors or advisory committees; Taiho Oncology, Inc.: Research Funding; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Membership on an entity's Board of Directors or advisory committees; PharmaEssentia: Other: Personal fees; AOP Orphan: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees. Benajiba: Gilead: Research Funding; Pfizer: Research Funding.

Introduction: Auto-immune and Inflammatory Diseases (AID) have been associated with myeloproliferative neoplasms (MPN) in a large population-based study (Kristinsson et al. Haematologica 2010). In myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML), epigenetic regulators TET2 and IDH1/2 were more frequently mutated in patients with AID, suggesting potentially common pathogenesis pathways (Zhao et al. Leukemia 2021). However, in the context of MPN, AID specific features remain poorly characterized, and no study has reported to date the mutational landscape of MPN patients with AID. The objectives of our study were to describe the clinical and molecular characteristics of MPN patients with associated AID and evaluate its impact on patient's outcome. Methods: A total of 1541 patients were diagnosed with MPN according to WHO criteria between January 2011 and January 2021 in our center, of whom 998 had a molecular analysis by next generation sequencing (NGS) targeting a panel of 36 genes involved in MPN, performed at diagnosis and/or during follow-up. AID diagnosis was based on international criteria, and all cases have been reviewed by internal medicine experts. Patients with AID induced by interferon-alpha treatment were not included. Results: The median age of our whole cohort was 51.3 years IQR[40.4-63.2]. Our cohort included 522 (34%), 709 (46%) and 229 (15%) diagnosis of polycythemia vera (PV), essential thrombocytemia (ET) and primary myelofibrosis (MF) respectively. A total of 100 patients (6.6%) had AID and were compared to the remaining 1441 MPN patients without AID. There were more females (66 (66%) versus 769 (53%), p=0.019) within the AID group compared to non-AID patients. MPN subtype, driver mutation, complete blood counts at diagnosis did not differ between the two groups. Occurrence of thrombosis and hemorrhage episodes did not vary either (44 (44%) versus 564 (39%), p=0.356). AID diagnosis was prior to MPN in 34% of cases, concomitant in 12% and posterior in 31% of cases. AID diagnosis included 45 (45%) organ-specific AID (mainly autoimmune thyroiditis, n=34), 13 (13%) inflammatory arthritis, 9 (9%) connective tissue diseases, 8 (8%) inflammatory dermatosis, 7 (7%) systemic vasculitis and 18 (18%) unclassified AID (Figure 1A). The AID fulfilled the required classification criteria in 70 (70%) cases, while complete criteria were not reached in 30 (30%) cases. The median interval of time between MPN diagnosis and NGS was 7.2 years IQR[2.1-13.3] in the whole cohort. Among patients with available molecular analysis, 44 (62%) and 571 (62%) patients had at least one additional non-driver mutated gene in the AID and control groups respectively. Interestingly, TET2 mutations were more frequent in MPN patients with AID (24 (34%) versus 205 (22%), OR=1.84 95%CI[1.08-3.07], p=0.028, Fig 1B). The prevalence of TET2 mutations did not significantly differ between the AID categories. When focusing on IDH1/2 mutations, as they act on the same biological epigenetic pathway as TET2, IDH1/2 mutations were more frequent in the AID cohort although not statistically significant (4 (6%) versus 27 (3%), OR=2.02 95%CI[0.74-5.51], p=0.27). No other mutations including other epigenetic factors, splicing regulators, transcription factors or high molecular risk mutations, were significantly associated with AID. After a median follow up of 8.3 years IQR[3.7-14.3] in the whole cohort, 10 (10%) and 122 (8%) patients died in the AID and control groups respectively. The presence of AID did not impact overall survival (p=0.82), secondary myelofibrosis free (p=0.98) or MDS/AML transformation free (p=0.53) survivals. Conclusion Our study reports on a large retrospective clinically and molecularly annotated cohort the prevalence of AID in MPN patients (6.6%). This prevalence did not differ from that of the general population. Interestingly, our data emphasize a high prevalence of TET2 mutations in patients with both AID and MPN, compared to MPN patients without AID. Although other studies are warranted to better define the causal relationship between MPN and AID, our results may suggest a common pathophysiology as it has been proposed in MDS patients, based on shared genetic susceptibilities with mutations in TET2 that could occur within early hematopoietic progenitors and give rise to both the inflammatory phenotype and myeloid malignancy. DE and LPZ contributed equally to this work. Figure 1 Figure 1. Disclosures Fenaux: Celgene/BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; JAZZ: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Syros Pharmaceuticals: Honoraria. Ades: Novartis: Honoraria; Takeda: Honoraria; Abbvie: Honoraria; JAZZ: Honoraria; Celgene: Honoraria, Research Funding. Raffoux: PFIZER: Consultancy; CELGENE/BMS: Consultancy; ABBVIE: Consultancy; ASTELLAS: Consultancy. Kiladjian: Incyte Corporation: Membership on an entity's Board of Directors or advisory committees; AOP Orphan: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Taiho Oncology, Inc.: Research Funding; PharmaEssentia: Other: Personal fees. Benajiba: Pfizer: Research Funding; Gilead: Research Funding.

Background: Although patients with MPN may achieve complete hematological remission (CHR) with cytoreductive therapy (CRT), lifelong treatment represents a major burden for these chronically ill patients. IFN has emerged as a major MPN therapy thought to positively alter the natural history of MPN and appears to be the only drug that can provide long-term CHR after discontinuation in some patients (Hasselbalch HC et al., Seminars in Immunopathology, 2019). In this study, we aimed to identify clinical and molecular factors associated with long-term CHR after IFN treatment discontinuation and to compare clinical outcome of patients who discontinued therapy, to patients who continued IFN treatment despite achieving a CHR. Methods: All MPN patients followed between January 2000 and May 2020 in our institution who received at least 3 months of IFN were included. Logistic regression analysis was performed to identify variables associated with long-term CHR after discontinuation. Cumulative incidence of relapse was calculated from time of IFN discontinuation, considering death without relapse as a competitive event. Overall survival (OS) and thrombotic/hemorrhagic events free survival (EFS) curves were estimated using the Kaplan-Meier method and compared by cause-specific hazard Cox models. Results: 381 patients treated with IFN were included in the study. Median age at MPN diagnosis was 44 years [interquartile range: 33-54]. 171 had polycythemia vera (PV), 169 essential thrombocythemia (ET) and 34 primary myelofibrosis (PMF). JAK2V617F was the most frequent driver mutation (78.8% of patients), while CALR and MPL were mutated in 15.5%, and 2.9% of patients respectively. Median driver variant allele frequency (VAF) at time of IFN therapy initiation was 34% [12; 51]. Reasons to start IFN included age younger than 50 years in 44.9%, intolerance/resistance to previous therapies in 17.8% or pregnancy in 1.8% patients. CHR was achieved with IFN in 77.2% of patients. After a median follow-up of 72.4 months [28.4; 119.7] from IFN initiation, 131 patients were still on IFN treatment, while 250 patients had discontinued therapy. No significant difference was observed between continued and discontinued IFN patients in terms of MPN subtype, initial clinical, biological or molecular characteristics. Reasons for discontinuation were toxicity in 128 (50.4%), prolonged hematological CHR in 76 (29.9%), failure in 16 (6.3%) and other in 30 (11.8%) patients. At time of IFN discontinuation, 170 (66.9%) patients were in CHR and the median driver mutation VAF was 12% [3; 35]. Of note, IFN was re-introduced in 61 patients who lost CHR with a second CHR rate of 83.6%, arguing for the absence of development of IFN resistance in post-discontinuation relapses. In multivariate logistic regression analysis, stopping for prolonged CHR (OR 3.52, 95%CI [1.18; 10.56], p=0.024) was associated with a higher CHR without CRT rate, while VAF ≥ 10% at time of IFN discontinuation (OR 0.26, 95%CI [0.1; 0.65], p=0.004) was associated with lower long-term CHR without CRT. Accordingly, VAF ≥ 10% at time of IFN discontinuation (HR 3.06 [1.59; 5.90], p=0.001) was independently associated with a higher cumulative incidence of relapse after IFN discontinuation (Figure A). Driver VAF at IFN discontinuation time was available for 117 patients. 53 patients (45.3%) had a driver VAF < 10% at IFN discontinuation. Finally, we compared discontinued IFN patients who stopped IFN for CHR (n=76) to patients who obtained CHR and are still on IFN therapy (n=116). Hematological transformation could not be evaluated due to very low incidence of events: 2 patients from each group progressed to myelofibrosis while leukemic progression was only observed in 1 patient. Importantly, OS (HR 0.23, 95%CI [0.5; 1.14], p=0.07) and EFS (HR 0.53, 95%CI [0.19; 1.45], p=0.217) were not significantly different between patients who discontinued and those who continued IFN. Conclusion: Overall, our study demonstrates that IFN discontinuation represents a safe strategy in MPN patients who achieved CHR, and particularly in patients with a driver VAF lower than 10% at time of discontinuation. Importantly, relapsed patients did not develop IFN resistance. Our data contributes to set the frame for future clinical trials evaluating the possibility of IFN treatment holidays in good responding MPN patients. Disclosures Benajiba: Gilead Foundation: Research Funding. Kiladjian:Abbvie: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; AOP Orphan: Membership on an entity's Board of Directors or advisory committees.

Introduction: Approximately 20% of Myelodysplastic Syndromes (MDS) and Chronic Myelomonocytic Leukemia (CMML) are associated with SIAD, but pathophysiological mechanisms underlying this association remain largely unknown and data on somatic mutations are very scarce. Autoreactive T lymphocytes play a major role in SIAD development. The main objective of this study was to investigate the mutational landscape of MDS/CMML associated with SIAD, and its impact on the immunological phenotype of T lymphocytes. Patients and Methods: This retrospective study was conducted in the hematology department of Hôpital Saint-Louis, Paris, in all MDS/CMML patients diagnosed between 2012 and 2017, and with a molecular analysis by NGS targeting a panel of 80 genes. MDS/CMML patients with associated SIAD (n= 85, whose diagnosis was based on usual international criteria) were compared with MDS/CMML patients without SIAD (n=319) who constituted the control cohort. Flow cytometry was performed on peripheral blood samples from 28 MDS/CMML patients (of whom 12/28 had SIAD) and 18 healthy controls, on a BD Fortessa X20 to study CD8+T lymphocytes subsets and the expression of immune checkpoints. Analysis was performed with FlowAI R v1.14.0 and Cytobank website for T cells clustering with unsupervised Citrus algorithm. Results: We included 404 MDS/CMML patients (323 MDS, 81 CMML), of whom 85 (21%) had SIAD diagnoses including 35 (34%) inflammatory arthritis, 20 (19%) systemic vasculitis, 16 (15%) autoimmune cytopenias, 15 (14%) connective tissue diseases, 9 (9%) neutrophilic dermatosis, 6 (6%) inflammatory bowel disease, and 3 (3%) unclassified SIAD. Both SIAD and control cohorts were similar in terms of age, levels of cytopenias, MDS/CMML subtypes and cytogenetic features. There was a preponderance of low risk MDS/CMML (85.9% and 82.8% in SIAD and control cohort), and the number of patients with CMML did not differ between the 2 groups (p=0.36). Median follow-up was 32.2 months in the whole cohort. Median overall survival was 95.7 months [60.7 - not estimable] and 101.0 months [70.8 - not estimable] in the control and SIAD cohort respectively (p=0.91). Figure A represents the mutational landscape of MDS/CMML patients for the recurrent mutated genes. Median number of mutations was 2 [1-4] in both cohorts (ns). TET2mutations were found in 39/85 (46%) and 108/319 (34%) patients in the SIAD and control cohorts respectively (p=0.04), and IDH1/2 mutationsin 12/85 (14%) patients in the SIAD cohort vs 14/319 (4%) in the control group (p SRSF2 mutations were also more frequent in the SIAD cohort (26/85 (31%) vs 47/319 (15%), p Flow cytometry analysis of CD8+ T cells from TET2/IDHmut patients (17/28, 60.7%) showed an increase of the terminally differenciated effector memory T cells (p Discussion Our study provides an extended mutational landscape of MDS/CMML associated with SIAD, and finds a correlation between TET2/IDH mutations, T lymphocyte imbalance and association with SIAD in those diseases. This correlation could suggest common mechanisms underlying both SIAD and MDS/CMML, and reinforces our observations of a frequent positive effect of Azacytidine (a drug with better response in patients with TET2mutation) on both MDS/CMML and SIAD in patients with both disorders (Fraison, Leuk Res 2016). Further analysis of the functional role of T lymphocytes in those patients is underway. Disclosures Clappier: Amgen: Honoraria, Research Funding. Itzykson:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Research Funding; Oncoethix (now Merck): Research Funding; Astellas: Honoraria; Sanofi: Honoraria; BMS (Celgene): Honoraria; Daiichi Sankyo: Honoraria; Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria; Amgen: Membership on an entity's Board of Directors or advisory committees; Otsuka Pharma: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Stemline: Membership on an entity's Board of Directors or advisory committees. Mékinian:LFB: Honoraria; CELGENE: Honoraria; CELGENE: Honoraria; SANOFI: Honoraria. Fenaux:BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Jazz: Honoraria, Research Funding. Ades:jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; novartis: Research Funding; Celgene/BMS: Research Funding.

Introduction: Ruxolitinib (RUX) is a JAK 1/2 inhibitor approved for the treatment of intermediate and high-risk primary or secondary MF. In addition to the intrinsic immune system modulation in MF patients, JAK inhibition exerts an immunosuppressive effect that may increase the risk of infections (Heine A et al., Blood, 2013). We aimed to investigate the association between treatment with RUX and infectious complications in a large monocentric cohort of MF patients. Methods: We performed a retrospective study including all patients diagnosed with primary, post-polycythemia vera or post-essential thrombocythemia MF in our MPN clinic between January 2011 and April 2020. Patients were considered RUX treated when exposed to treatment for at least two consecutive months. Clinical and biological characteristics at time of MF diagnosis and follow-up were collected from medical charts and electronic medical records. We used logistic regression models to identify specific infection subtypes associated with RUX treatment. Univariate and multivariate analysis assessing the impact of categorical and continuous variables on infectious events cumulative incidence were performed using Cox models. Results: 213 MF patients were included in the study. 114 (51.1%) patients were treated with RUX while 99 didn't receive RUX. Overall 102 patients exhibited a total of 231 infectious episodes. To search for factors associated with occurrence of infectious events, we evaluated the characteristics of MF, potential clinical and biological immune suppression factors (immunosuppressive treatment, prior non-MPN cancer, diabetes, hepatic/renal failure, neutropenia, lymphopenia, hypo-gammaglobulinemia, complement deficiency, prior history of infection), use of infection prophylaxis and RUX treatment using Cox models. In this cohort of MF patients, we found that RUX treatment (HR 5.91, 95%CI[3.48; 10.04], p 2 (HR 4.91, 95%CI[2.62; 9.21], p 41 (22.2%) and 16 (34.0%) infections were of grade 3-4, 61 (33.1%) and 19 (40.4%) required hospitalization, while 8 (4.3%) and 2 (4.2%) resulted in patients' death, in RUX treated and RUX naïve patients, respectively (all non-significantly different). Bacterial infections represented 48.0%, viral infections 16.0% and fungal infections 4.8% of the total infectious events. The most frequently infected sites were lungs/respiratory tract (28.1%) and skin/soft tissue (24.2%). RUX treatment was significantly associated with recurrence of HSV-1/2 or VZV (OR 7.57, 95%CI[1.01-57.30], p=0.050), and skin/soft tissue infections including the above herpetic recurrences (OR 3.33, 95%CI[1.13-9.78], p=0.029). 17 (14.9%) patients presented with HSV/VZV recurrence in the RUX treated group compared to 1 (1.0%) in non-treated patients (Figure B). We then thought to evaluate the impact of potential infections risk factors in RUX treated patients at time of treatment initiation in order to inform clinicians' therapeutic decision and follow-up guidance. For this analysis, we evaluated the characteristics of MF, potential clinical and biological immune suppression factors, treatment lines prior to RUX, dose and cumulative exposition to RUX. No clinical or biological factor was significantly associated with the overall risk of infectious events. However, hypo-gammaglobulinemia at time of RUX initiation was independently associated with HSV and/or VZV recurrence (HR 4.57, 95%CI[1.29-16.16], p=0.018). The higher rate of infections in RUX treated patients was associated with a not statistically significant trend towards shorter OS (HR 1.97, 95%CI[0.98; 3.94], p=0.055). Conclusion: This retrospective study shows an association between the occurrence of infectious complications and Ruxolitinib treatment in MF patients, and in particular, a higher incidence of HSV/VZV recurrence and skin/soft tissue infection. Patients with hypo-gammaglobulinemia at time of RUX initiation were at higher risk of HSV/VZV recurrence, suggesting that protein electrophoresis should be performed prior to treatment initiation and primary antiviral prophylaxis proposed to patients with hypo-gammaglobulinemia. Disclosures Rea: BMS: Membership on an entity's Board of Directors or advisory committees; Pfizer: 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; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kiladjian:AbbVie: Membership on an entity's Board of Directors or advisory committees; AOP Orphan: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Benajiba:Gilead Foundation: Research Funding.

Introduction: MPN are a heterogeneous group of chronic hematological malignancies often resulting from a combination of a driver gene mutation (JAK2, MPL or CALR) and a variety of somatic mutations harboring diverse prognosis values. A subset of MPN patients carry somatic mutations in the hematopoietic transcription factor NFE2 (nuclear factor erythroid 2) resulting in a functionally enhanced truncated form of NFE2 (Jutzi JS et al., JEM, 2013). Moreover, epigenetically induced overexpression of NFE2 has recently been reported in the majority of MPN patients (Peeken JC et al., Blood, 2018). In transgenic murine models, NFE2 overexpression results in an MPN phenotype (thrombocytosis, leukocytosis, EPO-independent colony formation, characteristic bone marrow histology and expansion of stem and progenitor compartments) and has recently been shown to predispose to the acquisition of additional genetic abnormalities and subsequent leukemic transformation (Kaufmann KB et al., JEM, 2012) (Jutzi JS et al., Blood, 2019). However, clinical impact of NFE2 mutations in MPN patients remains unknown. The aim of this study was to evaluate the phenotypic characteristics and prognostic impact of NFE2 somatic mutations in a large mono-centric cohort of MPN patients. Methods: A total of 1243 consecutive patients were diagnosed with MPN according to WHO criteria and followed in our hospital between January 2011 and May 2020. This study included 707 of them in whom a next-generation sequencing (NGS) molecular analysis targeting 36 myeloid genes was performed at diagnosis and/or during follow-up. Clinical and biological characteristics at time of diagnosis and follow-up were collected from medical charts and electronic medical records. Statistical analyses were performed using the STATA software (STATA 15.0 Corporation, College Station, TX). Results: In our cohort, 411 patients presented with polycythemia vera (PV), 577 with essential thrombocythemia (ET), 184 with primary or pre-fibrotic myelofibrosis (PMF), 59 with unclassified MPN and 12 with MDS/MPN. Median age at diagnosis was 51 years [40-63]. 73.1% patients had a JAK2V617F mutation, 14.1% a CALR mutation and 3.3% a MPL mutation. Overall, 64 (9.05%) patients harbored a NFE2 mutation with a variant allelic frequency (VAF) ≥ 0.5% and 36 had a VAF ≥ 5%, the latest were considered as NFE2 mutated for the rest of the study as VAF Conclusion: In this retrospective study we show that presence of NFE2 mutations with a VAF ≥5% is independently associated with an increased risk of leukemic transformation and shorter overall survival. These findings are in line with recently reported animal models and suggest that NFE2 mutations screening should be routinely performed in MPN patients. Disclosures Rea: Incyte: 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; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Kiladjian:AOP Orphan: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; 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. Benajiba:Gilead Foundation: Research Funding.

Introduction: Next generation sequencing (NGS) studies identified additional somatic mutations impacting disease evolution and prognosis in MPN. SF3B1, a component of the U2 small nuclear ribonucleoprotein splicing complex, is frequently mutated in myelodysplastic syndromes where it has been proposed to define a new entity (Malcovati et. al. Blood 2020). In MPN, SF3B1 is mutated in approximately 10% of patients with primary myelofibrosis (PMF) and 3-5% with polycytemia vera or essential thrombocytemia (ET). Recent reports suggested that spliceosome mutations may adversely affect myelofibrosis free survival (MFS) in ET (Tefferi et. al. Br J Haematol. 2020). The main objective of this study was to evaluate the impact of the concomitant presence of driver (JAK2, MPLor CALR) and SF3B1 clonal or sub-clonal mutations on MPN phenotype and evolution in a large single center cohort of MPN patients. Methods: A total of 1243 consecutive patients were diagnosed with MPN according to WHO criteria between January 2011 and May 2020 in our center, of whom 707 had molecular analysis by NGS targeting a panel of 36 myeloid genes performed at diagnosis and/or during follow-up. Significant variants were retained with a sensitivity of 0.5%. Patients were grouped according to variant allele frequencies (VAF) determined by NGS as "driver" SF3B1mutated patients when driver and SF3B1 mutations VAF were similar (double mutated clone), and as "non-driver" SF3B1 mutants when SF3B1VAF was lower than that of the driver mutation, suggestive of a sub-clone. 4 patients with SF3B1 mutations but no driver mutation were excluded. We then compared the characteristics and outcomes of 3 groups of patients according to their SF3B1 mutational status: wild type (WT), driver and non-driver SF3B1 mutations. Results: A total of 39/703 (5.6%) patients had SF3B1 mutations, of whom 11/39 (28.2%) and 28/39 (71.8%) harbored driver and non-driver SF3B1mutations, respectively. Driver SF3B1 mutations were associated with PMF (OR 6.1, 95%CI [1.1; 33.6], p= 0.039) and MPN unclassified (OR 15.6,95%CI [1.1; 116.5], p= 0.007) subtypes, presence of immature myeloid cells ≥ 2% (OR 9.3, CI [2.6; 32.8], p= 0.001) and peripheral blasts ≥ 1% (OR 5.0,95%CI [1.0; 24.7], p= 0.047) at diagnosis (Figure A). Other variables were not significantly different between patients with driver, non-driver and WT SF3B1, including age, driver mutation type, MPN-related symptoms, cytogenetics and high molecular risk mutations (ASXL1, EZH2, SRSF2, IDH1/2or U2AF1). There was no significant difference in the response to therapy: complete hematological response was seen in 5/11 (45.5%), 10/28 (35.7%) and 327/664 (49.3%) of patients with driver, non-driver and WT SF3B1 respectively. After a median follow-up of 103.7 months IQR [47.2; 175.6], evolution to myelofibrosis occurred in 5/7 (71.4%), 6/20 (30.0%) and 99/564 (17.6%) of patients with driver, non-driver and WT SF3B1 respectively. Interestingly, driver SF3B1 but not non-driver SF3B1 mutational status adversely impacted MFS (OR 7.56,95%CI[2.95; 19.38], p Conclusion: This study in a large cohort of MPN patients highlights for the first time to our knowledge the adverse impact on MFS of SF3B1 and MPN-driver co-mutated clones. In contrast, presence of an SF3B1 mutation at sub-clonal level didn't increase the risk of MF development. In line with our findings, a recent study reported an association between rapid progression to myelofibrosis and SF3B1 mutations in patients with age-related clonal hematopoiesis (Bartels et al. Leukemia 2020). Further studies are warranted to confirm our results on independent cohorts and to investigate the mechanisms of bone marrow fibrosis development in patients with SF3B1 and MPN-drivermutations. Disclosures Rea: Incyte: 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; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Kiladjian:BMS: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; AOP Orphan: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees. Benajiba:Gilead Foundation: Research Funding.

Chronic Coxiella burnetii vascular infection is rare and usually develops on a pre-existing vascular lesion, such as an aneurysm or vascular prosthesis. We report a case of proven C. burnetii aortic infection revealed by a massive retroperitoneal aortoiliac aneurysm rupture in a patient at apparent low risk for chronic Q fever. Emergency treatment consisted of resection of the infected aneurysm and replacement with an in situ graft angioplasty. Doxycycline and hydroxychloroquine therapy was started postoperatively. After 6 months of follow-up, the patient had no signs of infection, and C. burnetii serologic antibody titers had significantly decreased.

A 66-year-old diabetic man presented with fever, hypotension, lower abdominal pain, hematuria and supra pubic crepitation. Abdominal CT scan revealed gas in bladder wall, and pre bladder space (Fig A), The patient was referred to the operating room where surgical findings confirmed bladder rupture requiring conservative surgery. Urine, blood cultures and operative samples grew with a cefotaxime sensitive Klebsiella pneumoniae gas producing strain (Fig B and C). The patient recovered progressively and was discharged from ICU six weeks later.

Author details 1 Service de Reanimation Medicale, Hopital Saint‐Antoine, Assistance Publique–Hopitaux de Paris, Paris 75012, France. 2 Service de Microbiologie, Hopital Saint‐Antoine, Assistance Publique–Hopitaux de Paris, Paris, France. 3 Universite Pierre et Marie Curie (Universite Paris 6), 4 Place Jussieu, Paris, France. 4 Institut Pierre Louis d’Epidemiologie et de Sante Publique (IPLESP UMRS 1136), Paris, France.