Journal articles on the topic 'Bureau de la correspondance (Paris, France)'

The last three years have been marked by changes, highlights and progress. Organizationally, commission 7 has joined Division I and plans proceed for commissions 8 and 24 to merge in 2000. They have had a common vice president during this triennium. Sadly, the Royal Greenwich Observatory was closed after over 200 years, but Her Majesty’s Nautical Almanac Office has continued at Rutherford Appleton Laboratory. In St Petersburg, Russia, the Institute of Theoretical Astronomy was abolished, with some of the personnel relocated to the Institute of Applied Astronomy and Pulkova Observatory. In Paris, France, the Bureau des Longitudes was reorganized as the Institute of Celestial Mechanics-Bureau des Longitudes as part of the Paris Observatory.

Résumé Longtemps tues, les dissensions entre les différentes factions automatistes commencent aujourd'hui à poindre. À partir de la correspondance échangée entre Borduas et Riopelle, l'auteur analyse ici les enjeux de l'antagonisme, resté longtemps inavoué, qui opposa les deux peintres. Le projet téméraire de Borduas de s'expatrier en France en 1946 où il espère être reconnu par le célèbre marchand d'art français Pierre Loeb qui consacrera plutôt quelques années plus tard Riopelle, le refus de l'artiste de participer avec son groupe à l'exposition internationale du surréalisme à la Galerie Maeght à Paris en 1947, l'accusation de « paternalisme » portée par Riopelle, qui poussera Borduas à rédiger pour sa propre défense en 1950 sa « Communication intime à mes chers amis », constituent quelques jalons importants de cette mésentente par laquelle s'opéra un renversement des générations entre maître et disciple. La rivalité non liquidée entre ces deux artistes de premier plan affecta de façon importante la place du mouvement automatiste dans l'histoire du développement de la peinture non figurative.

Résumé Successeur de Michel Sarrazin, Jean-François Gaultier, médecin normand, arrive à Québec, en 1742, avec la charge de médecin du roi. Sa correspondance avec l’Académie royale des Sciences de Paris copmrend une description minutieuse d’observations météorologiques, botaniques, agricoles et médicales, de même que de brèves notes sur les maladies régnantes (fièvres, maladies pulmonaires, maladies dysentériques), de cette ville de Nouvelle-France. Aussi, il est important de comprendre qu’il appartient au mouvement européen de la médecine météorologique, une approche conçue initialement par Hippocrate puis développée par Sydenham en Angleterre dans la seconde moitié du 17e siècle, dont l’objectif est d’établir une corrélation étroite entre la météorologie et la maladie. A la lumière de l’historiographie actuelle, Gaultier est le premier médecin à en témoigner officiellement dans les colonies françaises.

Les relations commerciales entre la Librairie Honoré Champion de Paris et l’Institut d’Estudis Catalans de Barcelone et sa Bibliothèque (Biblioteca de Catalunya) durèrent plus de vingt-cinq ans (1909-1936). Champion ne fut pas seulement le représentant en France des publications de l’Institut mais aussi le fournisseur international le plus important dans la formation de la Biblioteca de Catalunya à ses débuts. L’article analyse cette dernière facette de fournisseur en se centrant principalement sur l’époque de la Première Guerre mondiale, époque au cours de laquelle la Librairie fut dirigée par Marie Champion. L’analyse de la correspondance commerciale conservée, étudiée dans son contexte historique, permet d’ébaucher la figure d’une femme qui – en plein conflit – défend efficacement l’affaire familiale et, de plus, imprègne de sa personnalité les relations commerciales qu’elle entretiendra avec cette institution académique catalane.

From December 1956 to December 1957, no fewer than four exhibitions presenting the oeuvre of Katarzyna Kobro and Władysław Strzemiński were organised: the Posthumous Exhibition of Władysław Strzemiński’s and Katarzyna Kobro’s Oeuvre, shown fi rst in Łódź (16 December 1956 – 14 January 1957) and then in Warsaw (18 January – 10 February 1957), and two exhibitions in Paris: 50 ans de peinture abstraite at Galerie Raymond Creuze (9 May – 12 June 1957) and Précurseurs de l’art abstrait en Pologne: Malewicz, Kobro, Strzemiński, Berlewi, Stażewski at Galerie Denise René (22 November 1957 – 10 January 1958). All received a strong response, both in Poland and abroad. Research focused on these exhibitions has brought some surprising results. None of them had been planned until 1956, and only after the events of October 1956 was it possible to show the works of Kobro and Strzemiński in Warsaw in 1957. The exhibition at the Łódź Division of the Central Bureau of Art Exhibitions was prepared with exceptional care and is immensely important, as it occasioned the fi rst attempt at preparing a catalogue of both Kobro’s and Strzemiński’s works, of Strzemiński’s biography and a bibliography of texts authored by Strzemiński and Kobro. In addition, it was there that Strzemiński’s treatise Teoria widzenia fi rst came to public attention; it was published only two years later. The exhibition was transferred, quite unexpectedly, to the Central Bureau of Art Exhibitions in Warsaw, which was the chief institution involved in exhibiting modern art in Poland; this gave offi cial sanction and a considerable status to the oeuvre of both avant-garde artists. The exhibition entitled Précurseurs de l’art abstrait en Pologne became, paradoxically, the fi rst-ever offi cial exhibition of Polish avant-garde art to be held abroad and organised by a state agency, i.e. the Central Bureau of Art Exhibitions, under the aegis of the ambassador of the People’s Republic of Poland in France. It was also the only exhibition in which Kazimierz Malewicz was regarded as a Pole and presented as belonging to the history of art in Poland; the mission initiated by Strzemiński in 1922 was thus completed. The institutions involved in arranging the loans of Malewicz’s works for this exhibition were the Ministry of Culture and Art, the Ministry of Foreign Affairs and its subordinate Polish embassies in Paris and Moscow. This was the fi rst time that the works of Kazimierz Malewicz were presented in the West, thanks to the efforts and under the aegis of the Polish Ministry of Foreign Affairs during the period of the post-Stalinist thaw; notably, this happened before their presentation at the Stedelijk Museum in Amsterdam (29 December 1957).

Abstract In the last decades of the nineteenth century the Paris Exchange was the second largest in the world, and engagement in financial markets had become popular on a previously unknown scale. How ordinary people encountered, thought about, and navigated this new financial landscape has nevertheless proved elusive. This article analyzes everyday financial practice in the first age of global capital from the vantage of letters written by ordinary individuals concerning their investments. As the numbers of investors and bondholders in France grew, “investor letters”—missives to financial, legal, and governmental authorities—proliferated. Their existence and concerns offer rich insights into how and with what effect France's financial markets were evolving at the end of the nineteenth century. These letters prompt us to reconsider the place of routine business correspondence in our studies of epistolary culture and allow reflection on economic life as modest investors “wrote upwards” and across the wealth gap of late nineteenth-century France. Vers la fin du dix-neuvième siècle, la Bourse de Paris était la deuxième place financière la plus importante au monde, et ses marchés étaient devenus « populaires » à une échelle sans précédent. La manière dont les gens ordinaires ont réussi à s'orienter dans ce nouveau paysage se révèle difficile à saisir. Cet article analyse la pratique financière quotidienne de l’âge d'or de la globalisation du capital selon les particuliers écrivant à propos de leurs investissements. A mesure que le nombre d'investisseurs et d'obligataires a augmenté, ces « lettres d'investisseurs » adressées aux autorités financières, juridiques et gouvernementales se sont multipliées. Leur existence et leurs sujets de préoccupation offrent de riches informations sur l’évolution des marchés financiers français de la fin du dix-neuvième siècle. Ces lettres nous incitent à reconsidérer la place de la correspondance commerciale dans la culture épistolaire, et en nous montrant comment de modestes investisseurs écrivent « vers le haut » de la hiérarchie économique et sociale, nous permettent d'accéder à des aspects méconnus de la vie économique de la fin du dix-neuvième siècle français.

A forgotten figure of the new Hungarian musical movement of the 1910s, Géza Vilmos Zágon (1889–1918) was a talented composer, pianist and music writer. He belonged among those young composers who turned toward French culture instead of the traditional German orientation and searched for new inspiration in Paris. He was, at the same time, one of the few to be personally acquainted with leading personalities of the city’s musical life: letters by Claude Debussy, Michel-Dimitri Calvocoressi, Louis Laloy, Émile Vuillermoz and Albert Zunz Mathot have survived in his legacy. During his stay in France between 1912 and 1914, he acted as the representant of the former UMZE (Új Magyar Zene Egyesület, New Hungarian Music Association), and did not only bring attention to himself as a performer of his own works, but was also instrumental in promoting those by Bartók and Kodály. In the present study, I seek to demonstrate that Zágon served as an important liaison for Bartók’s circle with some of the most influential groups of French avant-garde, the Société Musicale Indépendante, as well as Calvocoressi. In an effort to document these important relationships as well as Zágon’s activity, I publish a selection of his correspondence in original language, with French translation provided where appropriate.

Dès la fin des années 1540, la famille de Jean de Morel accueillait dans sa maison de la rue Pavée à Paris les poètes et les humanistes les plus proéminents de la capitale: Nicolas Bourbon, Jean Salmon Macrin, Jean Dorat parmi les néo-latins; Joachim Du Bellay, Ronsard, Jean-Antoine de Baïf, pour ne citer que quelques-uns des poètes de langue vulgaire. Or, la femme de Morel, Antoinette de Loynes, et ses trois filles, Camille, Lucrèce et Diane, avaient toutes les quatre reçu une éducation humaniste, leur permettant non seulement de participer aux activités littéraires et humanistes de ce que l'on a appelé le premier salon en France, mais encore d'attirer l'admiration du monde cultivé de l'époque. En examinant la correspondance des membres de la famille ainsi que certains ouvrages imprimés, cet article se propose d'illustrer les relations que les membres de la famille ont entretenues avec les visiteurs du salon ainsi que les changements d'attitude qui ont eu lieu au cours du XVIe siècle à l'égard de l'éducation des jeunes filles.

AbstractFounder of the most widely known matrimonial agency in postrevolutionary France, Claude Villiaume proved his talents as an enterprising ad man who exploited the uniquely commercial format of the Parisian Petites affiches to establish a virtual monopoly on the business under the Empire. Offering to serve as a conduit for men and women who pursued love anonymously in the Petites affiches, he skillfully marketed his “marriages by the classifieds” to lonely, uprooted individuals throughout imperial France. Villiaume pitched his unions as part of a new commercial and social world of movement in Paris. He sought to facilitate the circulation of capital and people by forging family alliances and love matches across multiple social and geographic borders. By linking marital choice and courtship to the vagaries of consumer capitalism, the agent transformed marriage into a form of commercial exchange associated with the new urban values of abundance, pleasure, and social mobility.Fondateur du bureau des mariages le plus connu à l'époque de l'Empire, Claude Villiaume a fait preuve de son talent comme publicitaire dynamique qui se servait du format commercial des Petites Affiches de Paris afin d'établir un monopole sur la profession de courtier matrimonial. Il s'est proposé comme entremetteur pour les gens à la recherche d'un conjoint dans l'anonymat des petites annonces et il a mis en valeur ses « mariages par les petites affiches » aux personnes solitaires et déplacées dans la France impériale. Villiaume a proposé ses mariages dans le cadre d'un nouveau monde commercial et social marqué par la circulation rapide des personnes et des marchandises à Paris. Il a tenté de faciliter les alliances familiales et les liens amoureux au-delà des frontières géographiques et sociales. En associant le modèle du choix du conjoint et de la cour au capitalisme consumériste, l'agent a transformé le mariage en une espèce d'échange commercial lié aux valeurs urbaines de l'abondance, du plaisir, et de la mobilité sociale.

Background:Golimumab (GLM) is the latest anti-TNFα to be indicated for treating rheumatoid arthritis (RA), psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA). The GO-PRACTICE study was performed in France at the request of the French Health Authorities, for the reevaluation of GLM in real-life.Objectives:The primary objective was to estimate GLM persistence at 2 years from initial prescription. This abstract focuses on a post-hoc analysis of the factors linked to GLM discontinuation in axSpA patients.Methods:Observational, prospective, multicenter study, that consecutively recruited adult patients with RA, PsA and axSpA who were newly prescribed GLM. Patients were followed-up for 2 years and outcomes data were collected at baseline (BL), 1 and 2 years. Patients’ sociodemographic characteristics, disease history, comorbidities and treatment history were also collected at BL. Persistence was estimated with the Kaplan-Meier method. Cox proportional hazard models were used to assess factors associated with persistence. Selected BL characteristics were studied in univariate models, where those associated withp-value <0.20 were included in multivariate analysis. Significance level was set atp<0.05.Results:478 patients with axSpA were included from Jan 2015 to Mar 2016. Mean age was 43 years and 55% were female; 61% of patients were biologic-naïve (BN, n=291) and 39% (n=187) were biologic-pretreated (BP). Median time-elapsed in years since axSpA diagnosis was 1.7 (range 0–45.1) and 6.9 (range 0.2–51.8) in BN and BP patients, respectively (P<0.001); 97% patients were prescribed 50 mg GLM monthly and co-treatments included DMARD (34%), corticosteroids (17%) and NSAIDs/analgesics (90%).Cumulative persistence probability of GLM at 2-years was 52.6% (Fig 1). Table 1 details the binary variables associated with GLM discontinuation atp<0.20. Among continuous variables, BL CRP level was associated withp<0.20. A multivariate analysis of these factors revealed that being female (HR 1.92, 95%CI 1.43–2.56,P<0.001) and being BP (HR 1.45, 95%CI (1.11–1.90),P=0.007) were risk factors for GLM discontinuation (Table 1).Table 1.Logistic model results for variables of interest and their link to GLM discontinuation in axSpAFactorModalitiesχ2(p)Hazard ratio (HR)95% CIHR following univariate analysis (p>0.20)AgeContinuous variable0.5201.000.99–1.02Disease duration0.4011.010.99–1.03Inflammatory bowel diseaseYes vs. No0.2770.740.43–1.28Gastrointestinal disease0.3441.270.78–2.06Uveitis0.2370.800.55–1.16Psoriasis0.2380.920.64–1.31 HR following multivariate analysis (variables with p<0.20 at univariate analysis)GenderFemale vs. Male< 0.0011.921.43–2.56Biologics historyPretreated vs. naïve0.0071.451.11–1.90Serum CRPContinuous variable0.1770.990.98–1.00DMARD historyYes vs. No0.0621.370.99–1.90Ongoing corticosteroids0.6931.080.73–1.61Anemia0.1701.820.78–4.24Kidney Disease0.5081.500.45–4.97Other physical illness0.4351.280.69–2.34Conclusion:2-year GLM persistence in axSpA patients was 52.6%. Females and those who were biologics-pretreated were at greater risk for discontinuing GLM before 2 years.Disclosure of Interests:Philippe Bertin Consultant of: MSD France, Philippe Goupille Grant/research support from: AbbVie, Amgen, Biogen, BMS, Celgene, Chugai, Lilly, Janssen, Medac, MSD France, Nordic Pharma, Novartis, Pfizer, Sanofi and UCB, Consultant of: AbbVie, Amgen, Biogen, BMS, Celgene, Chugai, Lilly, Janssen, Medac, MSD France, Nordic Pharma, Novartis, Pfizer, Sanofi and UCB, Speakers bureau: AbbVie, Amgen, Biogen, BMS, Celgene, Chugai, Lilly, Janssen, Medac, MSD France, Nordic Pharma, Novartis, Pfizer, Sanofi and UCB, Florence Tubach Grant/research support from: Florence TUBACH is head of the Centre de Pharmacoépidémiologie (Cephepi) of the Assistance Publique – Hôpitaux de Paris and of the Clinical Research Unit of Pitié-Salpêtrière hospital, both these structures have received research funding, grants and fees for consultant activities from a large number of pharmaceutical companies, that have contributed indiscriminately to the salaries of its employees. Florence Tubach didn’t receive any personal remuneration from these companies., Eric Lespessailles Consultant of: Amgen, Celgene, Lilly, MSD France, Novartis, UCB, Speakers bureau: Amgen, Celgene, Lilly, MSD France, Novartis, UCB, Naoual HARID Employee of: MSD France, Saannya Sequeira Consultant of: MSD France, Jean-Marie Fayette Consultant of: MSD France, Bruno Fautrel Grant/research support from: AbbVie, Lilly, MSD, Pfizer, Consultant of: AbbVie, Biogen, BMS, Boehringer Ingelheim, Celgene, Lilly, Janssen, Medac MSD France, Nordic Pharma, Novartis, Pfizer, Roche, Sanofi Aventis, SOBI and UCB, René-Marc Flipo Consultant of: Johnson and Johnson, MSD France, Novartis, Sanofi, Speakers bureau: Johnson and Johnson, MSD France, Novartis, Sanofi

Le débat public en apprentissage—Aménagement et environnement : Regards croisés sur les expériences française et québécoise, Louis Simard, Laurent Lepage, Jean-Michel Fourniau, Michel Gariépy et Mario Gauthier (sous la direction de), Paris : L'Harmattan, collection Villes et entreprises, 2006, 315 pp.L'ouvrage collectif franco-québécois, Le débat public en apprentissage—Aménagement et environnement, se propose de faire un bilan des mécanismes de consultation publique au Québec et en France. Les institutions qui encadrent ces débats publics, surtout en environnement, en énergie et en construction routière, nous semblent relativement récentes, mais dans certains cas, comme dans celui du BAPE (Bureau d'audiences publiques sur l'environnement) au Québec, elles fonctionnent depuis maintenant plusieurs décennies, et l'heure est donc aux bilans. Ou, comme le soulignent des contributeurs français, on est prêt à un “ débat sur le débat ”. Pour dresser ce bilan, on a eu la bonne idée de faire appel à des praticiens et à des universitaires, et ce, des deux côtés de l'Atlantique. Le résultat est un volume riche en pistes et en idées dont l'intégration est cependant laissée au soin des lecteurs.

Introduction Since interim results from the EuroNet-PHL-C1 study1were published in 2013 showing that the gonadotoxic drug procarbazine in COPP can be safely replaced with dacarbazine (COPDac) it is increasingly common practice to modify escalated BEACOPP (eBPP) by removing oral procarbazine and replacing it with intravenous dacarbazine (250mg/m2 D2-3), hoping to reduce haematopoietic stem cell and gonadal toxicity. However, published data of 'escalated BEACOPDac (eBPDac)' regimen are very limited. Methods We collected retrospective data from 15 centres in the UK, Ireland and France, that offer eBPDac therapy for first line advanced stage Hodgkin Lymphoma, and compared outcomes with matched patients treated with eBPP at 4 UK centres. Most patients were treated as per HD15 or HD18 protocol. The 24 patients treated in Paris followed the AHL2011 protocol with two courses of eBPDac given upfront and if iPET2 negative were deescalated to 4 cycles of ABVD. Results From 2009, 141 patients were managed first line with either eBPP (n=52) or eBPDac (n=89) with median follow-up 40 months for eBPP and 12.7 months for eBPDac patients. Patients were well matched with no significant differences in age (median: 28), sex, stage (stage 3/4: 82%) and international prognostic score (IPS3+:65%). More patients treated with eBPDac received only 4 cycles of treatment (43% vs 12%; p<0.001) reflecting recent publication of HD18 trial data2. In total, 74% patients achieved iPET2 Deauville score 2 or 3 and 96% patients achieved PET negative remission by end of treatment. Of eBPDac patients, 77% achieved iPET Deauville 2 or 3 which was statistically similar to the eBPP cohort (69%; p=0.391) and matched the 76% iPET D2/3 reported in HD181. Of 141 patients, 139 are alive and 136 continue in first remission. Two eBPP patients have relapsed at 13 and 41 months and the latter died of refractory disease. One eBPDac patient had primary refractory disease, another relapsed seven months after treatment, and one 56-year-old eBPDac patient with high IPS died with bowel perforation during cycle 1. Toxicity was compared over the first 4 cycles. There was no difference in day 8 ALT between the two regimens although the mean day 8 neutrophil count was lower in eBPDac than eBPP patients (1.84 vs 2.35; p=0.043; G-CSF given day 9). There was a trend to fewer non-elective days of in-patient care for eBPDac compared with eBPP (mean: 2.78 vs 6.00; p=0.0846), and eBPDac patients received fewer red cell transfusions during cycles 1 to 4 compared with eBPP patients (Mean 1.87 units vs 4.33 units; p<0.001). Women aged < 35, who completed ≥4 cycles of eBPDac/eBPP with > 6 months post chemotherapy follow-up had a similar rate of return of menstrual cycles (eBPP: 20/21; eBPDac: 13/16), although eBPDac patients appeared to restart menstruation earlier post chemotherapy completion (mean: 3.85 months vs 8.65 months, p=0.0018). However, this could also reflect the higher mean chemotherapy cycle number completed by the eBPP women (5.86 vs 4.67; p<0.001). The use of monthly Goserelin to suppress ovulation varied between centres. Conclusions Accepting the limitations of a retrospective study, we suggest that substituting dacarbazine for procarbazine is unlikely to compromise the efficacy of eBPP in frontline therapy of patients with advanced Hodgkin Lymphoma and may have some toxicity benefits. As it is highly unlikely that this single drug substitution will ever be tested in a prospective trial, publishing real-world data from eBPDac patients is important. References 1. EuroNet-PHL-C1 study interim report published 14/08/2013 http://www.anzchog.org/docs/public-resources/euronet-recommendation.pdf?sfvrsn=0 2. Borchmann P et al. 2018;390:2790-2802 Disclosures Brice: BMS: Honoraria; Takeda France: Consultancy, Honoraria; Millennium Takeda: Research Funding. Menne:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Research Funding, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Kite/Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Research Funding, Speakers Bureau; Kyowa Kirin: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Research Funding, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Daiichi Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Research Funding, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Research Funding, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Osborne:Novartis: Other: Travel; Pfizer: Honoraria, Speakers Bureau; Servier: Consultancy; MSD: Consultancy; Takeda: Consultancy, Honoraria, Other: Travel, Speakers Bureau; Gilead: Consultancy; Roche: Consultancy, Honoraria, Other: Travel, Speakers Bureau. Ardeshna:Gilead: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Collins:Gilead: Consultancy, Honoraria. Cwynarski:Adienne: Consultancy; Takeda: Consultancy, Other: conference and travel support , Speakers Bureau; Gilead: Consultancy, Other: conference and travel support, Speakers Bureau; Celgene: Consultancy; Roche,: Consultancy, Other: conference and travel support, Speakers Bureau; Autolus: Consultancy; KITE: Consultancy; Atara: Consultancy; Janssen: Other: conference and travel support, Speakers Bureau. Iyengar:Takeda: Honoraria; Janssen: Honoraria; Gilead: Honoraria; Abbvie: Honoraria; Roche: Honoraria. Martinez-Calle:ABBVIE: Other: Travel support. McKay:Epizyme: Consultancy, Honoraria. Nagumantry:Takeda: Honoraria, Speakers Bureau; Alexion: Speakers Bureau; Abbvie: Honoraria. Shah:Abbvie: Consultancy. Uttenthal:Roche: Honoraria; Takeda: Honoraria; Jazz: Honoraria. McMillan:BMS: Honoraria; F. Hoffmann-La Roche Ltd: Honoraria, Speakers Bureau; Sandoz: Honoraria; Celgene: Honoraria, Speakers Bureau; Novartis: Honoraria; Gilead: Honoraria; MSD: Honoraria; Pfizer: Honoraria, Research Funding. Follows:Roche: Consultancy, Honoraria, Speakers Bureau; AZ: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Abbvie: Consultancy, Honoraria, Speakers Bureau.

It has been attempted to make an empirical study of the framing of the Jewish pogroms upon the Ukrainian terrains in 1919 in the Ukrainian press in the West European languages in Europe (1919―1920s). For the first time, in the communication and media studies discourses, there have been elicited new, previously unknown, findings of specificity of the framing of the Jewish pogroms in the Ukrainian foreignlanguage periodicals. Those were: «Bulletiner fra det Ukrainske Pressburo» (Copenhagen, 1919—1920s), «La Voce dell “Ucraina”» (Roma, 1919—1920s), «The Ukraine» (London, 1919—1920s), «Bureau Ukrai nien de Presse: Bulletin d’Informations» (Paris, 1919—1920s), «France et Ukraine» (Paris, 1920), «L’Europe Orientale» (Paris, 1919—1920s), «Die Ukraine» (Berlin, 1918—1926s). First, it has been elucidated that the «attribution of responsibility» frame was dominant in the content of the Ukrainian foreign-language press in Western Europe. Second, the conclusion about dialectic of the frames of «attribution of responsibility» and «morality» in the coverage of the Jewish pogroms upon the Ukrainian terrains has been made. In this regard, we conclude that the «morality» frame was connected with the internationalization of this problematic in the geopolitical discourse of international relations of the postwar period. On the contrary, the frame of «attribution of responsibility» was linked to localization of the Jewish question in the multilateral conflict on the Ukrainian territories in 1919. The main conclusion of this paper is that the coverage of the Jewish pogroms in the Ukrainian foreign-language press in Europe was made primarily in counterpropaganda purposes. The follow-up studies are to make a comparative study of the stereotypes about Jews’ perception in the Ukrainian-language press both in Ukraine and abroad (in Europe or the USA), as well as in the West European and American press of the Ukrainian Revolution period (1917―1921s). Thus, these future studies will either refute or confirm the validity of the findings and conclusions of this research. Keywords: framing, the Jewish pogroms, the Ukrainian terrains, the foreign-language press, Europe.

Abstract Background: Flotetuzumab (FLZ; MGD006/S80880) is a novel CD123 x CD3 bispecific DART® protein being tested in a Phase 1/2 study (NCT02152956) in patients with relapsed/refractory acute myeloid leukemia (AML). As with all T-cell redirecting therapies, cytokine secretion, inherent in T-cell activation, with ensuing potential for cytokine release syndrome (CRS), remains an important side effect. We have previously reported that multi-step dosing mitigates CRS severity (1). CRS diagnosis and treatment is guided by the occurrence of non-specific clinical signs, such as fever, chills, hypotension and tachycardia. Therefore, identification of predictors of CRS will be useful for optimal pt. management. Here we report on potential biomarkers of CRS severity that may help guide CRS management. Methods: Data from pts treated with FLZ at RP2D (lead-in dose of 30ng/kg/d for 3d, 100ng/kg/d for 4d for week 1 followed by 500ng/kg/d CIV week 2-4 of cycle 1, and a 4d-on/3d-off schedule for Cycle 2 and beyond in 28-day cycles) was collected and analyzed. Incidence and severity of CRS were analyzed for correlation with cytokine levels and changes in BM blasts. Relation between immune cells (T-cell subsets, monocytes) with tumor burden, percent CD123+ AML blasts, and CD123 expression, were interrogated as potential determinants of CRS. Administration, dose and frequency of tocilizumab (TCZ), an IL-6 receptor antagonist, were evaluated for their relationship with CRS severity, frequency, CRP and cytokine levels. Results: 30 pts were dosed at RP2D. Most pts experienced mild to moderate CRS (G1 26.7%, G2 60%) of short duration (median 1 day(d), range 1-26 d) and were conservatively managed to full resolution. Grade ≥ 3 events occurred in 4/30 pts (13%), with vasopressors use in 2 pts, and a median duration of 2.5 d (range 2-13 d). CRS frequency decreased with time on treatment: 42% occurred within the first week (LID), 39.6% occurring in week 2 (step up to 500ng/kg/day) and 18% occurring during week 3 and 4. IL-6 levels showed the best relationship with CRS severity, as previously shown (1). IL-6 levels, however, did not correlate with response. Twenty pts (67%) received at least one dose of TCZ (median 2 doses/pt; range 1-12 doses). As anticipated, mean IL-6 levels increased after administration of TCZ. CRS severity showed a relationship with the baseline frequency of circulating CD4+ cells (median 47% in G1 vs 73% in G ≥2, p = 0.0082), while CD8+ cell frequency did not correlate with CRS. Disease burden (absolute AML blasts, % CD123 AML blasts), CD123 expression on AML blasts, monocytes levels or effector-to-target ratio in the peripheral blood did not show a relationship with CRS severity. Importantly, CRS severity was not correlated with FLZ anti-leukemic activity. Conclusion: The frequency of CD4+ cells at baseline may be a potential biomarker for identifying pts at risk of more severe CRS. Early use of TCZ can effectively modify the activity of IL-6, a significant contributor to CRS, and blunt CRS severity. Since severity of CRS and IL-6 levels did not correlate with FLZ anti-leukemic activity, blunting its severity should be aggressively pursued. Early identification of pts at greater CRS risk together with multistep dosing (1) and early use of TCZ can effectively manage CRS with no impact on FLZ anti-leukemic activity.Jacobs et al. ASH 2017, abstract #3856 Disclosures Jacobs: MacroGenics: Employment. Viero:Servier: Employment. Baughman:MacroGenics: Employment. Sun:MacroGenics: Employment. Ying:Macrogenics: Employment. Muth:MacroGenics: Employment. Hong:MacroGenics: Employment. Sweet:BMS: Honoraria; Agios: Consultancy; Phizer: Consultancy; Astellas: Consultancy; Jazz: Speakers Bureau; Jazz: Speakers Bureau; BMS: Honoraria; Novartis: Consultancy, Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Agios: Consultancy; Phizer: Consultancy; Celgene: Honoraria, Speakers Bureau; Astellas: Consultancy; Novartis: Consultancy, Honoraria, Speakers Bureau. Uy:Curis: Consultancy; GlycoMimetics: Consultancy. Ravandi:Xencor: Research Funding; Macrogenix: Honoraria, Research Funding; Bristol-Myers Squibb: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Abbvie: Research Funding; Jazz: Honoraria; Amgen: Honoraria, Research Funding, Speakers Bureau; Orsenix: Honoraria; Abbvie: Research Funding; Orsenix: Honoraria; Seattle Genetics: Research Funding; Seattle Genetics: Research Funding; Bristol-Myers Squibb: Research Funding; Sunesis: Honoraria; Sunesis: Honoraria; Xencor: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Amgen: Honoraria, Research Funding, Speakers Bureau; Macrogenix: Honoraria, Research Funding; Jazz: Honoraria. Foster:Celgene: Research Funding; Macrogenics: Research Funding; Pfizer: Research Funding; Shire: Honoraria. Rizzieri:Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Arog: Consultancy, Membership on an entity's Board of Directors or advisory committees; Teva: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees. Arellano:Cephalon: Research Funding. Rettig:Amphivena Therapeutics: Research Funding; Novimmune: Research Funding. Topp:F. Hoffmann-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees, Research Funding; Regeneron Pharmaceuticals, Inc.: Honoraria, Research Funding; Boehringer Ingelheim: Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding. Lelièvre:Servier: Employment. Lowenberg:Royal Academy of Sciences and Arts, The Netherlands: Membership on an entity's Board of Directors or advisory committees; international Scientific Advisory Board, Institute Gustave Roussy, Paris: Membership on an entity's Board of Directors or advisory committees; "Up-to-Date", section editor leukemia: Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Astex: Consultancy; Supervisory Board, National Comprehensive Cancer Center (IKNL), Netherlands: Membership on an entity's Board of Directors or advisory committees; Editorial Board "European Oncology & Haematology": Membership on an entity's Board of Directors or advisory committees; Elected member, Royal Academy of Sciences and Arts, The Netherlands: Membership on an entity's Board of Directors or advisory committees; Chairman, Leukemia Cooperative Trial Group HOVON (Netherlands): Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Editorial Board "International Journal of Hematology": Membership on an entity's Board of Directors or advisory committees; Clear Creek Bio Ltd: Consultancy, Honoraria; Editorial Board "The Netherlands Journal of Medicine": Membership on an entity's Board of Directors or advisory committees; Chairman Scientific Committee and Member Executive Committee, European School of Hematology (ESH, Paris, France): Membership on an entity's Board of Directors or advisory committees. Wigginton:MacroGenics: Employment. Davidson-Moncada:MacroGenics: Employment.

Résumé Le succès de la grammaire scolaire dans la France du XIXe siècle avait favorisé la traduction de certains de ses manuels, comme le Lhomond ou le Noël et Chapsal, pour servir de méthodes d’apprentissage aux étrangers. Le Lhomond tout particulièrement, après la traduction anglaise de Longfellow (1830) avait connu une traduction arabe, publiée à Paris en 1857 par un Tunisien du nom de Soliman al-Haraïri (1824–1877). Il y développe en fait, une double traduction: traduction libre et traduction littérale. Cette dernière, très paradoxalement, constitue le noyau d’une méthode présentée par l’auteur comme une invention didactique à laquelle il n’a jamais été précédé. L’effort de traduction y est considérable par rapport à ce que l’on trouve dans l’ouvrage anglais. La langue arabe, ainsi que la grammatisation autochtone qui s’y rapporte sont tellement éloignées du français et de sa grammatisation que le traducteur est amené à faire œuvre de linguiste et non de simple traducteur. La traduction de la terminologie, comme celle des exemples et des paradigmes, nécessite en effet une grande connaissance de l’arabe et de sa grammaire. Le recours au dialecte marque d’ailleurs l’épuisement des ressources de l’arabe classique. La transcription s’y ajoute pour faire encore reculer l’écart, au-delà de la grammaire et du système phonologique, jusqu’à l’écriture elle-même. Les éléments d’une recherche contrastive viennent, en outre, accompagner la traduction littérale comme pour en retracer les limites et révéler les irréductibles difficultés de l’apprentissage. Mais la correspondance entre les deux langues, incarnée dans cette traduction, a été expressément exagérée pour gagner plus de terrain dans le rapprochement du Lhomond, dans sa langue originale, à l’élève arabe. L’objectif étant de le mettre immédiatement en contact avec la langue française, via ce pré-texte qu’est la traduction littérale. Quant à la traduction libre, elle est considérée comme superflue, ne pouvant profiter qu’à l’élève français censé y trouver un ‘guide de bien traduire’.

Background:In knee osteoarthritis (KOA) recommendations, the first pharmacological analgesic line is paracetamol. However, its low efficacy, frequently leads to the use of weak opioids (WO) despite their poor tolerance, especially in elderly patients.Objectives:The primary objective was to compare analgesic efficacy and safety of a new wearable transcutaneous electrical nerve stimulation (W-TENS) to those of WO in the treatment of moderate to severe, nociceptive, chronic pain in KOA patients.Methods:ArthroTENS study was a phase 3, non-inferiority, multicentric, prospective, randomized, single-blinded for primary efficacy outcome, controlled, in 2-parallel groups, clinical study comparing W-TENS versus WO on two periods: a 3-month controlled period and an additional, optional, non-controlled, 3-month follow-up for patients in W-TENS group.Eligible participants were KOA patients, ≥55 years old, at Kellgren-Lawrence radiographic grade ≥2, with moderate to severe nociceptive chronic (≥3 months) mean 8-day pain ≥4 on a 11-point numerical rating scale, and in treatment failure with non-opioid analgesics, including NSAIDs. Patients with neuropathic pain were excluded.Co-primary endpoints were, for efficacy, mean pain intensity (PI), assessed at M3 and, for safety, the number of adverse events (AE) during the 3-month follow-up period.In W-TENS group, an advanced, mobile app enabled, wearable TENS was used. High (100 Hz) and low (2 Hz) frequency stimulations were delivered via electrodes with standardized positioning (Figure 1).Figure 1.Electrode’s positioningIn WO group, investigators chose, for each patient, the best suitable WO and its daily dose, and could switch to another WO, and/or adapt its daily dose if necessary.A non-inferiority analysis was performed on the primary efficacy endpoint using a pre-defined non-inferiority margin (0.825 point) on PI, below the minimal clinically significant improvement.Results:Demographic and baseline characteristics were balanced across both groups.110 patients (55/group) were randomized and 48/55 (87.3%) and 44/55 (80.0%) patients completed the 3-month follow-up in W-TENS and WO groups, respectively. WO’s prescriptions were balanced between codeine, opium-powder, tramadol and WO-paracetamol combinations.Non-inferiority of W-TENS was demonstrated in the PP and ITT populations (Table 1). Since the 95% confidence interval (CI) of the between-treatments difference was below 0 in the ITT population, a planned superiority analysis was performed showing that W-TENS was significantly superior to WO at M3 (p=0.0124) on PI. Additionally, the number of AEs was significantly lower (p<0.001) in W-TENS (n=7) group than in WO (n=36) group. In WO group, AEs were systemic AEs usually reported with WO while AEs in W-TENS group were local, related to the technique used, such as local cutaneous reaction (erythema).Table 1.Non-inferiority analyses on pain intensity at M3. ITT and PP populations. Least squares means for each study group and study group difference estimate and corresponding 95% CIGroup PopulationWithin-group changeBetween-group differenceW-TENSWOW-TENS - WOITT Population (n)5555Non inferiorityMean (SD)3.83 (0.28)<0.0014.74 (0.28)<0.001-0.92 (0.40)Non inferiority‡ demonstrated95% CI[3.27, 4.40][4.18, 5.30][-1.71, -0.12]PP Population (n)5247Mean (SD)3.87 (0.30)<0.0014.66 (0.32)<0.001-0.79 (0.44)Non inferiority‡ demonstrated95% CI[3.28, 4.46][4.03, 5.28][-1.65, 0.08]‡ Noninferiority was demonstrated when 95% CI < 0.825Thirty-nine (70.9%) patients wished to extend W-TENS treatment for 3 additional months. Only one patient discontinued this additional period and results obtained at M3 remained stable at M6.Conclusion:In this study, W-TENS was more effective and better tolerated than WO in the treatment of nociceptive KOA chronic pain and should represent an interesting non-pharmacological alternative to WO.Acknowledgements:We gratefully thank P. Fardellone (Amiens), E. Coudeyre (Clermont-Ferrand), Y. Donazzolo (Gieres), A. Amouzougan (Saint-Etienne), L. Grange (Grenoble), T. Conrozier (Belfort), E. Senbel (Marseille), J.P. Sanchez (Billere), R. Forestier (Aix-les-Bains), H. Bard (Paris) and E. Gibert (Ivry-sur-Seine) for their active contribution throughout arthroTENS studyDisclosure of Interests:Emmanuel Maheu Speakers bureau: TRB chemedica, Consultant of: SUBLIMED, Moirans, FRANCE; Sandrine Soriot-Thomas Speakers bureau: Grunenthal, Consultant of: SUBLIMED, Moirans, FRANCE;GrunenthalKyowa Kirin pharma, Grant/research support from: GrunenthalSanofiTevaMylanTherable, Eric Noel Consultant of: SUBLIMED, Moirans, FRANCE; Eric Lespessailles Consultant of: SUBLIMED, Moirans, FRANCE; Bernard Cortet Consultant of: SUBLIMED, Moirans, FRANCE;

Abstract Introduction and Methods: Salvage chemotherapy followed by high-dose therapy and autologous stem cell transplantation (ASCT) is standard care for relapsed/refractory DLBCL. In the CORAL study, 477 patients were assigned to one of two salvage regimens (R-DHAP or R-ICE). Only the 240 responding patients underwent per protocol ASCT and were randomly assigned to rituximab or observation. The four-year event-free survival (EFS) post ASCT were 52 and 53% for the rituximab and observation groups, respectively (p=.7). Secondary IPI (sIPI) independently predicted EFS, PFS and OS after ASCT (Gisselbrecht et al, JCO 2010 & 2012). Outcome data are limited in DLBCL patients who relapse after ASCT, with reported overall survival (OS) of 9.9 months in rituximab-pretreated patients (Nagle et al, AJH 2013). To shed more light on outcome and prognostic factor in this population, 75 patients included in the CORAL study who relapsed after scheduled BEAM/ASCT were reviewed. Results: Median time between ASCT scheduled in CORAL and relapse was 7.1 months (range 3.1-61.9) with 32.9% relapsing > 12 months. Median age was 56.1y (range 20.9-67.7), M/F ratio 51/24, sIPI 0-2 in 71.6%, >2 in 28.4%. 49.3% were in the rituximab and 45.3% in the observation arm of the CORAL. All patients had previously received rituximab. Third-line therapy consisted of ICE-type (17.3%), DHAP-type (24%), gemcitabine-containing (28%), CHOP-like (13.3%), and miscellaneous regimens (17.3%). Overall response rate to third-line chemotherapy was 44%, with 32% complete response (CR)/CR unconfirmed (CRu), and 12% PR. Among the 75 patients, 16 (21.6%) could eventually be transplanted 3 ASCT and 13 allogeneic SCT with conditioning regimens including fludarabine. Median OS, calculated from time of relapse until death, was 10.0 months (95% CI 6.6-12.6; min: 0.9-max: 55.2 months; median follow-up: 32.8 months) with an estimated 1-y OS of 39.1%. Median OS was statistically different (p=.0007) according to sIPI at CORAL failure: sIPI 0-2: 12.6 months (1-y OS 51.3%), sIPI > 2: 5.3 months (1-y OS 21.6%, HR 2.805). Median OS in patients achieving CR/CRu, PR, or no response after third-line regimen was 37.7 m (1-y OS 90.5%, p<.0001, HR 0.132), 10.0 m (1-y OS 44.4%, p=.03, HR 0.375), and 6.3 months (1-y OS 13.4%), respectively. Median OS of patients who could eventually be transplanted was 17.4 months (1-y OS 68.2%), as compared to a median OS of 8.0 months in those who were not transplanted (1-y OS 31.2%) with a HR of 0.575 (p=.11). Median OS was particularly dismal among patients who relapsed < 6 months after CORAL-scheduled ASCT (5.7 months, n=28), as compared to those relapsing either > 6 and < 12 months (11.3 months, n=21) or > 12 months after ASCT (12.6 months, p=0.01, fig. 1)). In multivariate Cox analysis (with the following variables entered: age, sex, sIPI, response to third line and time between CORAL ASCT and relapse), sIPI >2 (HR 2.464, p=0.01), achievement of CR (HR 0.1, p<.0001) or PR (HR 0.242, p=0.02), and post-ASCT remission lasting < 6 months (HR 2.270, p=0.05) independently predicted for OS. Conclusions: Overall, the outcome of DLBCL patients relapsing after second-line R-DHAP/R-ICE followed by ASCT is poor. However, prognostic factors predicting better outcome in this group are late (> 6 months) relapse, lower sIPI and achieving at least PR after third-line salvage followed by transplantation. In the transplanted patients (allo SCT or second ASCT) a 2-year OS of 50% was observed. Thus, new salvage regimens can be a bridge to transplantation in patients with late relapse and/or low sIPI,. New drugs improving salvage efficacy are urgently needed, especially for patients relapsing < 6 months following ASCT. Figure 1. OS (months) in DLBCL patients relapsing after CORAL-scheduled ASCT according to interval between ASCT and relapse (<6 months, 6-12 months, > 12 months) Figure 1. OS (months) in DLBCL patients relapsing after CORAL-scheduled ASCT according to interval between ASCT and relapse (<6 months, 6-12 months, > 12 months) Disclosures Schmitz: Roche, Takeda, Gillead, Riemser und ctilifesciences: Other: Advisory board, Speakers Bureau. Gill:Sanofi Aventis: Research Funding; Roche: Honoraria; AbbVie: Honoraria; Roche: Research Funding. Milpied:Celgene: Honoraria, Research Funding. Briere:St. Louis Hospital, Paris, France: Employment. Thieblemont:St. Louis Hospital, Paris, France: Employment. Salles:Celgene Corporation; Roche and Gilead Sciences: Research Funding; Celgene Corporation; Roche: Speakers Bureau; Calistoga Pharmaceuticals, Inc.; Celgene Corporation; Genentech, Inc.; Janssen Pharmaceutica Products, L.P.; Roche: Consultancy. Gisselbrecht:roche: Research Funding, Speakers Bureau.

Abstract Acute myeloid leukemia (AML) blasts and leukemia stem cells highly express the α chain of the IL-3 receptor (CD123), compared to normal hematopoietic stem cells. CD123 expression is associated with high-risk features, increased risk of induction failure and poor prognosis (Vergez F, et al. Haematologica 2011; 96: 1792-8). Flotetuzumab (FLZ), a CD123 × CD3 bispecific DART molecule, is being tested in a phase 1/2 study in patients with relapsed/refractory (R/R) AML. The recommended Phase 2 dose (RP2D) of FLZ is 500 ng/kg/day (d) administered as a 7-day/week continuous infusion. Patients receive a lead-in dose (30 ng/kg/d x 3d then 100 ng/kg/d x 4d) during week (W) 1, followed by 500 ng/kg/d during W2-4 of cycle 1, and a 4d on/3 d off schedule for cycle 2 and beyond. Disease status was assessed by modified IWG criteria; samples were collected to investigate candidate biomarkers, including CD123 receptor density/cell (RD), and gene expression profiling using the NanoString® PanCancer IO 360™ assay. This platform was used to assess the expression of 770 genes, including 14 immune cell types and 32 immuno-oncology biological signatures in bone marrow (BM) samples from patients treated with FLZ. Thirty patients with R/R AML, median age 64.5 years, received FLZ at the RP2D. Most patients enrolled had primary refractory disease (60% [18/30; 14 to cytotoxic chemotherapy (refractory to ≥ 2 induction attempts, or first CR with initial CR <6 months), and 4 to hypomethylating agents (HMA; failure of ≥ 4 cycles of HMA)]). 25/30 (83.3%) of patients had high-risk disease (ELN adverse (18)/intermediate risk cytogenetics [CTG] (7)). At baseline, the median percentage of CD123+ BM blasts was 85% (range 1.4100%), and the median CD123 receptor density on BM blasts was 4,084 (range 357-28,818 RD). Infusion-related reaction/cytokine release syndrome (IRR/CRS), the most common AE, occurred in all patients, including grade ≥3 in 4/30 (13.3%) of patients. IRR/CRS was managed with conventional supportive care and a management paradigm based on early intervention with tocilizumab (anti-IL-6R) to ameliorate the progression of CRS. Most IRR/CRS events were of short duration and reversible with protocol-specified supportive care. Antileukemic activity was reported in 18/27 (67%) response-evaluable patients, with an overall response rate (ORR) of 22% (6/27) and a CR/CRi rate of 19% (5/27). Interestingly, responsiveness to FLZ appeared quite distinct in patients with relapsed disease versus those who were refractory to standard induction chemotherapy. Estimates from the literature indicate that up to 45% of AML patients are refractory to standard front-line therapy. In patients treated with FLZ, the CR/CRi rate was 31% (4/13) among patients with primary chemotherapy refractory AML, while no responses (0/11) were observed in relapsed patients. A prior report suggests that AML patients with an immune-enriched tumor microenvironment (TME) as evidenced by increased expression of genes associated with CD8 T cells, Th1 cells, B cells, cytotoxicity, CXCL9 and CXCL10, are less likely to respond to anthracycline-based cytotoxic chemotherapy and experience significantly shorter relapse-free survival (Vadakekolathu J, et al. Blood 2017; 130: 3942A). We hypothesized that the presence of an immune-enriched gene signature in the BM TME of patients with AML could help to identify patients more likely to respond to FLZ immunotherapy. Initial exploratory studies suggest that the expression of inflammatory genes may be increased in patients with refractory AML, including patients that respond to FLZ. In conclusion, among this initial cohort of patients treated at the RP2D (500 ng/kg/day), FLZ demonstrates antileukemic activity with an acceptable safety profile, in particular, among refractory patients, a difficult-to-treat patient population that represents a significant area of unmet medical need. Enrollment to the current study has now been expanded to further define the antileukemic activity of FLZ in patients with refractory AML, and investigate candidate biomarkers to enable identification of patients more likely to respond to FLZ. In addition, studies are now being initiated to investigate opportunities to expand the antileukemic activity of FLZ via combined administration with either concurrent or sequenced anti-PD-1 checkpoint blockade. Disclosures Uy: GlycoMimetics: Consultancy; Curis: Consultancy. Rettig:Novimmune: Research Funding; Amphivena Therapeutics: Research Funding. Foster:Celgene: Research Funding; Macrogenics: Research Funding; Pfizer: Research Funding; Shire: Honoraria. Rizzieri:Arog: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy; Teva: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees. Arellano:Cephalon: Research Funding. Topp:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding; Boehringer Ingelheim: Research Funding; Regeneron Pharmaceuticals, Inc.: Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees, Research Funding. Sweet:Phizer: Consultancy; BMS: Honoraria; BMS: Honoraria; Agios: Consultancy; Jazz: Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Astellas: Consultancy; Astellas: Consultancy; Jazz: Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Agios: Consultancy; Celgene: Honoraria, Speakers Bureau; Phizer: Consultancy; Novartis: Consultancy, Honoraria, Speakers Bureau. Ravandi:Abbvie: Research Funding; Xencor: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Seattle Genetics: Research Funding; Bristol-Myers Squibb: Research Funding; Jazz: Honoraria; Jazz: Honoraria; Macrogenix: Honoraria, Research Funding; Sunesis: Honoraria; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Orsenix: Honoraria; Macrogenix: Honoraria, Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Xencor: Research Funding; Orsenix: Honoraria; Astellas Pharmaceuticals: Consultancy, Honoraria; Sunesis: Honoraria; Abbvie: Research Funding. Church:NanoString Technologies: Employment. Rutella:NanoString Technologies: Research Funding. Sun:MacroGenics: Employment. Yang:MacroGenics: Employment. Baughman:MacroGenics: Employment. Curtis:MacroGenics: Employment. Timmeny:MacroGenics: Employment. Cali:MacroGenics: Employment. Tran:MacroGenics: Employment. Muth:MacroGenics: Employment. La Motte-Mohs:MacroGenics: Employment, Equity Ownership. Poirot:Servier: Employment. Pallis:Servier: Employment. Cesano:NanoString Technologies: Employment. Bonvini:MacroGenics: Employment, Equity Ownership. Wigginton:MacroGenics: Employment. Lowenberg:Astex: Consultancy; Agios Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Clear Creek Bio Ltd: Consultancy, Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees; Supervisory Board, National Comprehensive Cancer Center (IKNL), Netherlands: Membership on an entity's Board of Directors or advisory committees; Royal Academy of Sciences and Arts, The Netherlands: Membership on an entity's Board of Directors or advisory committees; international Scientific Advisory Board, Institute Gustave Roussy, Paris: Membership on an entity's Board of Directors or advisory committees; Editorial Board "International Journal of Hematology": Membership on an entity's Board of Directors or advisory committees; Elected member, Royal Academy of Sciences and Arts, The Netherlands: Membership on an entity's Board of Directors or advisory committees; Chairman, Leukemia Cooperative Trial Group HOVON (Netherlands): Membership on an entity's Board of Directors or advisory committees; Chairman Scientific Committee and Member Executive Committee, European School of Hematology (ESH, Paris, France): Membership on an entity's Board of Directors or advisory committees; Editorial Board "The Netherlands Journal of Medicine": Membership on an entity's Board of Directors or advisory committees; "Up-to-Date", section editor leukemia: Membership on an entity's Board of Directors or advisory committees; Editorial Board "European Oncology & Haematology": Membership on an entity's Board of Directors or advisory committees. Davidson-Moncada:MacroGenics: Employment.

Abstract Background: Veno-Occlusive Disease (VOD) or Sinusoidal Obstruction syndrome (SOS), is a rare but potentially life-threatening complication after Hematopoietic Stem Cells Transplantation (HSCT). The clinical diagnosis of VOD relies on signs and symptoms, such as weight gain, painful hepatomegaly and jaundice, directly correlated to the development of sinusoidal portal hypertension (PH). It has been demonstrated that the earlier is the treatment start better the outcome. For this reason, non-invasive diagnostic tools of VOD/SOS diagnosis are needed. Ultrasound (US) Elastography techniques, assessing the Liver Stiffness Measurements (LSM), have been demonstrated to be able to assess PH degree. The role of LSM in VOD/SOS has not yet been reported in the setting of adult HSCT. Methods: We report the results of a prospective single center study evaluating the role of LSM assessed by Transient Elastography (TE), in adult patients undergoing allogeneic HSCT for haematological malignancies since April 2016 at the Institute of Hematology "L. and A. Seràgnoli", Sant'Orsola-Malpighi University Hospital, Bologna, Italy. The exclusion criteria were patients with Body Mass Index (BMI) over 40 kg/m2, ascites and diagnosis of advanced chronic liver disease (ACLD) at pre-HSCT assessment. LSM were assessed bedside of patients by TE, using the FibroScan® apparatus with "M" probe (Echosens, Paris, France), after overnight fasting and after a complete abdominal US exam, before the start of conditioning regimen and then at 3 time points after transplant (on days +9/10, +15/17 and +22/24). Results: Over the study period, among of 89 patients referred to our centre 78 patients fulfilled the inclusion criteria. Median age was 54 years (40-60). The most frequent indication was Acute Myeloid Leukemia (44.9%). 66.7% of patients received a myeloablative conditioning while 33.3% received a RIC regimen. 15.4% were transplanted from HLA identical sibling donor, 74.4% from unrelated donor, 3.8% from Haplo and 6.4% from Cord Blood. The baseline median LSM was 4.2 kPa (3.8-5.3). During the study, 4 out 78 patients (5.1%) met clinical diagnostic criteria of VOD/SOS. The median day of VOD/SOS diagnosis was +17 (+1 - +29). Most of the VOD/SOS were Severe/Very severe (3/4), one of them leading to Multiple Organ Failure and death. Accordingly with EBMT criteria, the total number of pre-HSCT VOD/SOS risk factor was significantly higher in patients who developed VOD/SOS. We also valuated the US signs, according to Lassau criteria, in patients with VOD/SOS: 3 out 4 patients had ≥3 Grey-scale US morphologic Criteria and none presented ≥3 US Colour Doppler Criteria. Only portal vein diameter >12 mm was presented in all patients with VOD/SOS diagnosis. LSM values for each time points were reported in Figure 1; LSM by TE showed increased values in all patients who developed VOD/SOS (red continuous lines). Pre-HSCT (T0) LSM tended to be slight (p-value 0.079) higher (6.9 kPa vs 4.2 kPa) in patients who developed VOD/SOS. In these patients, the LS values increased before VOD/SOS clinical diagnosis, with values significantly different from pre-HSCT and from the previous assessments, anticipating from 2 to 12 days the clinical VOD/SOS development. After starting VOD/SOS specific treatment (defibrotide and diuretics) LSM values consensually decreased to pre-transplant values within 2-4 weeks. In univariate analysis an LSM increase after HSCT was significantly associated with VOD/SOS development (OR: 1.837; 95%CI [1.1107- 3.0384], p<0.01); indeed, ROC analysis of LSM increase over pre-HSCT assessment resulted an AUC of 0.997 with sensitivity of 75% and specificity of 98.7%. For instance, an increase ≥+10 kPa over pre-HSCT assessment showed a sensitivity of 100% and specificity of 98.7% for VOD/SOS diagnosis.During the study, 24 out 74 patients developed other HSCT-related liver complications: for them the increase of LSM after HSCT was not significantly different (p: 0.677) compared to patients who did not developed. Interpretation: LSM by TE showed significantly increased values in all patients who developed VOD/SOS, anticipating by some days the clinical criteria for VOD/SOS diagnosis. By our knowledge this is the first prospective study focused on the use of LSM for early prediction of VOD/SOS. Further validation of these data are warranted to confirm the diagnostic role and the predictive value of LSM in the VOD/SOS development. Figure 1. Figure 1. Disclosures Zinzani: Takeda: Membership on an entity's Board of Directors or advisory committees; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celltrion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; SERVIER: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astra Zeneca: Speakers Bureau; MSD: Honoraria, Speakers Bureau; TG Pharmaceuticals: 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; Bayer: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Cavo:GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Rationale: Inotuzumab ozagomicin (IO) has been linked to an increased incidence of veno-occlusive disease (VOD) and liver alterations. Most VOD events occurred during hematopoietic stem cell (HSCT) transplantation after IO therapy. We have previously described that the measurement of liver stiffness can anticipate the diagnosis of VOD in the context of HSCT. The mechanisms underlying the increased risk of VOD and liver damage in patients receiving IO are not well understood; in the pathogenesis endothelial damage, ozagomicin release and on-target off-tumor effects may be involved. Here, we aimed to assess the effects of IO on the changes of liver, vascular and biochemistry parameters. Methods: Intensive monitoring of the liver was incorporated into the standard of care of patients who received IO for relapsed or refractory (R / R) acute lymphoblastic leukemia (ALL). Upper abdomen ultrasound with Doppler was performed at baseline and at the end of therapy; liver stiffness measurement (LSM) by Fibroscan® (Echosens, Paris, France) at every IO course or at every IO infusion. With the exception of ursodeoxycholic acid, the patients did not receive prophylaxis for VOD. Data was collected after anonymous aggregation, in accordance with GCP and Helsinki declaration. Results are reported as median with interquartile ranges (IQR). Results: At data cut-off, 1st Apr 2019, 16 patient received baseline assessment and at least a post-IO assessment in our monitoring program. In our patent set, median age was 44.5 (IQR 30.7 - 64.0); 12/16 (75 %) patients relapsed after the last treatment and 4/16 (25 %) patients were refractory to the last treatment; patients received a median of 3 (IQR 2 - 3.7) lines before IO; 6/16 (37.5 %) patients undergone HSCT before IO, of which a patient had 1st and 2nd HSCT before IO; 5/16 (31.25 %) undergone HSCT after IO therapy (no patients had second HSCT after IO). Patients received a median of 2 (IQR 2.0 - 3.7) IO administration according to the schedule of the phase 3 trial. The median duration of the therapy was 61.5 days (IQR 43.2 - 114.0) and median progression-free survival in our population was 278.0 days (95% C.I. 264.0 - 292.0). In our patient set, we performed 113 biochemistry determination, 30 liver ultrasounds with Doppler and 116 LSM examination. One patient received a liver biopsy. Among the biochemical exams (AST, ALT, GGT and alkaline phosphatase) only the AST values significantly increased after 1st course of IO (from the median value of 21 U/L to 53 U/L after course 3). Liver ultrasound with Doppler revealed portal hypertension signs in half of the patients during IO monitoring program. Among these patients 7/16 (44%), 3/16 (17%), 5/16 (33.3%) and 3/16 (17%) showed splenomegaly, recanalization of the paraumbilical vein, dilatation of portal vein and ascites, respectively. Median LSM significantly increased from a baseline value of 6 kPa to 7.8 kPa after last post-IO assessment (p-value<0.01). The median increase of LSM values on the baseline after course 1 of IO was 3.3% (0%- 4.9%), after course 2 was 38.3% (26.4% - 45.2%) after course 3 was 43.3% (35.4% - 48.6%) and after course 4 was 56.7 (45.8% - 60.1%), see figure. Eight of the 16 patients (50%) showed an increase in LSM with values comparable to fibrosis higher than 2 (> 7.1 kPa). With a median follow up of 387.5 days (IQR 182.8-524.5) we observed one VOD event (7%); the VOD was graded severe and occurred after HSCT post-IO. Conclusions: Our clinical experience represents the first step to better understand the IO-related liver alterations, as we described the frequency and relevance of quantitative markers. Most of the patients in our set developed ultrasound and/or elastography alteration during IO therapy. Furthermore, these alterations do not seem to correlate with biochemistry. Even if most of the patients had sub-clinical vascular and parenchymal alterations of the liver portal-hypertension related, VOD incidence in our set is comparable with literature. Long-term follow-up results are expected to test whether alterations return or evolve over time. Stratifying the tailored risk liver complications with prospective non-invasive and marker-driven strategies in term of IO dosing and HSCT timing could be a great benefit for patients. * FR and GM contributed to this manuscript equally # AC and CP contributed to this manuscript equally Figure Disclosures Martinelli: Roche: Consultancy; BMS: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; ARIAD: Consultancy. Cavo:janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations, Speakers Bureau; bms: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; novartis: Honoraria; takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations, Speakers Bureau. Papayannidis:Amgen: Honoraria; Novartis: Honoraria; Teva: Honoraria; Pfizer: Honoraria; Incyte: Honoraria; Shire: Honoraria.

Je pense que prendre en considération le développement historique du langage peut nous aider à comprendre son fonctionnement actuel. Par conséquent je vais étudier un échantillon des premiers exemples de la traduction d’articles savants entre deux langues vernaculaires. Le premier périodique savant est le Journal des Sçavans, paru à Paris le 5 janvier 1665. Deux mois plus tard, le 6 mars 1665, les Philosophical Transactions parurent à Londres. Le Journal des Sçavans était rédigé par Denis de Sallo, à l’instigation de Colbert, dont l’objectif était le contrôle de la connaissance nouvelle et son utilisation pour célébrer la gloire de Louis XIV. La France était totalement stable et elle était le centre économique et culturel de l’Europe. Les Philosophical Transactions furent lancés comme une entreprise privée par Henry Oldenburg, un des secrétaires de la Royal Society, comme moyen d’augmenter ses revenus. L’Angleterre venait de traverser un demi-siècle parmi les plus chaotiques de son histoire, mais, à ce moment-là elle se confortait dans l’espoir retrouvé de la Restauration de la monarchie. Le Journal des Sçavans traitait toutes les disciplines de la nouvelle connaissance, y compris la théologie, le droit et l’histoire, et comportait principalement des recensements de livres. Les Philosophical Transactions se restreignaient aux sciences et à la technologie, et se basaient sur le courrier de H. Oldenburg. Son courrier était volumineux car il était au centre d’un réseau de correspondance scientifique. Le premier numéro des Philosophical Transactions comporte la traduction d’un item paru dans le premier numéro du Journal des Sçavans. Cela constitue alors la toute première traduction d’un article savant d’une langue vernaculaire vers une autre. Une étude des traits linguistiques (notamment la thématisation et les types de procès) de ces deux textes démontre que H. Oldenburg suivit de près le texte français, bien qu’il simplifiât son organisation afin de le rendre plus clair. Le Journal des Sçavans fut supprimé après 13 semaines, mais fut ressuscité au début de l’année suivante avec l’Abbé Bignon comme rédacteur. Le numéro du 11 janvier 1666 comporte la traduction d’un item paru aux Philosophical Transactions le 8 mai 1665. Le texte français le présente comme étant un résumé, mais il s’agit plutôt de la traduction d’extraits choisis que d’un résumé proprement dit. L’étude des traits linguistiques fait ressortir les différences entre les deux textes. Etudier ces textes s’avère fascinant en soi. Mis à part leur intérêt propre, il faut souligner le fait qu’ils étaient les premières tentatives de traduire des articles savants. Par conséquent, on peut considérer que l’évolution de la traduction de l’article savant commence ici.

Background:Behçet’s syndrome, a chronic, multi-system variable vessel vasculitis, is often characterized by painful oral ulcers (OU) affecting quality of life (QoL). Apremilast (APR), an oral PDE4 inhibitor, demonstrated efficacy in OU treatment in the phase 3 multinational RELIEF study.Objectives:To evaluate APR efficacy in OU treatment in patients with active Behçet’s syndrome in a prespecified subgroup of patients enrolled in 13 European RELIEF sites (France, Germany, Greece, and Italy).Methods:patients were adults with active Behçet’s syndrome and ≥3 OU at randomization or ≥2 OU at screening and randomization, without active major organ involvement. Patients were randomized (1:1) to APR 30 mg BID or PBO during a 12-week double-blind phase. The primary endpoint was area under the curve for the number of OU through Week 12 (AUCWk0-12). Other outcomes were OU pain visual analog scale (VAS); achievement of OU complete response (ie, OU-free) and maintenance of OU complete response (ie, complete response at Week 6 and remaining OU-free for ≥6 additional weeks); OU partial response (ie, OU reduction ≥50%); disease activity (Behçet’s Syndrome Activity Score [BSAS]; Behçet’s Disease Current Activity Form [BDCAF], including Behçet’s Disease Current Activity Index [BDCAI], and Patient’s and Clinician’s Perception of Disease Activity); and QoL (BDQoL; Short Form Health Survey version 2 [SF-36v2], including Physical Functioning [PF] scale and Physical and Mental Component Summary [PCS, MCS]).Results:Of 207 patients randomized and treated in RELIEF, 52 were in the European subgroup. Mean (±SD) age in the subgroup was 39 (±12) years; 54% were women. Baseline disease characteristics were similar between treatment groups (Table 1). Patients receiving APR achieved lower AUCWk0-12 for OU vs PBO (Figure 1) and greater reduction in pain. A greater proportion of patients receiving APR achieved complete, maintained, or partial OU responses at Week 12 vs those receiving PBO (Table 1). Consistent treatment effects favoring APR vs PBO were observed in disease activity, as shown by BSAS and BDCAF component scores at Week 12 (Table 1). Greater improvement in SF-36v2 MCS was observed favoring APR vs PBO at Week 12, and moderate treatment differences were seen for other QoL measures (BDQoL, SF-36v2 PF, and SF-36v2 PCS).Conclusion:In the European subgroup of patients with Behçet’s syndrome and OU in RELIEF, APR resulted in greater reduction in OU count, OU pain, and disease activity as well as favorable treatment effect on QoL measures than PBO. These results are consistent with the efficacy of APR treatment in the overall RELIEF population.Baseline Disease Characteristics, Mean*PBO (n = 27)APR (n = 25)Duration of BD, years9.08.2OU count3.84.0OU pain (VAS 0-100)60.664.2BSAS (0-100)38.741.4BDCAI (0-12)3.53.6BDQoL (0-30)10.59.0Efficacy Outcomes at 12 Weeks*PBO (n = 27)APR (n = 25)Treatment Difference [95% CI]OU pain (VAS 0-100), mean†–17.7–48.7–31.0 [–44.7, –17.3]OU complete response, n (%)‡4 (14.8)16 (64.0)51.5 [29.8, 73.3]OU maintained response, n (%)‡1 (3.7)8 (32.0)26.7 [7.4, 46.0]OU partial response, n (%)‡11 (40.7)21 (84.0)46.0 [23.9, 68.0]BSAS (0-100)†,§–5.23–20.68–15.5 [–22.6, –8.3]BDCAI (0-12)†,§–0.0–1.4–1.4 [–2.2, –0.6]Patient’s Perception of Disease Activity†,§–0.4–1.6–1.2 [–2.1, –0.4]Clinician’s Overall Perception of Disease Activity†,§−0.6−1.7–1.0 [–1.7, –0.4]BDQoL (0-30)†,§–1.25–2.37–1.12 [–3.8, 1.5]SF-36v2 MCS (0-100)†,§–2.14.26.3 [2.2, 10.4]*ITT population.†LS mean of the change from baseline at Week 12.‡Non-responder imputation for missing data.§LOCF approach. All efficacy endpoints (except BDQoL) were significant at the level of P<0.05.Acknowledgements :This study was funded by Celgene. Additional analyses were funded by Amgen Inc. Writing support was funded by Amgen Inc. and provided by Kristin Carlin, RPh, MBA, of Peloton Advantage, LLC, an OPEN Health company.Disclosure of Interests:Alfred Mahr Speakers bureau: Chugai; Roche, Consultant of: Celgene; Chugai, Gulen Hatemi Speakers bureau: AbbVie, Novartis, and UCB, Grant/research support from: Celgene, Mitsuhiro Takeno Speakers bureau: AbbVie, Esai, and Mitsubishi-Tanabe, Consultant of: Celgene, Grant/research support from: Novartis, Doyoung Kim: None declared, Melike Melikoglu: None declared, david Saadoun Consultant of: AbbVie, Celgene, Janssen, and Roche, Grant/research support from: AbbVie and Roche, Christos C. Zouboulis Speakers bureau: Amgen, Galderma, Pierre Fabre, PPM and Sobi, Consultant of: AbbVie, AccureAcne, Almirall, Bayer Healthcare, GSK/Stiefel, Incyte, Inflarx, Janssen, Novartis, PPM, Regeneron, and UCB, Grant/research support from: Celgene, NAOS-BIODERMA, and Relaxera, Sue Cheng Employee of: Amgen Inc, Sven Richter Employee of: Amgen Inc, Shauna Jardon Employee of: Amgen Inc, Maria Paris Employee of: Amgen Inc, Mindy Chen Employee of: Amgen Inc, Yusuf Yazici Consultant of: Bristol-Myers Squibb, Celgene, Genentech, and Sanofi

Abstract Abstract 592 Background: PTLD represent a rare but aggressive graft complication. Patients who have received a solid organ transplantation have a 20 to 120 fold higher incidence of non-Hodgkin's lymphoma. EBV reactivation represents a major predictive factor for PTLD, especially during the first year after transplantation, but there is no consensual attitude in this situation Aim: We conducted a monocentric prospective study in the Hospital of Pitie Salpêtriere, Paris, France, on all new heart transplanted patients. EBV viral load (EVL) on whole blood samples was systematically followed and confirmed reactivations were treated depending on viral load. Methods: All heart transplanted patients who had at least one EVL between January 2004 and December 2008 were included. Immunosuppression consisted on anti-lymphocyte sera, ciclosporin, mycophenolate-mofetyl (MM) and prednisone. Twelve to 15 blood samples per year were analysed. If the EVL was more than 105 copies/ml, a CT scan or a PET-san was performed in order to detect any PTLD and patients were treated by diminution of the immunosupression (DIS), mainly by MM arrest. One injection of Rituximab (R) (375 mg/m2) was used in case of failure and/or if EVL was over 106 copies/ml. Results: A total of 251 patients were included, 59 femals/192 men, of a median age of 50 years [16-72]. All but 6 were EBV positive before the graft. Reactivations were detected in 29 cases (11,55%) and treated by DIS only in 20 cases, DIS followed by R in 5 and directly by DIS and R in 4. All EBV negative patients developed a primoinfection in the first year, 2 with an EVL over 105, one presented non documented hepatic lesions which disappeared after DIS. All EBV reactivations were controlled, with a relapse in only one case (reactivations treated the first time by DIS, 10 months later by DIS and R and 6 months later by DIS). With a median follow-up of 1118 days [53-2100] only one PTLD has been diagnosed (in a patient lost to follow up and taken in charge in an other unit) and 24 patients died (9,5%). Analyse of DIS +/− R on graft rejection and potential link between CMV reactivation and EBV reactivation will be presented at the ASH. From 1987 to December 2003, 24 (1,8/year) PTLD have been treated in the same unit (18 EBV positive, 5 negative, 1 unknown), of which 13 were early PTLD (all EBV positive) diagnosed within one year post transplantation. Conclusions: EBV reactivation after organ transplantation can be managed by diminution of immunosupression and/or rituximab, depending on viral load, without serious complication. This adapted management seems to decrease dramatically the incidence of EBV positive PTLD. Disclosures: Choquet: ROCHE: Consultancy. Leblond:ROCHE: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MUNDIPHARMA: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CELGENE: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Abstract BACKGROUND: Ivosidenib (AG-120) and enasidenib (AG-221) are oral inhibitors of mutant IDH1 (mIDH1) and mutant IDH2 (mIDH2), respectively, approved for the treatment of relapsed/refractory IDH-mutant acute myeloid leukemia (AML). Here we report updated results from a phase 1 study on the safety and efficacy of each of these agents when combined with intensive chemotherapy in patients with newly diagnosed AML, as well as data regarding the rate of measurable residual disease (MRD)-negative complete remissions (CRs), mutation clearance and molecular profiling. METHODS: In this open-label, multicenter, phase 1 study (NCT02632708), eligible patients with newly diagnosed mIDH1 or mIDH2 AML are treated with induction therapy (daunorubicin 60 mg/m2/day or idarubicin 12 mg/m2/day x 3 days with cytarabine 200 mg/m2/day x 7 days) in combination with either ivosidenib 500 mg once daily (for mIDH1) or enasidenib 100 mg once daily (for mIDH2). After induction, patients may receive ≤4 cycles of consolidation therapy while continuing the mIDH inhibitor. Patients who complete or are ineligible for consolidation may continue on maintenance ivosidenib or enasidenib until the end of study. For patients who proceed to allogeneic hematopoietic stem cell transplant (HSCT), mIDH inhibitor treatment is discontinued prior to transplant and is not resumed post-transplant. mIDH1/2 variant allele frequency (VAF) is assessed in bone marrow mononuclear cells using Digital PCR Technology (Sysmex-Inostics Inc). IDH1/2 mutation clearance (IDH-MC) is defined as a reduction in the mIDH1/2 VAF to a level below the limit of detection of this assay (0.02-0.04%) for ≥1 on-treatment time point on or after Day 28 of induction. MRD in bone marrow aspirates is analyzed using multi-parameter flow cytometry. Baseline co-occurring mutations are identified with a 95-gene next generation sequencing panel targeted to hematologic malignancies. RESULTS: As of May 1, 2018, 134 patients had been treated: 47 with ivosidenib (median age 63 years, range 24-76) and 87 with enasidenib (median age 63 years, range 27-77; Table 1). Secondary AML (sAML; arising after myelodysplastic syndrome or another antecedent hematologic disorder, or after exposure to genotoxic injury) was present in 33/87 (38%) patients with mIDH2 and in 16/47 (34%) patients with mIDH1. The most frequent co-occurring baseline mutations were DNMT3A, NPM1 and NRAS for patients with IDH1 mutations; and DNMT3A, SRSF2 and ASXL1 for patients with IDH2 mutations. Ivosidenib or enasidenib combined with induction and consolidation was well tolerated, based on the frequency of grade ≥3 non-hematologic adverse events (Table 2) and hematologic recovery (Table 3). Times for ANC and platelet count recovery were nominally longer in patients with sAML. Among the 41 ivosidenib-treated patients evaluable for efficacy, a response of CR, CRi or CRp was achieved in 26/28 (93%) patients with de novo AML and 6/13 (46%) patients with sAML (Table 4). Twenty-one patients received ≥1 cycle of consolidation therapy and 11 patients received maintenance after consolidation. Seventeen patients proceeded to HSCT. Among the 77 enasidenib-treated patients evaluable for efficacy, a response of CR, CRi, or CRp was achieved in 33/45 (73%) patients with de novo AML and in 20/32 (63%) patients with sAML (Table 4). Thirty-seven patients received ≥1 cycle of consolidation therapy, 6 patients received maintenance directly after induction and 11 patients received maintenance after consolidation. Thirty-three patients proceeded to HSCT. Longitudinal VAF data are available for 31 ivosidenib-treated patients and 60 enasidenib-treated patients. In patients who achieved a CR, IDH-MC was observed in 41% (9/22) of those with mIDH1 (Table 5) and in 30% (11/37) of those with mIDH2 (Table 6). Flow cytometry assessments are available for 21 patients achieving a CR: MRD-negative CRs were observed in 89% (8/9) of those with mIDH1 and in 58% (7/12) of those with mIDH2. CONCLUSION: Ivosidenib or enasidenib in combination with induction and consolidation therapy has an acceptable safety profile with robust remission rates, MRD-negative CRs, and mutation clearance in a population of older, high-risk patients with mIDH AML. The clinical benefit of adding ivosidenib or enasidenib to induction, consolidation and maintenance therapy for patients with newly diagnosed mIDH AML will be further evaluated in a randomized phase 3 trial. Disclosures Stein: Celgene: Consultancy; Agios: Consultancy; Daiichi Sankyo: Consultancy; Bayer: Consultancy; Pfizer: Consultancy; Novartis: Consultancy. DiNardo:Karyopharm: Other: Advisory role; Medimmune: Other: Advisory role; Celgene: Other: Advisory role; Bayer: Other: Advisory role; Agios: Consultancy, Other: Advisory role; AbbVie: Consultancy, Other: Advisory role. Fathi:Jazz: Honoraria; Takeda: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Agios: Honoraria, Research Funding; Boston Biomedical: Consultancy, Honoraria; Astellas: Honoraria. Mims:Abbvie Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy. Pratz:Boston Scientific: Consultancy; AbbVie: Consultancy, Research Funding; Millenium/Takeda: Research Funding; Agios: Research Funding; Astellas: Consultancy, Research Funding. Savona:Boehringer Ingelheim: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding. Stein:Celgene: Speakers Bureau; Amgen: Speakers Bureau. Stone:AbbVie: Consultancy; Merck: Consultancy; Argenx: Other: Data and Safety Monitoring Board; Agios: Consultancy, Research Funding; Sumitomo: Consultancy; Pfizer: Consultancy; Amgen: Consultancy; Cornerstone: Consultancy; Astellas: Consultancy; Celgene: Consultancy, Other: Data and Safety Monitoring Board, Steering Committee; Otsuka: Consultancy; Jazz: Consultancy; Fujifilm: Consultancy; Arog: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Ono: Consultancy; Orsenix: Consultancy. Döhner:Astellas: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; AROG Pharmaceuticals: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Jazz: Consultancy, Honoraria; AROG Pharmaceuticals: Research Funding; AbbVie: Consultancy, Honoraria; Agios: Consultancy, Honoraria; Astex Pharmaceuticals: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celator: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Astex Pharmaceuticals: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria; Bristol Myers Squibb: Research Funding; Bristol Myers Squibb: Research Funding; Janssen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria, Research Funding; Jazz: Consultancy, Honoraria; Pfizer: Research Funding; Celator: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Pfizer: Research Funding. Pollyea:Celgene: Membership on an entity's Board of Directors or advisory committees; Argenx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celyad: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Curis: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees. McCloskey:Amgen Pharmaceuticals: Speakers Bureau; Celgene Pharmaceuticals: Honoraria, Speakers Bureau; Pfizer: Consultancy; Takeda Pharmaceuticals: Consultancy, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Speakers Bureau; COTA: Equity Ownership. Odenike:ABBVIE: Honoraria, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; CTI/Baxalta: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Dava Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncotherapy Science: Research Funding; Agios: Research Funding; Celgene: Research Funding; NS Pharma: Research Funding; Janssen: Research Funding; Astex: Research Funding; Gilead Sciences: Research Funding. Lowenberg:Clear Creek Bio Ltd: Consultancy, Honoraria; Chairman Scientific Committee and Member Executive Committee, European School of Hematology (ESH, Paris, France): Membership on an entity's Board of Directors or advisory committees; Editorial Board "International Journal of Hematology": Membership on an entity's Board of Directors or advisory committees; Editorial Board "The Netherlands Journal of Medicine": Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Astex: Consultancy; "Up-to-Date", section editor leukemia: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Editorial Board "European Oncology & Haematology": Membership on an entity's Board of Directors or advisory committees; Elected member, Royal Academy of Sciences and Arts, The Netherlands: Membership on an entity's Board of Directors or advisory committees; Supervisory Board, National Comprehensive Cancer Center (IKNL), Netherlands: Membership on an entity's Board of Directors or advisory committees; Chairman, Leukemia Cooperative Trial Group HOVON (Netherlands): Membership on an entity's Board of Directors or advisory committees; international Scientific Advisory Board, Institute Gustave Roussy, Paris: Membership on an entity's Board of Directors or advisory committees; Royal Academy of Sciences and Arts, The Netherlands: Membership on an entity's Board of Directors or advisory committees. Ossenkoppele:Roche: Consultancy, Honoraria; Karyopharm: Consultancy, Research Funding; Genmab: Research Funding; Pfizer: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Johnson & Johnson: Consultancy, Honoraria, Research Funding. Patel:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Dava Oncology: Honoraria; France Foundation: Honoraria. Lersch:Celgene: Employment. Nabhan:Agios: Employment. Choe:Agios: Employment, Equity Ownership. Wang:Agios: Employment, Equity Ownership. Hua:Agios: Employment, Equity Ownership. Almon:Agios: Employment, Equity Ownership. Cooper:Agios: Employment, Equity Ownership. Tallman:Cellerant: Research Funding; BioSight: Other: Advisory board; Daiichi-Sankyo: Other: Advisory board; ADC Therapeutics: Research Funding; Orsenix: Other: Advisory board; AbbVie: Research Funding; AROG: Research Funding.

Approximately 40% of patients (pts) with newly diagnosed (AML) either fail to achieve complete remission with intensive induction therapy or experience disease recurrence after a short remission duration (< 6 months). These pts, herein considered to have primary refractory disease, are an extremely challenging population to treat, with only 14% achieving remission following conventional chemotherapy and with subsequent salvage attempts being nearly universally ineffective (1). Increased immune infiltration of the tumor microenvironment (TME) and high CD123 expression on AML blasts have been associated with primary induction failure and poor prognosis (2, 3). Flotetuzumab (FLZ), a CD123 x CD3 bispecific DART molecule, is currently being tested in a phase 1/2 study in pts with either relapsed or refractory (R/R) AML. We have previously reported FLZ activity in primary refractory AML (4); herein, we provide additional scientific rationale supporting the investigation of FLZ in this patient population. The recommended Phase 2 dose (RP2D) of FLZ identified in an ongoing Phase 1/2 study is 500 ng/kg/day administered as a 7 -day/week continuous infusion. Pts receive a lead-in dose during week (W) 1, followed by 500 ng/kg/day during W2-4 of Cycle 1, and a 4-day on/3-day off schedule for Cycle 2 and beyond. Disease status was assessed by modified IWG criteria; bone marrow (BM) samples were collected to investigate biomarkers, including CD123 receptor density (RD), and gene expression profiling using the NanoString PanCancer IO 360™ panel, which measures the expression of 770 genes, including 14 immune cell types and 32 immuno-oncology biological signatures. Gene expression comparisons are presented at fold change (FC) and a t-test was used for statistical analysis. Fifty pts with R/R AML received FLZ at the RP2D. Thirty (60%) pts had primary refractory AML: 24 failed ≥2 induction attempts and 6 recurred after remission of <6 months (median duration of remission 32 [range: 29-45] days). This population was heavily pretreated (median 4 previous lines of therapy [range 2-9]), with 40% (12/30) having secondary AML and most having non-favorable cytogenetic risk (60% adverse and 23% intermediate by ELN 2017 risk category). Compared to relapsed pts, those with primary refractory disease had greater CD123 expression on AML blasts (11277±3246 vs 6254±1779 sites/cell), with baseline BM samples showing higher inflammatory chemokine signature scores (1.7x increase, p=0.018), and an enhanced interferon gamma (IFNγ) signaling gene expression score (1.85x increase, p=0.014), a signature associated with resistance to cytotoxic chemotherapy (2). Among 28 primary refractory pts evaluable for disease assessment, FLZ complete remission (CR) rate was 32.1% (3 CR, 3 CRh, 3 CRi). Four pts (1 CR, 1CRh, and 2 CRi) subsequently underwent allogeneic hematopoietic stem cell transplantation. For comparison, the expected CR rate to conventional salvage therapy in this population was calculated as <10%, estimated based on historical response rates of pts subjected to similar numbers and types of salvage therapies (1, 5). Pts with CR showed higher CD123 RD compared to pts with no response (15186.5 vs 10836.8 sites/cell). FLZ anti-leukemic activity (>30% decrease in BM blasts) was associated with increased baseline immune gene signatures, including significantly higher IFNγ scores (1.8 FC, p=0.0212; AUROC=0.74), and an increased tumor inflammation signature (TIS) score (1.658 FC, p=0.00827, AUROC=0.847 compared to non-responders. FLZ was well tolerated, with no increased cytokine release syndrome events in primary refractory pts (30% G1, 67% G2, 3% G3) compared to relapse pts (26% G1, 58% G2, 16% G3), notwithstanding the increased CD123 RD in the former. In conclusion, we show that FLZ elicits clinical response in heavily treated patients with poor response rates to primary therapy. We also show that increased IFNγ signaling gene expression scores in baseline BM appears to associate with response to FLZ therapy. Enrollment has been expanded to further define FLZ's activity specifically in pts with primary refractory AML, and candidate biomarkers to enable identification of pts more likely to respond to FLZ. Estey E, et al. Blood (1996), 88 (2) 756Vadakekolathu J, et al. Blood (2017) 130:3942Vergez F, et al. Haematologica (2011), 96(12):1792-8Uy GL, et al. Blood (2018) 132:764Duong V, et al. Leukemia (2013),13(6):711-5 Disclosures Uy: Astellas: Consultancy; Pfizer: Consultancy; Curis: Consultancy; GlycoMimetics: Consultancy. Aldoss:Agios: Consultancy, Honoraria; AUTO1: Consultancy; Jazz Pharmaceuticals: Honoraria, Other: travel/accommodation/expenses, Speakers Bureau; Helocyte: Consultancy, Honoraria, Other: travel/accommodation/expenses. Foster:Bellicum Pharmaceuticals, Inc: Research Funding; Daiichi Sankyo: Consultancy; MacroGenics: Research Funding; Celgene: Research Funding. Sallman:Celgene: Research Funding, Speakers Bureau; Celyad: Membership on an entity's Board of Directors or advisory committees; Incyte: Speakers Bureau; Jazz: Research Funding; Novartis: Speakers Bureau; Abbvie: Speakers Bureau. Sweet:Abbvie: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Celgene: Speakers Bureau; Stemline: Consultancy; Pfizer: Consultancy; Jazz: Speakers Bureau; Incyte: Research Funding. Rizzieri:AbbVie, Agios, AROG, Bayer, Celgene, Gilead, Jazz, Novartis, Pfizer, Sanofi, Seattle Genetics, Stemline, Teva: Other: Advisory Board; AROG, Bayer, Celgene, Celltron, Mustang, Pfizer, Seattle Genetics, Stemline: Consultancy; Celgene, Gilead, Seattle Genetics, Stemline: Other: Speaker; Stemline: Research Funding. Advani:Amgen: Research Funding; Macrogenics: Research Funding; Abbvie: Research Funding; Pfizer: Honoraria, Research Funding; Glycomimetics: Consultancy, Research Funding; Kite Pharmaceuticals: Consultancy. Emadi:Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; NewLink Genetics: Research Funding; Genentech: Consultancy, Honoraria; KinaRx: Membership on an entity's Board of Directors or advisory committees, Other: Co-Founder and Scientific Advisor, Patents & Royalties; Jazz Pharmaceuticals: Research Funding. Wieduwilt:Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen, Leadiant, Merck, Servier: Research Funding; Reata Pharmaceuticals: Equity Ownership. Vey:Novartis: Consultancy, Honoraria; Janssen: Honoraria. Church:NanoString Technologies, Inc.: Employment, Equity Ownership. Rettig:WashU: Patents & Royalties: Patent Application 16/401,950. Arellano:Gilead: Consultancy. Löwenberg:Up-to-Date", section editor leukemia: Membership on an entity's Board of Directors or advisory committees; Frame Pharmaceuticals: Equity Ownership; Elected member, Royal Academy of Sciences and Arts, The Netherlands: Membership on an entity's Board of Directors or advisory committees; Editorial Board "European Oncology & Haematology": Membership on an entity's Board of Directors or advisory committees; Clear Creek Bio Ltd: Consultancy, Honoraria; Abbvie: Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Astex: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; CELYAD: Membership on an entity's Board of Directors or advisory committees; Chairman Scientific Committee and Member Executive Committee, European School of Hematology (ESH, Paris, France): Membership on an entity's Board of Directors or advisory committees; Chairman, Leukemia Cooperative Trial Group HOVON (Netherlands: Membership on an entity's Board of Directors or advisory committees; Supervisory Board, National Comprehensive Cancer Center (IKNL), Netherland: Membership on an entity's Board of Directors or advisory committees; Hoffman-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees; Royal Academy of Sciences and Arts, The Netherlands: Membership on an entity's Board of Directors or advisory committees. Ravandi:Selvita: Research Funding; Xencor: Consultancy, Research Funding; Menarini Ricerche: Research Funding; Macrogenix: Consultancy, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cyclacel LTD: Research Funding. Muth:MacroGenics, Inc.: Employment, Equity Ownership. Tran:MacroGenics: Employment. Timmeny:MacroGenics, Inc.: Employment, Other: Stock Ownership. Topp:Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Regeneron Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Guo:Macrogenics: Employment. Zhao:MacroGenics, Inc.: Employment. Wigginton:MacroGenics, Inc.: Employment, Equity Ownership; Western Oncolytics: Other: clinical advisory board. Bonvini:MacroGenics, Inc.: Employment, Equity Ownership. Rutella:NanoString Technologies, Inc.: Research Funding; MacroGenics, Inc.: Research Funding. Walter:Seattle Genetics: Research Funding; Race Oncology: Consultancy; Pfizer: Consultancy, Research Funding; New Link Genetics: Consultancy; Kite Pharma: Consultancy; Agios: Consultancy; Amgen: Consultancy; Amphivena Therapeutics: Consultancy, Equity Ownership; Aptevo Therapeutics: Consultancy, Research Funding; Argenx BVBA: Consultancy; Astellas: Consultancy; BioLineRx: Consultancy; BiVictriX: Consultancy; Boehringer Ingelheim: Consultancy; Boston Biomedical: Consultancy; Covagen: Consultancy; Daiichi Sankyo: Consultancy; Jazz Pharmaceuticals: Consultancy. Davidson-Moncada:MacroGenics, Inc.: Employment, Equity Ownership. DiPersio:Amphivena Therapeutics: Consultancy, Research Funding; RiverVest Venture Partners Arch Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cellworks Group, Inc.: Membership on an entity's Board of Directors or advisory committees; NeoImmune Tech: Research Funding; Macrogenics: Research Funding, Speakers Bureau; Magenta Therapeutics: Equity Ownership; WUGEN: Equity Ownership, Patents & Royalties, Research Funding; Celgene: Consultancy; Incyte: Consultancy, Research Funding; Bioline Rx: Research Funding, Speakers Bureau; Karyopharm Therapeutics: Consultancy.

Background: Cytokine release syndrome (CRS) management in acute myeloid leukemia (AML) patients treated with flotetuzumab, an investigational CD123xCD3 bispecific DART® molecule for T cell redirected therapy. CRS is a hallmark of T cell activating therapy and can be correlated with efficacy, specifically, with CAR-T cells(1). Identification of patients at risk for high grade CRS will help guide CRS management. Flotetuzumab (MGD006) is anovel CD123xCD3 bispecific DART® molecule in Phase 1/2 testing in patients with relapsed/ refractory AML. Several strategies have been successfully employed to mitigate CRS severity, some have been previously reported (2, 3). Here we report on further refinement of CRS management and subsequent investigation of potentiel predictive biomarkers of severity. Methods: The recommended phase 2 dose (RP2D) of flotetuzumab is 500ng/kg/d CIV. Week 1 comprises a step-wise lead-in dose (LID) (1-step: 100 ng/kg/day days 1-4; 2-step: 30ng/kg/d for 3days, 100ng/kg/d for 4days, or multi-step (MS) LID at 30, 60, 100, 200, 300, 400 and 500 ng/kg/day each for 24 hours) in order to improve flotetuzumab tolerability. Tocilizumab usage recommended early in CRS management. The relationships between immune cells (T-cell subsets, monocytes) and tumor burden (percent CD123+ AML blasts, CD123 expression) were further interrogated as potential determinants of CRS. Results: 50 patients have been treated at the RP2D. While almost all patients experienced IRR/CRS events, the majority of these patients experienced IRR/CRS that were mild-moderate in severity (28% Grade(G)1, 62% G2, and 8% G3), of short duration (median 1 day for G1, 2 days G2, 2.5 days G3), and resolved completely with no clinical sequalae reported. Most CRS events occured in the first week of treatment (38.3%) and gradually decreased with continuous dosing (24.8%, 7.4%, and 4.3% during weeks 2-4, respectively). Several key interventions have helped mitigate CRS severity. Sequential increment in steps of LID schedules (1 step, 2-step or multi-step LID) have successfully decreased CRS severity and incidence. For example, CRS mean grade±SEM for week 1 was 2.0±0.26 vs 1.4±0.72 vs 1.5±0.63 and for week 4, 0.67±0.42 vs 0.2 ±0.50 vs 0.1 ±0.50 (1 step, 2-step or multi-step LID, respectively). Moreover, LID improved overall tolerability. Introduction of early use of tocilizumab has helped forestall CRS development; 27 patients received tocilizumab (10 doses for G1, 27 for G2, and 2 for G3 events), only 5 pts have required steroids (4 for G2 and 1 for G3), and no pts have required vasopressor support. Blunting of CRS events did not impact antileukemic activity. CRS severity showed a relationship with baseline frequency of circulating CD4+ cells (mean 0.2 K/µL in patients with no CRS vs. 1.0 K/µL in G1 vs 1.6 K/µL in G ≥2, p < 0.000.1), and peak CRS grade in week 1. Conclusion: Like other T-cell activating therapies, flotetuzumab is associated with CRS. Several mitigating factors have helped to blunt the severity of CRS, including lead-in dosing and early tocilizumab usage. Circulating CD4+ cells at baseline continues to be associated with CRS risk, and may be a helpful marker to identify patients at increased risk for CRS. 1. Maude, SL. et al. Managing Cytokine Release Syndrome Associated With Novel T Cell-Engaging Therapies. Cancer J. 2014; 20(2): 119-122. 2. Jacobs, K, et al.Lead-in Dose Optimization to Mitigate Cytokine Release Syndrome in AML and MDS Patients Treated with Flotetuzumab, a CD123 x CD3 Dart® Molecule for T-Cell Redirected Therapy. Blood 2017 130:3856. 3. Jacobs, K, et al.Management of Cytokine Release Syndrome in AML Patients Treated with Flotetuzumab, a CD123 x CD3 Bispecific Dart® Molecule for T-Cell Redirected Therapy. Blood 2018 132:2738. Disclosures Bakkacha: Macrogenics,Inc: Employment, Equity Ownership. Uy:Astellas: Consultancy; Pfizer: Consultancy; Curis: Consultancy; GlycoMimetics: Consultancy. Aldoss:Helocyte: Consultancy, Honoraria, Other: travel/accommodation/expenses; AUTO1: Consultancy; Jazz Pharmaceuticals: Honoraria, Other: travel/accommodation/expenses, Speakers Bureau; Agios: Consultancy, Honoraria. Foster:Bellicum Pharmaceuticals, Inc: Research Funding; Daiichi Sankyo: Consultancy; MacroGenics: Research Funding; Celgene: Research Funding. Sallman:Celyad: Membership on an entity's Board of Directors or advisory committees. Sweet:Pfizer: Consultancy; Incyte: Research Funding; Agios: 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; Celgene: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Stemline: Consultancy; Jazz: Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees. Rizzieri:Celgene, Gilead, Seattle Genetics, Stemline: Other: Speaker; AbbVie, Agios, AROG, Bayer, Celgene, Gilead, Jazz, Novartis, Pfizer, Sanofi, Seattle Genetics, Stemline, Teva: Other: Advisory Board; AROG, Bayer, Celgene, Celltron, Mustang, Pfizer, Seattle Genetics, Stemline: Consultancy; Stemline: Research Funding. Advani:Glycomimetics: Consultancy, Research Funding; Kite Pharmaceuticals: Consultancy; Amgen: Research Funding; Pfizer: Honoraria, Research Funding; Macrogenics: Research Funding; Abbvie: Research Funding. Emadi:Genentech: Consultancy, Honoraria; KinaRx: Membership on an entity's Board of Directors or advisory committees, Other: Co-Founder and Scientific Advisor, Patents & Royalties; NewLink Genetics: Research Funding; Jazz Pharmaceuticals: Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Wieduwilt:Reata Pharmaceuticals: Equity Ownership; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen, Leadiant, Merck, Servier: Research Funding. Vey:Novartis: Consultancy, Honoraria; Janssen: Honoraria. Arellano:Gilead: Consultancy. Löwenberg:Up-to-Date", section editor leukemia: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Astex: Membership on an entity's Board of Directors or advisory committees; Chairman, Leukemia Cooperative Trial Group HOVON (Netherlands: Membership on an entity's Board of Directors or advisory committees; Clear Creek Bio Ltd: Consultancy, Honoraria; Editorial Board "European Oncology & Haematology": Membership on an entity's Board of Directors or advisory committees; Elected member, Royal Academy of Sciences and Arts, The Netherlands: Membership on an entity's Board of Directors or advisory committees; Frame Pharmaceuticals: Equity Ownership; Hoffman-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees; Royal Academy of Sciences and Arts, The Netherlands: Membership on an entity's Board of Directors or advisory committees; Supervisory Board, National Comprehensive Cancer Center (IKNL), Netherland: Membership on an entity's Board of Directors or advisory committees; Chairman Scientific Committee and Member Executive Committee, European School of Hematology (ESH, Paris, France): Membership on an entity's Board of Directors or advisory committees; CELYAD: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Ravandi:Cyclacel LTD: Research Funding; Menarini Ricerche: Research Funding; Selvita: Research Funding; Xencor: Consultancy, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Macrogenix: Consultancy, Research Funding. Tran:MacroGenics: Employment. Muth:MacroGenics, Inc.: Employment, Equity Ownership. Baughman:MacroGenics, Inc.: Employment, Equity Ownership. Timmeny:MacroGenics, Inc.: Employment, Other: Stock Ownership. Topp:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Regeneron Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Guo:Macrogenics: Employment. Zhao:MacroGenics, Inc.: Employment. Wigginton:macrogenics: Employment, Equity Ownership; western oncolytics: Consultancy, Other: consultancy. Bonvini:MacroGenics, Inc.: Employment, Equity Ownership. Walter:Daiichi Sankyo: Consultancy; Amgen: Consultancy; Agios: Consultancy; Boston Biomedical: Consultancy; Covagen: Consultancy; Amphivena Therapeutics: Consultancy, Equity Ownership; Aptevo Therapeutics: Consultancy, Research Funding; Argenx BVBA: Consultancy; Astellas: Consultancy; BioLineRx: Consultancy; BiVictriX: Consultancy; Boehringer Ingelheim: Consultancy; Pfizer: Consultancy, Research Funding; Race Oncology: Consultancy; Seattle Genetics: Research Funding; Jazz Pharmaceuticals: Consultancy; Kite Pharma: Consultancy; New Link Genetics: Consultancy. Davidson:Macrogenics,Inc: Employment, Equity Ownership. DiPersio:Incyte: Consultancy, Research Funding; Celgene: Consultancy; Karyopharm Therapeutics: Consultancy; Bioline Rx: Research Funding, Speakers Bureau; RiverVest Venture Partners Arch Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cellworks Group, Inc.: Membership on an entity's Board of Directors or advisory committees; Magenta Therapeutics: Equity Ownership; WUGEN: Equity Ownership, Patents & Royalties, Research Funding; Amphivena Therapeutics: Consultancy, Research Funding; NeoImmune Tech: Research Funding; Macrogenics: Research Funding, Speakers Bureau. Jacobs:Macrogenics,Inc: Employment, Equity Ownership.

Background Peripheral T-cell lymphoma (PTCL) is a heterogeneous and accounts for approximately 10% of all lymphomas. Outcome of relapse/refractory (R/R) PTCL is poor with median progression-free survival (PFS) and overall survival (OS) of 3 and 6 months in the absence of stem-cell transplantation (SCT). [Mak, JCO, 2013]. Brentuximab vedotin (BV) monotherapy is approved for R/R systemic anaplastic large cell-lymphoma (ALCL) based on 86% overall response rate (ORR) and 57% complete remission (CR). [Pro, JCO, 2012]. In other CD30-positive (CD30+) R/R PTCL, the ORR of BV is 41%. Gemcitabine (G) used as monotherapy in control arm in the randomized phase 3 LUMIERE trial, provided ORR and CR rates of 35 and 22% respectively. [O'Connor, JCO, 2019]. Considering these results we designed a phase 2 study for R/R CD30+ PTCL combining G and BV with the primary end point to increase the ORR by 15%, compared to G monotherapy. Patients (pts) and Methods: Pts with histologically confirmed CD30+ (≥5%) PTCL who failed or were refractory to 1-3 prior lines of systemic therapy, with measurable disease and ECOG performance status < 3 were eligible. Pts received an induction of 4 cycles of G-BV (28-days cycles; G: 1000 mg/m² at D1 and D15 plus BV: 1.8 mg/kg at D8). Pts with CR or partial remission (PR) and non-eligible for SCT, received BV maintenance 1.8 mg/kg at D1 (21-days cycles) up to 12 cycles. The primary endpoint was the ORR (CR + PR) according to Lugano criteria based on CT-scan. Secondary objectives included tolerance and safety, DOR, PFS, OS and impact of BV maintenance. Eligible pts were censored at time of SCT. (NCT03496779). Results: From April 2018 to October 2019, 71 pts were included. Pathology central review according to WHO 2017 criteria, so far available for 50 patients, confirmed angioimmunoblastic T-cell lymphoma (AITL) (22 ; 31%); nodal PTCL-TFH (5 ; 7%); PTCL-NOS (5 ; 7%); ALK- ALCL (10 ; 14.1%) ; ALK+ ALCL (4 ; 5.6%), Enteropathy associated T-cell lymphoma (EATL) (2 ; 2.8%); unclassified PTCL (2 ; 2.8%). There were 47 male and 24 female with a median age of 66 years (20-79) and 17 pts were > 75 years. Median time from diagnosis to enrolment was 9.4 months (range, 6-21). Sixty-five pts (91.6%) presented with stage III-IV. The number of prior lines of therapy were 1 (57 pts), 2 (11 pts) or 3 (3 pts), all pts had received previous CHOP-like chemotherapy, 11 pts previous autologous SCT, 5 pts epigenetic modifiers and 39.4% were refractory to their last line of treatment prior to inclusion. The cut-off date of this analysis was 01/31/2020. The 4 cycles of G-BV induction were completed in 45 pts (63%). The reasons for early discontinuation were progression (21 pts), death (3 pts) or adverse event (2 pts). In intention-to-treat analysis, the ORR at the end of induction (EOI) was 47.9% including CR (14 pts; 19.7%), PR (20 pts; 28.2%). PET performed in all patients reaching EOI showed overall and complete metabolic responses in 45.1 and 23.9%, respectively. During G-BV induction 58 pts (81.7%) had at least one G > 3 adverse event (AE) including neutropenia (67.2%), thrombopenia (17.2%), infections (15.5%), peripheral neuropathy (PN) (5.2%) and cardiac event (5.2%). Overall PN of any grade was recorded in 8/71 patients (11%) during G-BV induction and caused BV withdrawal in one case. Among the 34 responding pts after EOI, 27 pts began BV maintenance and 7 pts remain on maintenance at cut-off date. Eight pts were removed from the study due to SCT eligibility, either after the 4 GBV induction (4 pts) or after 1 or 2 maintenance BV cycles (4 pts). With a median follow-up (FU) of 9.5 (0.5-19.4) months, median PFS is 4.5 months (95%CI [3.5 - 10]) and median OS is 12 months (95%CI [8.6 - NR]). Among the 34 patients in PR/CR after induction, the duration of response (DOR) is 12.8 months (95%CI [10.3 - NR]). At last FU were recorded 32 deaths. Disease status at time of death was PD (25 pts), CR (1 pt) NE or missing (6 pts). Conclusion: The addition of BV to G increases the overall response rate by 15% in the treatment of R/R CD30+ PTCL. OS data are encouraging for this overall R/R patient population but PFS is overall short and a longer FU is mandatory. Especially the DOR of pts achieving CR or PR after 4 cycles of G-BV exceeds 1 year on BV maintenance. This combination is generally well tolerated and this study suggests that G-BV combination could be an interesting alternative for R/R CD30+ PTCL. Disclosures Tournilhac: Janssen: Consultancy, Honoraria, Other: Travel grant; INNATE Pharma: Consultancy, Honoraria; GILEAD: Consultancy, Honoraria, Other: Travel Grant; ABBVIE: Consultancy, Honoraria, Other: Travle grant; Takeda: Consultancy, Honoraria, Other: Travel grant. Laribi:novartis: Honoraria, Research Funding; amgen: Research Funding; abbvie: Honoraria, Research Funding; takeda: Research Funding. Ysebaert:AbbVie: Consultancy; Roche: Consultancy; Janssen: Consultancy. Guidez:BMS: Honoraria; TAKEDA: Honoraria; Service Hématologie et Thérapie cellulaire CHU POITIERS: Current Employment; AMGEN: Honoraria; CELGENE: Honoraria; JANSEN: Honoraria. Le Gouill:Loxo Oncology at Lilly: Consultancy; Roche Genentech, Janssen-Cilag and Abbvie, Celgene, Jazz pharmaceutical, Gilead-kite, Loxo, Daiichi-Sankyo and Servier: Honoraria. André:Celgene: Other, Research Funding; Takeda: Consultancy; Bristol-Myers-Squibb: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Karyopharm: Consultancy; Gilead: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Novartis: Consultancy, Research Funding; Amgen: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Johnson & Johnson: Research Funding; CHU UCL Namur, site Godinne, Yvoir, Belgium: Current Employment; Roche: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Abbvie: Consultancy; Seattle Genetics: Consultancy. Dupuis:Henri Mondor University Hospital Creteil France: Current Employment. Thieblemont:Roche, Amgen, Kyte Gilead, Celgene, Abbvie, Novartis, Cellectis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Roche, Hospita: Research Funding; Cellectis: Speakers Bureau. Bachy:Beigene: Membership on an entity's Board of Directors or advisory committees; Roche, Gilead: Consultancy; Amgen: Research Funding; Roche, Celgene, Amgen, Janssen, Gilead, Novartis, Sanofi: Honoraria. Morschhauser:Celgene: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; F. Hoffmann-La Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Epizyme: Membership on an entity's Board of Directors or advisory committees; Genentech, Inc.: Consultancy; Servier: Consultancy; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Feugier:janssen: Consultancy, Honoraria, Research Funding; gilead: Consultancy, Honoraria, Research Funding; roche: Consultancy, Honoraria, Research Funding; astrazeneca: Consultancy, Honoraria, Research Funding; abbvie: Consultancy, Honoraria, Research Funding. Cartron:F. Hoffmann-La Roche: Consultancy, Honoraria; Abbvie: Honoraria; Jansen: Honoraria; Celgene: Consultancy, Honoraria; Sanofi: Honoraria; Gilead: Honoraria. Camus:ROCHE: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); JANSSEN: Honoraria; AMGEN: Honoraria; PFIZER: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Sibon:takeda france: Consultancy. Snauwaert:roche: Other: travel; janssen: Other: travel; abbvie: Other. Delarue:BMS: Other: stock options ; Celgene/BMS: Current Employment. De Leval:Abbvie: Honoraria; Lausanne University Hospital & Lausanne University Institute of Pathology: Current Employment; Roche Diagnostics: Honoraria; Lunaphore Technologies SA: Consultancy, Honoraria. Gaulard:CHU Henri Mondor, Assistance Publique-Hôpitaux de Paris: Current Employment; TAKEDA: Consultancy, Honoraria, Research Funding; INNATE PHARMA: Research Funding; Roche: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company).

Abstract Introduction Diffuse Large B Cell Lymphoma (DLBCL) is the most common lymphoid malignancy, accounting for 30-40% of all Non Hodgkin Lymphomas. Gene expression profiling (GEP) has identified three main subtypes of DLBCL: Germinal Center B-cell like (GCB), Activated B-Cell like (ABC) and Primary Mediastinal B-cell Lymphoma (PMBL). Recently, Next Generation Sequencing (NGS) has enabled a more detailed characterization of DLBCL mutational profiles. Conventional techniques such as immunohistochemistry (IHC) and FISH are also widely used to describe DLBCL. However, no study has yet performed an integrative analysis of the mutational, gene expression, IHC and FISH profiles of DLBCL, in order to provide a comprehensive view of this disease. Methods 215 patients with de novo DLBCL in the prospective, multicenter and randomized LNH-03B clinical trials led by the LYmphoma Study Association (LYSA) were included in this study. Microarray-based GEP identified 81 ABC, 83 GCB, 18 PMBL and 33 other. Mutational profiles of patients' tumor DNA were established using Lymphopanel NGS, designed to identify mutations in 34 genes important for lymphomagenesis. For each recurrently mutated gene, we applied ROMER (Ritchie, Nucleic Acids Res, 2015) to perform gene set enrichment analysis on differential expression profiles of mutant and wild-type patients, using a multifactorial model accounting for subtype. The gene sets were obtained from the MSIGDB Hallmarks (Subramanian A, PNAS, 2005) and Signaturedb (Schaffer, Immunol Rev, 2006) collections. When possible, IHC was performed for IgM (n=150), MYC (n=140), BCL2 (n=148), BCL6 (n=146), CD10 (n=152), FOXP1 (n=147) and MUM1 (n=152); FISH was performed for MYC (n=131), BCL2 (n=133) and BCL6 (n=131). Results As expected, EZH2 mutations were significantly associated with upregulation of GCB gene expression (p<10-3), as well as downregulation of bivalent genes (p<10-2), H3K27me3 targets (p<10-2) and GSK343 upregulated genes (p=0.02) (Beguelin et al, Cancer Cell, 2013). IHC and FISH data further cemented EZH2 mutations' link to GCB subtype, and particularly the t(14;18)-positive subset (CD10+: OR=3.9 and p=0.01, MUM1-: OR=0.12 and p<10-3, BCL2+: OR=8.1 and p=0.04, BCL2 rearranged: OR=6.1 and p=0.04). BCL2 and CREBBP mutations were also linked to GCB subtype (CD10+ and MUM1-), and BCL2 mutations correlated with double-hit GCB DLBCL (Myc+: OR=6.6 and p<10-2, MYC rearranged: OR=7.6 and p=0.03, BCL2 rearranged: OR=20 and p<10-3). An association between BCL6 translocations and ABC subtype was confirmed, via a correlation with ABC-enriched CD79B mutations (p=0.02), although interestingly not with MYD88 mutations. MYD88 mutations were correlated with an upregulation of genes involved in proliferation or repressed by PRDM1 (FDR=0.04 each), as well as with an upregulation of genes involved in checkpoint controls, such as E2F targets and genes involved in DNA repair (FDR=0.03 each). All MYD88 mutants expressed FOXP1 in IHC (p<10-3) and MYD88 mutations were also correlated with IgM IHC positivity (OR=3.3 and p<10-2). TNFAIP3 mutations, also involved in constitutive NFkB activation, were associated with an upregulation of genes regulated by NFkB in response to TNF (FDR=0.02), as well as with an upregulation of KRAS-activated genes (FDR<10-2). PMBL-enriched mutations in our cohort were frequently associated with IgM and FoxP1 negative IHC, as expected (WHO 2008 and Roschewski, Nat Rev Clin Onc). XPO1 and ITPKB mutations were correlated with JAK-STAT pathway activation in the total cohort, including upregulation of interferon-inducible genes for both gene mutations (FDR=0.02 and FDR=0.08 respectively) and upregulation of BCL6-repressed genes for XPO1 mutations only (FDR=0.02). Interestingly, CD58 mutations were significantly correlated with upregulation of Nfkb pathway target genes (FDR=0.06), perhaps due to their negative impact on CD2 activation and ROS production inhibition. Conclusion The results herein provide steps toward a comprehensive, multi-level overview of DLBCL. We highlight differential gene set expression linked to gene mutation status, as well as driver translocation-associated mutational profiles. By using an integrative analysis approach, this study broadens our understanding of DLBCL subtypes' diverse genetic backgrounds. Disclosures Briere: St. Louis Hospital, Paris, France: Employment. Salles:Celgene Corporation; Roche: Speakers Bureau; Calistoga Pharmaceuticals, Inc.; Celgene Corporation; Genentech, Inc.; Janssen Pharmaceutica Products, L.P.; Roche: Consultancy; Celgene Corporation; Roche and Gilead Sciences: Research Funding.

Abstract Introduction. Haploidentical stem cell transplantation (Haplo-SCT) using post-transplant cyclophosphamide (PT-Cy) is being increasingly used in patients who lack a matched related or unrelated donor. It provides the opportunity for nearly all patients to benefit from hematopoietic stem cell transplantation when a matched donor is unavailable. However, while the use of PT-Cy has proven to be very effective to prevent graft-versus-host disease (GVHD) in the haplo setting, this effect may be associated with an enhanced and prolonged immunosuppression leading to a higher infectious related morbidity and mortality in those patients. Therefore, we performed this retrospective study to evaluate comprehensively the incidence and features of infectious complications in adult patients receiving PT-Cy haplo-SCT. Patients and Methods. Seventy-two consecutive adult patients who underwent haplo-SCT with PT-Cy between December 2012 and December 2016, in Saint-Antoine Hospital, Paris, France were included in this study. Graft was either bone marrow (BM, n=21) or peripheral blood stem cell (PBSC, n=51). All patients received PT-Cy 50 mg/Kg/d, either one (BM, n=20; PBSC, n=1) or two days (BM=1, PBSC, n=50), for GVHD prophylaxis. In addition all patients received cyclosporine A and mycophenolate mofetil and 60 patients (83%) received antithymocyte globuline. Conditioning regimens were reduced in 23 patients (32%), sequential in 27 (38%) and myeloablative (reduced toxicity) in 22 (30%). 42 recipients (58%) and 48 donors were CMV positive, whereas 66 donors and recipients (92%) were EBV positive. The HSCT comorbidity index (Sorror Score) was 0 in 29 patients (40%), 1 or 2 in patients 29 (40%) and ≥3 patientsin 14 (%20). Main transplant outcomes and cumulative incidence (CI) of bacterial, fungal and viral were evaluated. Results. Median age at transplantation was 48 (range, 15-72) years. 44 patients (61%) had myeloid malignancies and 28 patients (39%) had lymphoid malignancies. Disease risk index was low/intermediate in 42 patients (59%) and high/very-high in 30 patients (41%). Median dose of total nucleated cells was 3.61´108 (range, 1.16-11.86) cells/kg. Median follow-up was 23.3 (range, 4.7-48.9) months. The 2-years overall survival and progression free survival were respectively 60% and 40%. The 2-years CI of relapse was 18%. The CI of NRM was 16% at day 100, 31% at one year and 33% at 2-years. Neutrophil recovery was achieved at a median time of 17 (range: 12-88) days after haplo-SCT. The days CI of grade II-IV and grade 180III-IV acute GVHD were, respectively, 28% and 15%. The 2-years, CI of overall .and extensive chronic GVHD were, respectively, 31% and 12% The CI of bacterial infections was 43% at day 100, 46% at one year and 48% at 2-years. 8 patients were admitted to intensive care unit for bacterial infections. The CI of fungal infections was 24% at day 100, 28% at one year and 28% at 2-years. Although the CI of cytomegalovirus (CMV) reactivation was 56% at day 100 and 60% at one and 2-years, only one patient presents a CMV disease (CMV retinitis). With a CI of Epstein Barr Virus (EBV) reactivation was 54% at day 100, 68% at one year and 72% at 2-years, only 2 patients developed an EBV related post-transplant lymphoproliferative disease (PTLD, 2-years CI: 2.8%). The CI of BK virus and severe BK virus cystitis were respectively 31% and 24% at day 100, and 33% and 25% at one and 2-years. Concerning Human Herpes Virus 6 reactivation, the CI was 65% at day 100, 67% at one year and 69% at 2-years. Finally, the CI of infectious-related mortality (IRM) was 13% at day 100, and 20% at one year and 2-years. Of note, type of graft and dose of Cy have no impact on IRM and CI of infections. Conclusion. In conclusion, this data shows that haplo-SCT is associated with a high incidence of infections, in particular viral reactivation, and that these complications occur mainly within the first 100 days after allo-SCT. However, beside BK virus cystitis, these complications remain manageable as highlighted by the low incidence of CMV disease and PTLD. The high incidence of severe BK virus cystitis remains a matter of concern and strategies must be developed to prevent this complication. Overall, the high incidence IRM, haplo-SCT appears to be an effective strategy in patients with a 2-years overall survival of 60%. Finally, further improvements are required to decrease the incidence of infectious complication and improve patients' outcome after haplo-SCT. Disclosures Mohty: Sanofi: Honoraria, Speakers Bureau.

Background Acute myeloid leukemia (AML) is a molecularly and clinically heterogeneous hematological malignancy. Chemotherapy resistance is common, and relapse is the major cause of treatment failure. Although immunotherapy may be an attractive modality to exploit in patients with AML, the ability to predict the groups of patients and the types of cancer that will respond to immune targeting remains limited. Methods Immune gene expression profiling for the high-dimensional analysis of the immunological landscape of bone marrow (BM) samples from patients with newly-diagnosed (de novo) non-promyelocytic AML (n=387) was employed to analyze the tumor microenvironment (TME). We derived immune scores from mRNA expression levels and devised an RNA-based, quantitative metric of immune infiltration, as previously published (Danaher P, et al. JITC 2017 and 2018). The PanCancer IO360™ gene expression assay was used to profile BM samples collected prior to and during flotetuzumab (FLZ) treatment from 30 AML patients treated at the RP2D (500 ng/kg/day) in the CP-MGD006-01 clinical trial (NCT#02152956), primary refractory, n=23 or relapsed, n=7. IO360 score comparisons are presented as mean ± SD and significance was assessed by the Mann Whitney U test. Results Analysis of pre-treatment BM samples from de novo AML revealed distinct immune signature modules, reflecting the co-expression of genes associated with 1) an IFNγ-dominant TME, 2) adaptive immune responses, and 3) myeloid cell abundance. When considered in aggregate, the relative intensity of gene expression in the immune modules stratified BM samples into two subgroups, which will be herein termed immune-infiltrated and immune-depleted. When AML patients were dichotomized based on median immune scores, high versus low, a higher percentage of primary refractory patients was observed within the IFNγ high module (65.4% versus 34.6%; p=0.0022). In multivariate logistic regression, an IFNγ high profile (derived from the IFNγ-dominant module) was predictive of therapeutic resistance to induction chemotherapy, even more than ELN risk categories (AUROC = 0.815 versus 0.702 with ELN risk only). In a validation cohort, Beat AML series, the IFNγ high profile when compared to other clinically established prognostic indicators in AML, i.e. disease type (primary versus secondary), WBC count, patient age at diagnosis, and ELN risk categories was significantly more predictive of therapeutic resistance to induction chemotherapy (AUROC=0.921 versus 0.709 with ELN cytogenetic risk alone; two-tailed p value=0.002673). Similarly, a higher percentage of patients with an IFNγ high profile AML in the HOVON series failed to achieve CR in response to induction chemotherapy when compared to AML cases with an IFNγ low profile (27.2% versus 15.2%; p=0.0004). We hypothesized that higher expression of IFNγ inducible genes, while underpinning chemotherapy resistance, might identify AML patients who derive benefit from immunotherapy with FLZ. BM samples from 92% of patients with evidence of FLZ anti-leukemic activity (ALA), which was defined as either CR, CRh, CRi, PR or overall benefit (>30% reduction in BM blasts), had an immune infiltrated TME relative to non-responders (SD or PD). Interestingly, the IFNγ-signaling score was significantly higher in patients with chemotherapy-refractory AML compared with relapsed AML at time of FLZ treatment, and in individuals with evidence of ALA compared to non-responders (p<0.0001). Additionally, another IFNγ-related score, the tumor inflammation signature (TIS), had strong predictive power of anti-leukemic activity to FLZ, with an AUROC value of 0.847 (p=0.001). FLZ also modified the TME, and on-treatment BM samples (available in 19 patients at the end of cycle 1) displayed increased expression of antigen presentation and immune activation genes relative to baseline, and had higher TIS scores (6.47±0.22 versus 5.93±0.15, p=0.0006), antigen processing machinery scores (5.67±0.16 versus 5.31±0.12, p=0.002), IFNγ signaling scores (3.58±0.27 versus 2.81±0.24, p=0.0004) and PD-L1 expression (3.43±0.28 versus 2.73±0.21, p=0.0062). Conclusions Our findings to date suggest that microenvironmental immune gene profiles could be used to inform the delivery of personalized immunotherapies to patients with IFNγ-dominant AML subtypes, and identify patients less likely to respond to cytotoxic chemotherapy. Disclosures Minden: Trillium Therapetuics: Other: licensing agreement. Hood:NanoString Technologies, Inc.: Employment. Church:NanoString Technologies, Inc.: Employment, Equity Ownership. Sullivan:NanoString Technologies, Inc.: Employment. Viboch:NanoString Technologies, Inc.: Employment. Warren:NanoString Technologies, Inc.: Employment. Liang:NanoString Technologies, Inc.: Employment. Cesano:NanoString Technologies, Inc.: Employment. Löwenberg:Chairman, Leukemia Cooperative Trial Group HOVON (Netherlands: Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Astex: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Up-to-Date", section editor leukemia: Membership on an entity's Board of Directors or advisory committees; CELYAD: Membership on an entity's Board of Directors or advisory committees; Chairman Scientific Committee and Member Executive Committee, European School of Hematology (ESH, Paris, France): Membership on an entity's Board of Directors or advisory committees; Elected member, Royal Academy of Sciences and Arts, The Netherlands: Membership on an entity's Board of Directors or advisory committees; Editorial Board "European Oncology & Haematology": Membership on an entity's Board of Directors or advisory committees; Clear Creek Bio Ltd: Consultancy, Honoraria; Hoffman-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees; Frame Pharmaceuticals: Equity Ownership; Royal Academy of Sciences and Arts, The Netherlands: Membership on an entity's Board of Directors or advisory committees; Supervisory Board, National Comprehensive Cancer Center (IKNL), Netherland: Membership on an entity's Board of Directors or advisory committees. Tasian:Incyte Corportation: Research Funding; Gilead Sciences: Research Funding; Aleta Biotherapeutics: Membership on an entity's Board of Directors or advisory committees. Rettig:WashU: Patents & Royalties: Patent Application 16/401,950. Davidson-Moncada:MacroGenics, Inc.: Employment, Equity Ownership. DiPersio:Celgene: Consultancy; NeoImmune Tech: Research Funding; Macrogenics: Research Funding, Speakers Bureau; Incyte: Consultancy, Research Funding; Karyopharm Therapeutics: Consultancy; RiverVest Venture Partners Arch Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cellworks Group, Inc.: Membership on an entity's Board of Directors or advisory committees; Amphivena Therapeutics: Consultancy, Research Funding; Magenta Therapeutics: Equity Ownership; WUGEN: Equity Ownership, Patents & Royalties, Research Funding; Bioline Rx: Research Funding, Speakers Bureau. Rutella:NanoString Technologies, Inc.: Research Funding; MacroGenics, Inc.: Research Funding.

Introduction Adult T-cell leukemia/lymphoma (ATL) is a peripheral T-cell neoplasm triggered by HTLV1 infection. According to the Japanese studies, the median onset of disease is around age 60 (Yamada Y et al. Br J of Haematol 2001, Kamiunten A et al. Hematol Oncol 2018). The aggressive forms exhibit a poor prognosis, due to intrinsic or acquired chemotherapy resistance and severe immunosuppression. Combination chemotherapy can improve the response rates, and consolidation with allogenic hematopoietic stem cell transplantation (allo-HSCT) prolongs complete remission (CR) (Yamada Y et al. Br J of Haematol 2001, Kamiunten A et al. Hematol Oncol 2018). The overall survival (OS) rates at 1 and 2 years after transplantation were reported to be 34% and respectively 27% (Kamiunten A et al. Hematol Oncol 2018). Romania is one of the regions with the highest prevalence of HTLV1 infection (5.33 at 10.000 donors in 2003-2008, Leperche S et al. Vox Sang 2009), therefore the prevalence of ATL is also higher. Methods A prospective observational study was performed on all patients with aggressive forms of ATL, diagnosed in Bucharest between April 2010 and January 2019, respectively 56 patients. Patients under 18 years of age and with chronic or smoldering type were excluded. The goal of this study was to better describe the disease characteristics and to discover novel factors that influence response and survival. All patients were assessed in collaboration with Necker Hospital, Paris, France, as reference center. Clinical and lab data were collected, the treatment was administered at investigator choice using CHOP/CHOP-like, Hyper-CVAD and LSG15 regimens, and allo-HSCT was offered to all eligible patients as soon as CR was obtained. Statistical analyses were performed using IBM SPSS Statistics 25. For survival analysis we used Kaplan-Meier estimate. The ROC curve was used to set cutoff values. The statistical significance was calculated using Chi-squared test and Fisher's exact test. Results In this study we analyzed a total of 56 ATL patients (M:F=1:1.3), with a median age of 42.5 years, all having aggressive types. Within this group, 33.9% had hypercalcemia and 73.2% elevated LDH (64.3% >2xN). Most used chemotherapy regimens were: CHOP/CHOP-like (60.7%), followed by LSG15 (23.2%) and Hyper-CVAD (7.1%); antiretroviral therapy (51.8%) and allo-HSCT (12.5%) were also used. LSG15 regimen is not fully applicable in our country due to unavailability of Ranimustine and Vindesine, therefore a small proportion of patients received this treatment. In multivariate analysis, factors showing significant association with lower rate of CR were: age >40.5 years, leukocytosis with a cut-off of 8950/μl, hypercalcemia >9.5 mg/dl, high LDH >512 U/L. LSG15 was associated with a higher CR rate (50%) compared to CHOP/CHOP-like (22.7%) and Hyper-CVAD (33.3%), although not statistically significant. Median OS was 6.5 months (5.1 - acute type, 8.0 - lymphomatous type), versus 3.5 months in acute type and 9.5 months in lymphomatous type in previous data in our center. Early death rate (< 1 month) was found in 8.9% (n=5) of patients. Factors associated with early death were: acute type (n=4), leukocytosis (n=5), hypercalcemia (n=4), high LDH (n=5), extranodal involvement (n=4). Patients who obtained CR (n=9) had a better survival that those who did not (median OS 40.7 vs 5.1 months, p=0.000) (Fig a); undergoing allo-HSCT also significantly increased OS (median OS not reached vs 6.1 months, p=0.003) (Fig b). Among patients who underwent allo-HSCT, OS at 1 year and 2 years after the allo-HSCT were 57.1% and 42.9%, respectively. Three patients died, all less than 1 year after transplantation. Conclusions Median age at diagnosis in our group was lower (42.5 years) versus the Japanese studies (Yamada Y et al. Br J of Haematol 2001, Kamiunten A et al. Hematol Oncol 2018). This might reflect an origin of infection in the 1980s in Romania, where other outbreaks occurred by horizontal transmission in that period, including an outbreak of HIV-1 (Patrascu I V et al, Lancet 1990). Future in-depth studies of this cohort might better correlate age of infection, HTLV1 subtype and latency to ATL. The best predictors of better survival were obtaining CR and receiving allo-HSCT. Among the treatments we used, LSG15 regimen had higher rate of CR. Survival after transplantation was higher in our group compared to the Japanese studies (Kamiunten A et al. Hematol Oncol 2018). Disclosures Constantinescu: AgenDix GmbH: Other: Co-Founder, MyeloPro Research and Diagnostics; AlsaTech: Other: Co-Founde; Wiley & Sons: Other: Editor in Chief, Journal of Cellular and Molecular Medicine; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hermine:Celgene: Research Funding; AB science: Consultancy, Equity Ownership, Honoraria, Research Funding; Novartis: Research Funding.

AbstractAs was the case with silversmiths (Note 3), many more cabinet-makers were wcrking in Amsterdam during the second half of the 18th century than in any other city in the Dutch Republic, the names of 195 of them being now known as opposed to 57 in The Hague and 32 in Rotterdam (Note 2). Most of those 195 names have been culled from the few surviving documents of the Guild of St. Joseph in Amsterdam, to which the cabinet-makers belonged (Note 4), supplemented by other sources, such as printed registers of craftsmen and shopkeepers (Note 6). Another important source is the newspaper the Amsterdamsche Courant with its advertisements placed by craftsmen themselves, with notices of sales, bankruptcies, lotteries and annual fairs and with advertisements concerning subsidiary or related trades. Since these advertisements were directed at the consumer, they often contain stylistic descriptions such as are not found elsewhere. Moreover, they aford valuable clues to archival material. Hence an investigation of all the advertisements from the years 1751-1800 has formed the basis for a study of Amsterdam cabinet-making, some results of which are presented here. Such a study is doomed largely to remain theoretical. The records can hardly ever be linked with surviving pieces, as these are virtually always anonymous since Amsterdam cabinet-makers were not required to stamp or sign their work. Moreover, only a few pieces of Dutch 18th-century furniture have a known provenance, so that it is only rarely possible to link a piece with a bill or another document and identify its maker. Thus it is not yet possible to form a reliable picture of a local Amsterdam style, let alone embark on attributions to individual makers (Note 8). In this light special importance may be attached to two commodes of the third quarter of the century which are exceptional in that they bear a signature, that of Andries Bongen (Figs. 1, 2, Notes 10, 11). These commodes, being entirely French-inspired, illustrate a specific and little-known aspect of Amsterdam cabinet-making. French furniture was so sought after in Amsterdam at that period that in 1771 a strict ban was imposed on its importation in order to protect local cabinet-makers (Note 12). It had begun to be imitated even before that and the commodes by Bongen exemplify this development. Andries Bongen, who was probably born in Geldern, south of Cleves and just east of the border of the Dutch Republic, is first recorded in Amsterdam in May 1763 on his marriage to Willemina, daughter of the smith Lambert van der Beek. He registered as a citizen on 5 July 1763 and became a master cabinet-maker some time between March 1763 and March 1764 (Note 19), so that, accordirtg to the Guild regulations, he must previously have trained for two years under an Amsterdam master (Note 20). At the time of his marriage he was living in St. Jorisstraat, but by the end of 1766 he had moved to Spui and between 1769 and 1771 he moved again, to Muiderpleinlje. When he and his wife made their will in 1772, their possessions were worth something under 8000 guilders (Note 23). This suggests that the business was quite flourishing, which seems to be confirmed by the fact that Bongen received a commission from the city of Amsterdam in 1771. Two more pieces were made for the city in 1786 and 1789, but in the latter year Bongen was declared bankrupt. The inventory of his possessions drawn up then (see Appeytdix) shows how parlous his conditions had become, his goods being valued at only 300 guilders. The reference to a shop indicates that Bongen sold his own furniture, although he had no stock to speak of at that point. The mention of eight work-benches, however, sugests that his output had previously been quite large. This is confirmed by the extent of his debts, notably that to the timber merchant Jan van Mekeren (Note 27). Other creditors included 'Rudolfeus Eyk', who probably supplied iron trelliszvork for bookcases and the like (Note 28), and the glass merchants Boswel en Zonen (Note 29) No debtors are listed and the only customer who can tentatively be identified is a 'Heer Hasselaar' who might be Pieter Cornelis Hasselaer (1720-95), several times burgomaster of Amsterdam between 1773 and 1794 (Note 30). Bongen died three years after his bankruptcy, at which time he was living in Nieuwe Looiersstraat. He appears to have continued working as a cabiytet-maker up to his death and his widow probably carried on the business until her own death in 1808, but nothing is known of this later period. The clearest insight into the character of part of Bongen's output is aforded by the advertisement he placed in the Amsterdamsehe Courant of 4 December 1766, describing three pieces of furniture 'in the French manner'. This is the first announcement by an 18th-century Amsterdam cabinet-maker of work in the French style. Bongen mentions two commodes decorated with floral marquetry, a technique which had flourished in Amsterdam in the late 17th and early 18th centuries (Note 34), but which had largely fallen into disuse on the advent around 1715 of a more sober type of furniture with plain walnut veneers on the English model (Note 36). In France a form of floral marquetry reappeared in the 1740s, being further developed in the following decade under the influence of Jean-François Oeben (1721-63). From the late 1750s there are indications of the presence of pieces of French marquetry furniture in the new style in Amsterdam (Notes 42, 43). The earliest explicit description of floral marquetry appears in a sale catalogue of 5 June 1765 (Note 44), while in another of 25 March 1766 (Note 46) many French pieces are detailed. Obviously, then, Bongen was endeavouring to capture a share, of this new market. The reappearance of elaborate marquetry on Amsterdam-made furniture was the result of a desire to emulate the French examples. The two commodes described in Bongen's advertisement can be identified with the one now in Amsterdam (Fig.2) and the one sold in London in 1947 (Fig.1). The latter still had more of its original mounts at the time nf the sale (Fig. 4) and the two probably formed a pair originally. The unusual fact that they are signed indicates that Bongen intended them to serve as show-pieces to demonstrate his skill at the beginning of his career (cf. Note 51, for another craftsman from abroad who began his career in Amsterdam by similarly advertising a spectacular piece). The commode in Amsterdam, with all its original mounts, demonstrates most clearly how close Bongen came to French prototypes, although his work has many personal traits nonetheless. In the marquetry the vase on a plinth on the front and the composition of the bouquets on the sides are notable (Fig.5), as are the large, full-blown blooms. The carcase, made entirely of oak, is remarkably well constructed and has a heavy, solid character. The commodes are outstanding for the complete integration of the marquetry and the mounts, in the manner of the finesl French furniture. The mounts presenl a problem, as it is not clear where they were made. They do not appear to be French or English, but one hesitates to attribute them to Amsterdam, as it is clear from documentary material that ornamental furniture-mounts were hardly ever made there in the second half of the 18th century. The mounts advertised by Ernst Meyrink in 1752 (Note 53) were probably still of the plain variety of the early part of the century and there is no further mention of mounts made in Amsterdam in the Amsterdamsche Courant. Once, in 1768, the silversmith J. H. Strixner placed an advertisement which refers to their gilding (Note 55). There is virtually no indication either of French mounts being imported and there is little Dutch furniture of this period that bears mounts which are indisputably French. In contrast to this, a large number of advertisements from as early as 1735 show that many mounts were imported from England, while among English manufacturers who came to sell their wares in Amsterdam were Robert Marshall of London (Note 60), James Scott (Note 61), William Tottie of Rotterdam (Note 62), whose business was continued after his death by Klaas Pieter Sent (Note 64), and H. Jelloly, again of Rotterdam (Notes 66, 67). It seems surprising that in a period when the French style reigned supreme so many mounts were imported from England, but the English manufacturers, mainly working in Birmingham, produced many mounts in the French style, probably often directed expressly at foreign markets. On the two commodes by Bongen only the corner mounts and the handles are of types found in the trade-catalogues of the English manufacturers (Figs. 7, 8, Notes 65, 70). The corner mounts are of a common type also found on French furniture (Note 71), so they doubtless copy a French model. The remaining mounts, however, are the ones which are so well integrated with the marquetry and these are not found elsewhere. Recently a third commode signed by Bongen has come to light, of similar character to the first two (Fig.3). Here all the mounts are of types found in the catalogues (Figs.7-10, Note 72). Apparently Bongen could not, or did not choose to, obtain the special mounts any more, although he clearly wanted to follow the same design (Fig. 6). This third commode was undoubtedly made somewhal later than the other two. The marquetry on it is the best preserved and it is possible to see how Bongen enlivened it with fine engraving. Because this piece is less exceptional, it also allows us to attribute some unsigned pieces to Bongen on the basis of their closeness to it, namely a commode sold in London in 1962 (Fig.11, Note 73) and two smaller, simpler commodes, which may originally have formed a pair, one sold in London in 1967 (Fig.12, Nole 74) and the other in a Dutch private collection (Figs.13, 14). The first one has a highly original marquetry decoration of a basket of flowers falling down. On the sides of this piece, and on the front of the two smaller ones, are bouquets tied with ribbons. These were doubtless influenced by contemporary engravings, but no direct models have been identified. The construction of the commode in the Netherlands tallies completely with tltat of the signed example in Amsterdam. The mounts are probably all English, although they have not all been found in English catalogues (Fig.15, Note 76). A seventh commode attributable to Bongen was sold in Switzerland in 1956 (Fig.16, Note 77). It is unusual in that walnut is employed as the background for the floral marquetry, something virtually unknown in Paris, but not uncommon on German work of French inspiration (Note 78). That commodes constitute the largest group among the furniture in the French style attributable to Bongen should cause no surprise, for the commode was the most sought after of all the pieces produced by the ébénistes not only in France, but all over Europe. Two other pieces which reveal Bongen's hand are two tables which look like side-tables, but which have fold-out tops to transform them into card-tables, a type seldom found in France, but common in England and the Netherlands (Note 80). One is at Bowhill in Scotland (Figs.17, 19, 20), the other was sold in London in 1972 (Fig.18, Note 79). The corner mounts on the Bowhill table, which probably also graced the other one originally, are the same as those on the two small commodes, while the handles are again to be found in an English catalogue (Fig.21, Note 81). What sounds like a similar card-table was sold at auction in Amsterdam in 1772 (Note 82). In Bongen's advertisement of 1766 mention is also made of a secretaire, this being the first appearance of this term in the Amsterdamsche Courant and Bongen finding it necessary to define it. No secretaire is known that can be attributed to him. A medal-cabinet in the form of a secretaire in Leiden (Figs.22, 23) hasfloral marquetry somewhat reminiscent of his work, but lacking its elegance, liveliness and equilibrium. Here the floral marquetry is combined with trompe l'oeil cubes and an interlaced border, early Neo-Classical elements which were first employed in France in the 1750s, so that this piece represents a later stage than those attributable to Bongen, which are all in a pure Louis xvstyle. Virtually identical in form to the medal-cabinet is a secretaire decorated solely with floral marquetry (Fig. 24, Note 87). This also appears not to be by Bongen, but both pieces may have been made under his influence. The picture we can form of Bongen's work on the basis of the signed commodes is clearly incomplete. His secretaire was decorated with '4 Children representing Trade', an exceptionally modern and original idea in 1766 even by French standards (Note 88). His ambitions in marquetry obviously wentfar beyondflowers, but no piece has yet beenfound which evinces this, nor is anything known of the Neo-Classical work which he may have produced after this style was introduced in Amsterdam around 1770. Bongen may perhaps have been the first Amsterdam cabinet-maker to produce marquetry furniture in the French style, but he was not to remain the only one. In 1771 and 1772 furniture in both the Dutch and French mode was advertised for sale at the Kistenmakerspand in Kalverstraat, where all furniture-makers belonging to the Guild of St. Joseph could sell their wares (Note 89). The 'French' pieces were probably decorated with marquetry. Only a small number of cabinet-makers are known to have worked in this style, however. They include Arnoldus Gerritsen of Rheestraat, who became a master in 1769 and sold his stock, including a 'small French inlaid Commode', in 1772, and Johan Jobst Swenebart (c.1747 - active up to 1806 or later), who became a master in 1774 and advertised in 1775 that he made 'all sorts of choice Cabinet- and Flower-works', the last term referring to furniture decorated with floral marquetry. Not only French types of furniture, but also traditional Dutch pieces were now decorated with French-inspired marquetry,for example a collector's cabinet advertised in 1775 by Johan Jacob Breytspraak (c.1739-95), who had become a master in 1769-70; a bureau-bookcase, a form introduced in the first half of the century probably under English influence (Note 100), exhibited in 1772 (Note 99); and a display cabinet for porcelain supplied, though not necessarily made, by Pieter Uylenburg en Zoon in 1775 (Notes 101, 102). Even long-case clocks were enriched with marquetry, witness the one advertised by the clock-maker J. H. Kühn in 1775 and another by him which was sold by auction in Edam in 1777 (Note 104). The latter was, like the bureau-bookcase exhibited in 1772, decorated with musical instruments, again a motif borrowed from France, where it was used increasingly from the 1760s onwards (Note 105). A clock signed by the Amsterdam clock-maker J. George Grüning also has a case with marquetry of musical instruments. This must date from about 1775-80, but its maker is unknown (Fig. 25, Notes 106, 107). All four of the Amsterdam cabinet-makers known to have done marquetry around 1770 came from Germany and all were then only recently established in Amsterdam. In fact half of the 144 Amsterdam cabinet-makers working in the second half of the 18th century whose origins it has been possible to trace came from Germany, so the German element was even stronger there than in Paris, where Germans comprised about a third of the ébénistes (Note 108) and where they had again played an important role in the revival of marquetry. None qf the four in Amsterdam was exclusively concerned with marquetry. Indeed, for some of them it may only have been a secondary aspect of their work. This was not true of Bongen, but he too made plain pieces, witness the four mahogany gueridons he made for the city of Amsterdam in 1771 or the two cupboards also made for the city in 1786 and 1789 (Notes 111, 112).No marquetry is listed in his inventory either. Perhaps fashions had changed by the time of his bankruptcy. Such scant knowledge as we have of Amsterdam cabinet-making between 1775 and 1785 certainly seems to suggest this. In the descriptions of the prizes for furraiture-lotteries, such as took place regularly from 1773 onwards (Note 114), marquetry is mentioned in 1773 and 1775 (Notes 115, 116), but after that there is no reference to itfor about tenyears. Nor is there any mention of marquetry in the very few cabinet-makers' advertisements of this period. When the clock-maker Kühn again advertised long-case clocks in 1777 and 1785, the cases were of carved mahogany (Notes 121, 122). Certainly in France the popularity of marquetry began to wane shortly before 1780 and developments in the Netherlands were probably influenced by this. Towards the end of the 1780s, however, pieces described as French and others decorated with 'inlaid work' again appear as prizes in lotteries, such as those organized by Johan Frederik Reinbregt (active 1785-95 or later), who came from Hanover (Note 128), and Swenebart. The latter advertised an inlaid mahogany secretaire in 1793 (Note 132) and similar pieces are listed in the announcement of the sale of the stock of Jean-Matthijs Chaisneux (c.1734-92), one of a small group of French upholsterers first mentioned in Amsterdam in the 1760s, who played an important part in the spread of French influence there (Note 134). In this later period, however, reference is only made to French furniture when English pieces are also mentioned, so a new juxtaposition is implied and 'French' need not mean richly decorated with marquetry as it did in the 1760s. In fact the marquetry of this period was probably of a much more modest character. A large number of pieces of Dutch furniture in the late Neo-Classical style are known, generally veneered with rosewood or mahogany, where the marquetry is confined to trophies, medallions on ribbons, geometric borders and suchlike. A sideboard in the Rijksmuseum is an exceptionally fine and elaborately decorated example of this light and elegant style (Fig. 26) None of this furniture is known for certain to have been made in Amsterdam, but two tobacco boxes with restrained marquetry decoration (Fig.27, Note 136) were made in Haarlem in 1789 by Johan Gottfried Fremming (c.1753-1832) of Leipzig, who had probably trained in Amsterdam and whose style will not have differed much from that current in the capital. Boxes of this type are mentioned in the 1789 inventory of the Amsterdam cabinet-maker Johan Christiaan Molle (c.1748-89) as the only pieces decorated with inlay (Note 138). In the 1792 inventory of Jacob Keesinger (active 1764-92) from Ziegenhain there are larger pieces of marquetry furniture as well (Note 139), but they are greatly in the minority, as is also the case with a sale of cabinet-makers' wares held in 1794 (Note 141), which included a book-case of the type in Fig.28 (Note 142). Similarly the 1795 inventory of Johan Jacob Breytspraak, one of the most important and prosperous cabinet-makers of the day, contains only a few marquetry pieces (Note 144). The 1793 inventory of Hendrik Melters (1720-93) lists tools and patterns for marquetry, but no pieces decorated with it (Note 145). Melters seems to have specialized in cases for long-case clocks, the Amsterdam clock-maker Rutgerus van Meurs (1738-1800) being one of his clients (Note 146). The cases of clocks signed by Van Meurs bear only simple marquetry motifs (Note 147). The Dutch late Neo-Classical furniture with restrained marquetry decoration has no equivalent in France; it is more reminiscent of English work (Note 148). The pattern-books of Hepplewhite and Sheraton undoubtedly found their way to the Dutch Republic and the 'English' furniture mentioned in Amsterdam sources from 1787 probably reflected their influence. However, the introduction of the late, restrained Neo-Classical style in furniture was not the result of English influence alone. Rather, the two countries witnessed a parallel development. In England, too, marquetry was re-introduced under French influence around 1760 and it gradually became much simpler during the last quarter of the century, French influences being amalgamated into a national style (Notes 150, 151). On the whole, the Frertch models were followed more closely in the Netherlands than in England. Even at the end of the century French proportions still very much influenced Dutch cabinet-making. Thus the typically Dutch late Neo-Classical style sprang from a combirtation of French and English influences. This makes it difficult to understand what exactly was meant by the distinction made between ;French' and 'English' furniture at this time. The sources offer few clues here and this is even true of the description of the sale of the stock of the only English cabinet-maker working in Amsterdam at this period, Joseph Bull of London, who was active between 1787 and 1792, when his goods were sold (Notes 155, 156).

Abstract At its General Assembly in Paris, France, on 10-11 July 2019, the IUPAC Council will be asked to elect a Vice President, a Secretary General, a Treasurer, and members of the Bureau to fulfill the vacancies created by retiring members. IUPAC National Adhering Organizations are invited to submit nominations no later than 31 March 2019.