Abstract: It is not clear whether pre-existing macrovascular complications (ischemic heart disease, stroke or peripheral artery disease) are associated with health outcomes in people with diabetes mellitus hospitalized for COVID-19. Methods We conducted cohort studies of adults with pre-existing diabetes hospitalized for COVID-19 infection in the UK, France, and Spain during the early phase of the pandemic (between March 2020—October 2020). Logistic regression models adjusted for demographic factors and other comorbidities were used to determine associations between previous macrovascular disease and relevant clinical outcomes: mortality, intensive care unit (ICU) admission and use of invasive mechanical ventilation (IMV) during the hospitalization. Output from individual logistic regression models for each cohort was combined in a meta-analysis. Results Complete data were available for 4,106 (60.4%) individuals. Of these, 1,652 (40.2%) had any prior macrovascular disease of whom 28.5% of patients died. Mortality was higher for people with compared to those without previous macrovascular disease (37.7% vs 22.4%). The combined crude odds ratio (OR) for previous macrovascular disease and mortality for all four cohorts was 2.12 (95% CI 1.83–2.45 with an I 2 of 60%, reduced after adjustments for age, sex, type of diabetes, hypertension, microvascular disease, ethnicity, and BMI to adjusted OR 1.53 [95% CI 1.29–1.81]) for the three cohorts. Further analysis revealed that ischemic heart disease and cerebrovascular disease were the main contributors of adverse outcomes. However, proportions of people admitted to ICU (adjOR 0.48 [95% CI 0.31–0.75] , I 2 60%) and the use of IMV during hospitalization (adjOR 0.52 [95% CI 0.40–0.68], I 2 37%) were significantly lower for people with previous macrovascular disease. Conclusions This large multinational study of people with diabetes mellitus hospitalized for COVID-19 demonstrates that previous macrovascular disease is associated with higher mortality and lower proportions admitted to ICU and treated with IMV during hospitalization suggesting selective admission criteria. Our findings highlight the importance correctly assess the prognosis and intensive monitoring in this high-risk group of patients and emphasize the need to design specific public health programs aimed to prevent SARS-CoV-2 infection in this subgroup.

Abstract: Introduction: A number of approaches have been explored to prevent relapse in AML setting, including immune-strategies such as dendritic cells (DC) vaccination. There is no report so far of the use of autologous apoptotic leukemic cells as a source of tumor antigen for DC vaccine. Methods: The main objective of this prospective monocentric Phase I/II study was to explore the feasibility to produce autologous leukemic apoptotic corpse-pulsed DC for elderly AML patients in first or second complete remission (CR) and to report the toxicity of such a vaccine. Inclusion criteria were AML (except promyelocytic) patients older than 59 years with a good performans status (ECOG 〈 =2), not eligible for allogeneic transplantation or another trial, with 〉 =50% of leukemic blasts in bone marrow (BM) or peripheral blood, and with no contra-indications to apheresis. Vaccines were produced by Nantes UTCG according to good manufacturing practices for cell and gene based therapies in order to comply to the French AFSSAPS (currently ANSM) agency guidelines. Patients had to be pre-included (refractory or not) at diagnosis or at time of first relapse in order to collect sufficient leukemic cells ( 〉 2.4 108) prior to chemotherapy after 1 or 2 days of collection. After blasts collection, the choice of chemotherapy regimen was at the discretion of the investigator. Few courses of chemotherapy were allowed before vaccine production but not after. Patients were definitively included only in case of CR to allow collecting autologous non-leukemic peripheral monocytes by apheresis to generate the DC vaccine. Patients were programmed to receive up to 5 doses of vaccine (days +1 +7 +14 +21 and +35 +2) which consisted of 10 millions pulsed DC, including 9 millions administered subcutaneously (1 mL) and 1 million administered intradermally (0.1mL). Minimal residual disease (MRD) was studied after vaccines using flow cytometry. Results: Between November 2009 and March 2015, 23 patients were pre-included but 2 patients were excluded for analyses because blast collection was finally not performed. Thus, overall, 21 elderly AML patients (male n=14; median age: 74 years (range: 65-84), secondary AML n=8) were considered either at time of diagnosis or at time of first relapse. The median % of BM blasts was 63% (range: 20-92), including 3 and 4 cases with less than 40% and between 40-49%, respectively (protocol deviation). Although it was not the case for one patient with 〉 50% of BM blasts, all patients between 40-49% of BM blasts reached the threshold of 2.4x108blasts required for the study. Two patients out of 3 with less than 40% BM blasts had insufficient blast collection to pursue the protocol. After blast collection, the majority of patients (n=19) received non-intensive chemotherapy. 5/21 (24%) cases achieved CR, a rate that was expected for this very old population. All of CR patients could proceed to apheresis after 2 (n=4) or 4 (n=1) courses of non-intensive consolidation. Production of the 5 vaccines was possible for all of them and first infusion was made at a median of 25 days (range: 20-28) from the apheresis. However, a median of 27 vaccines (range: 8-85) could have been theoretically produced in CR patients, suggesting the possibility to realize a longer maintenance therapy to prevent relapse in the future. All patients received as expected the 5 vaccines and no adverse events were documented. Durations of response from CR were: +8.5, +8, +4.5, +4, +12 months and from first vaccine: +5.5, +4.5, +1.8, +1.8, and +9 months. Two patients had relapsed before day+55. At this time, the 3 other patients were documented with negative MRD. In July 2016, 2 patients are still alive, 1 at +30 months from CR in relapse and 1 at +13 months in CR. The 3 other cases died of relapse at +15.5, +8 and +5.5 months from CR. The median OS from pre-inclusion was significantly higher for vaccinated CR patients (13 months (9-41) vs 4.75 months (1-24), p=0.009). Conclusion: Our strategy seems promising for elderly AML patients achieving CR in terms of relapse prevention. Vaccine production is reproducible and compliant for clinical use. Larger Phase 2 studies are required to confirm our results in younger and older AML population. The trial is registered at Clinicaltrials.gov NCT01146262. This study was supported by a grant from the French National Cancer Institute. Disclosures Moreau: Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Janssen: Honoraria, Speakers Bureau; Novartis: Honoraria; Takeda: Honoraria; Amgen: Honoraria.

Abstract: Gene expression profiling has provided new insights into the understanding of mature B cell neoplasms by relating each one to its normal counterpart, so that they can be to some extent classified according to the corresponding normal B-cell stage. Thus, diffuse large B cell (DLBCL) and follicular lymphoma (FL) have been related to a germinal center precursor whereas mantle cell lymphoma (MCL) or marginal zone lymphoma (MZL) are more likely to derive from naïve and memory B cell, respectively. However, little is still known about the physiopathology of B-cell lymphomas and particularly the deregulated pathways involved in their oncogenesis. To further investigate that point, we performed laser capture microdissection (LCM) of the three anatomic lymphoid compartments (i.e germinal center, mantle zone and marginal zone) taken from nine normal spleens and lymph nodes and magnetic cell separation of the four normal B cell subpopulations (i.e naïve B cells, centroblasts, centrocytes and memory B cells) purified from twelve normal tonsils for gene expression profiling by cDNA microarray. These molecular profiles have been compared to those of the four most frequent mature B cell neoplasms in adult (i.e DLBCL, FL, MZL and MCL), each one isolated from five previously untreated patients. Unsupervised analysis by hierarchical clustering of the normal anatomic and cellular populations could discriminate the germinal from the extra-germinal populations by genes involved in cell proliferation (e.g. E2F5, CCNB2, BUB1B and AURKB), DNA repair (e.g. PCNA and EXO1), cytokine secretion (e.g. IL8, IL10RB, IL4R and TGFBI) and apoptosis (e.g. CASP8, CASP10, BCL2 and FAS). Supervised analysis of the comparison between each B-cell lymphoma and its anatomic and cellular physiologic equivalent identified molecular deregulations concerning several genes’families characterizing the different histologic subtypes. Genes associated with cellular adhesion and ubiquitin cycle were significantly up-regulated in MCL (FCGBP, ITGAE, USP7, VCAM1) and MZL (CTGF, CDH1, ITGAE) whereas germinal center derived lymphomas (i.e. DLBCL and FL) mainly showed up-regulation of genes involved in cell proliferation (TNFRSF17, SEPT8) and immune response (FCER1G, XBP1, IL1RN). Few deregulated genes were common to the four subtypes, principally associated with cell proliferation (CYR61, GPNMB), cytosqueleton organization (EPB41L3) and carbohydrates metabolism (GNPDA1), suggesting potential similar oncogenic pathways. Those preliminary results are compatible with both subtype-specific and overall mechanisms of lympomagenesis and should be verified in a wider range of samples to confirm the oncogenic events involved in this heterogeneous disease.

Abstract: Introduction Aggressive B-cell lymphomas are heterogeneous in their clinical course and biological characteristics. They include diffuse large B-cell lymphoma not otherwise specified (DLBCL-NOS), high grade-B-cell lymphoma with double/triple-hit or NOS (HGBL), primary mediastinal B-cell lymphoma (PMBL). In order to better differentiate these entities, the WHO classification recommends using immunohistochemistry (IHC), FISH, targeted sequencing and gene expression profiles (GEP). However, these techniques are most often performed retrospectively in clinical trials, which is not representative of real life. In order to use these information to improve the current standard of treatment with targeted therapies adapted to lymphoma biology, we have set up a national network on behalf of the LYSA called RT3 (for Real-time tailored therapy) to demonstrate that we are able to comprehensively characterize aggressive B cell lymphomas in a clinically relevant timeline. Materials and methods Patients & gt; 18 years of age with untreated aggressive B-cell lymphoma were included prospectively from 21 LYSA centers. FFPE specimens were analyzed and classified according to WHO classification, benefiting from an IHC profile (Hans algorithm, BCL2, MYC), FISH analysis (BCL6, BCL2, MYC break apart and MYC-IGH/IGL/IGK fusion probes), targeted NGS analysis and a targeted GEP using RT-MLPA (Bobée et al. J Mol diagn 2017). A first part of the study phase was carried out in an oligocentric manner with only 2 referral platforms for pathological analysis and molecular characterization. The second phase was the implementation of 7 RT3 platforms spread over France. The main objective was to evaluate the capacity of the network to provide an exhaustive histopathological and molecular characterization 4 days before theoretical R-CHOP21 C3 administration (within 38 days after D1 cycle 1). Results The oligocentric cohort 1 prospectively included 72 patients in 6 months: 19 had insufficient material or inappropriate diagnosis to be qualified and 53 benefited from the complete analysis on referral platforms. A complete characterization 4 days before RCHOP-C3 was provided to the clinician in 47 cases (88.7%), allowing to further implement the network with 7 platforms and 23 clinical investigation centers. 183 patients were included in the second phase in 9 months, 35 were excluded for inadequate diagnosis/material. On this population, 143 (96.6%) complete patient-reports were provided with a median time of 32 days (1-50). Finally, 201 cases were retained in the Full Analysis Set for which tumor samples fulfilled all prerequisites and diagnosis of DLBCL was confirmed by RT3 platforms. The clinical characteristics were as follows: median age of 61 y (20-92), with 45.2% of pts with aaIPI 2-3and 67.1% with Ann Arbor stage III-IV; 1L treatment consisted mainly of RCHOP (RCHOP14/21 = 136, 72.3%). 7% of patients were treated with experimental drugs. 76% presented with extranodal involvement. After pathological review, 139 (69%) patients were classified as DLBCL-NOS (41% GCB; 58% nGCB), 11 (5%) as HGBL-NOS, 8 (4%) as HGBL-DH and 18 (9%) as PMBL, 3 (1%) as EBV+ DLBCL-NOS, 9 (4%) as FL-3B, 7 (3%) transformed DLBCL, 2 (1%) plasmablastic, 1 (0.5%) unclassified, 1 (0.5%) DLBCL with IRF4 rearrangement. By immunohistochemistry, 22 cases were CD5+, 74% were BCL2+, and 53% MYC+ and 49% as double expressors. BCL2/18q21, BCL6/3q27 and MYC/8q24 breaks were observed in 14% (29/201), 25% (50/201) and 12% (25/201) of the cases respectively. MYC partner gene was available in 10/29 cases (5 MYC-IG, 5 non-IG). At the molecular level, PIM1 was the most frequently mutated gene in the entire cohort (36%). In the ABC subtype, MYD88 was mutated in 48% of cases. In the GCB cohort, SOCS1 was the most frequently mutated gene (30%). In the HGBL cohort, MYC was the most mutated gene (43%). Conclusion This study demonstrates that this RT3 LYSA network allowed a real time pathological and molecular characterization of aggressive B-cell lymphomas according to the WHO recommendations. The RT3 network provides relevant informations to the clinician before R-CHOP21 C3, that might contribute to modify the treatment eventually adding targeted therapies or tailor a second line treatment. This network should be used as a basis for future clinical trials. Inter platforms reproducibility and prognostic relevance of the RT3 project will be presented. Disclosures Haioun: Gilead: Honoraria; Janssen: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Miltenyi: Honoraria; Servier: Honoraria; Roche: Honoraria; Celgene: Honoraria. Le Gouill:Roche Genentech, Janssen-Cilag and Abbvie, Celgene, Jazz pharmaceutical, Gilead-kite, Loxo, Daiichi-Sankyo and Servier: Honoraria; Loxo Oncology at Lilly: Consultancy. Ribrag:arGEN-X-BVBA: Research Funding; BAY1000394 studies on MCL: Patents & Royalties; Institut Gustave Roussy: Current Employment; argenX: Current equity holder in publicly-traded company, Research Funding; Epizyme: Consultancy, Current equity holder in publicly-traded company, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Infinity: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses; Nanostring: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Honoraria; Pharmamar: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AZD: Honoraria, Other; Eisai: Honoraria; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Immune Design: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees. Salles:Takeda: Honoraria; Karyopharm: Honoraria; Genmab: Honoraria, Other; Debiopharm: Consultancy, Honoraria, Other: consultancy or advisory role; Autolos: Other: consultancy or advisory role; Abbvie: Other: consultancy or advisory role; Roche: Honoraria, Other: consultancy or advisory role; Novartis: Honoraria, Other: consultancy or advisory role; MorphoSys: Honoraria, Other: consultancy or advisory role; Janssen: Honoraria, Other: consultancy or advisory role; Epizyme: Honoraria, Other: consultancy or advisory role; Kite, a Gilead Company: Honoraria, Other: consultancy or advisory role ; BMS/Celgene: Honoraria, Other: consultancy or advisory role. Sujobert:Sunesis: Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead/Kyte: Membership on an entity's Board of Directors or advisory committees. Bouabdallah:Gilead Sciences: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Roche: Consultancy, Honoraria. Sibon:takeda france: Consultancy.

Abstract: Abstract 1607 Background: Lymphoid malignancies derived from T and NK cells (PTCLs) constitute a heterogeneous group of uncommon disease entities, with marked geographic variation in their distribution. The most recent data from the International T-cell Lymphoma Project based on a retrospective analysis of PTCLs diagnosed between 1990 and 2002 (Blood. 2011;117(25): 6756–67) indicate that PTCL, not otherwise specified (PTCL,NOS) represents the most common PTCL worldwide (25,9%), followed by angioimmunoblastic T-cell lymphoma (AITL) (18,5%). Over the last few years, a better characterization of the cellular origin and pathophysiology of PTCLs has led to the development of new diagnostic markers. Aim of the study: To characterize the epidemiology of mature T/NK-cell malignancies in Western Europe (France and bordering countries) and to examine whether the availability of new tools/antibodies and changing concepts over the past years might have translated into an apparent change in the relative distribution of PTCL entities. Materials and methods: The histopathological diagnosis of PTCL entities according to the 2008 WHO classification were collected through two independent sets of PTCLs in France and bordering countries. Results: Over the past two years (2010–2011), 933 newly diagnosed non-cutaneous PTCLs were reviewed in reference centers through the prospective network “Lymphopath” aiming to review any newly diagnosed lymphoma in France. According to the 2008 WHO classification, the 933 PTCLs comprised: 314 AITL (33,6%), 239 PTCL,NOS (25,6%), 78 ALK-positive anaplastic large cell lymphoma (ALCL) (8,3%), 72 ALK-negative ALCL (7,7%), 59 extranodal NK/T-cell lymphomas (ENKTL 6%), 33 enteropathy-associated T-cell lymphoma (4%), 32 HTLV1+ adult T leukemia/lymphoma (3%), 7 hepatosplenic T-cell lymphoma (1%) and 99 cases of other entities or unclassifiable (11%). A high prevalence of AITL was also found in an independent set of PTCLs retrospectively collected in the framework of a multicentric T-cell lymphoma research consortium “Tenomic” where non-cutaneous PTCL with frozen material available (n=623) from 1999 to 2009 in France and Belgium were retrieved and collegially reviewed for consensus diagnosis. In this collection, AITL (n=288, 46%) also outnumbered PTCL, NOS (n=215, 35%). Of the 196 AITL cases extensively investigated for CD10, TFH markers (PD1, CXCL13), CD21/CD23 follicular dendritic cells (FDC) and EBV, the initial diagnosis was recorded in 178 cases as: AITL in 155 cases (87%), PTCL, NOS in 21 cases (12%), and intermediate between PTCL,NOS and AITL (PTCL,NOS/AITL) in 2 cases, indicating the impact of additional stainings for the diagnosis of AITL. The 107 PTCL,NOS cases also extensively immunostained included 9 follicular variant of PTCL,NOS, 8 PTCL,NOS/AITL cases, 5 cases intermediate between PTCL,NOS and ALK-negative ALCL (of which 2 had been diagnosed as such and two as PTCL,NOS), and 85 remaining cases truly unspecified. Of these, 60 had been initially diagnosed as PTCL,NOS; 2 as PTCL,NOS/AITL; 4 as ALK-negative ALCLs and 1 as ENKTL. Conclusion: This study based on two independent large cohorts of non-cutaneous PTCLs highlights AITL as the most prevalent entity in Western Europe. It shows that extensive studies including investigation for CD10, TFH markers, FDC and EBV can at least partly contribute to the reclassification of some PTCL, NOS into the AITL spectrum category. Disclosures: No relevant conflicts of interest to declare.

Abstract: To prospectively assess the clinical impact of expert review of lymphoma diagnosis in France. Materials and Methods From January 2010 to December 2013, 42,145 samples from patients with newly diagnosed or suspected lymphomas were reviewed, according to the 2008 WHO classification, in real time by experts through the Lymphopath Network. Changes in diagnosis between referral and expert review were classified as major or minor according to their potential impact on patient care. Results The 42,145 reviewed samples comprised 36,920 newly diagnosed mature lymphomas, 321 precursor lymphoid neoplasms, 314 myeloid disorders, and 200 nonhematopoietic neoplasms, with 4,390 benign lesions. There were 4,352 cutaneous and 32,568 noncutaneous lymphomas. The most common mature noncutaneous lymphomas were diffuse large B-cell lymphomas (32.4%), follicular lymphomas (15.3%), classic Hodgkin lymphomas (13%), peripheral T-cell lymphomas (6.3%) of which angioimmunoblastic T-cell lymphomas (2.3%) were the most frequent, and mucosa-associated lymphoid tissue lymphomas (5.8%). A diagnostic change between referral and expert review occurred in 19.7% of patients, with an estimated impact on patient care for 17.4% of patients. This rate was significantly higher for patients sent with a provisional diagnosis seeking expert second opinion (37.8%) than for patients sent with a formal diagnosis (3.7%). The most frequent discrepancies were misclassifications in lymphoma subtype (41.3%), with 12.3% being misclassifications among small B-cell lymphoma entities. Fewer than 2% of changes were between benign and malignant lymphoid conditions. Minor changes (2.3%) mostly consisted of follicular lymphoma misgrading and diffuse large B-cell lymphoma subtype misclassification. Conclusion To our knowledge, this study provides the largest ever description of the distribution of lymphoma entities in a western country and highlights how expert review significantly contributes to a precise lymphoma diagnosis and optimal clinical management in a proportion of patients.