Abstract: Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency–Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.

Abstract: Abstract 3238 A central dogma of human immunology is that proliferation of immature T-cells, and their development after release from the bone marrow, occurs in the central thymus. Recently, we identified several patients with aberrant polyclonal immature TdT+ precursor T-cell populations in extra-thymic lymphoid tissues. Here we demonstrate that immature precursor T-cell populations, with a cortical thymocyte phenotype, in fact, are expanded in extra-thymic lymphoid tissues of patients with Castleman disease (P 〈 0.001; n = 29), and angioimmunoblastic T-cell lymphoma (P = 〈 0.001; n =31) and increased in cases of Castleman disease in association with follicular dendritic cell sarcoma (Figures 1 and 2). Analysis of the proliferation marker, MiB-1, and the morphologic presence of mitoses reveal that these populations are undergoing extra-thymic proliferation and expansion, arguing against simple release from the central thymus and sequestration in these extra-thymic organs. Finally, these populations of immature T-cells are not associated with a particular anatomic site (i.e. neck or mediastinum). These findings challenge the dogma that proliferation of immature human T-cell populations occurs nearly exclusively in the central thymus and demonstrates that stimulation and significant proliferation of extra-thymic immature T-cells does, and can occur in a subset of patients. Disclosures: No relevant conflicts of interest to declare.

Abstract: INTRODUCTION Diffuse large B-cell lymphoma (DLBCL) represents several distinct clinical pathologic entities recently identified by molecular profiling. Treatment with anti-CD19 chimeric antigen receptor (CAR) T-cell therapies is now standard for many patients with relapsed/refractory (R/R) disease. Although antigen loss of CD19 represents a known cause of late relapses, the majority of CAR-T cell treatment failure occurs very soon after treatment at which time the impact of molecular subtype and other somatic mutations of DLBCL is undefined. We sought to determine impact of molecular features of DLBCL tumors on clinical outcomes in a cohort of patients with R/R disease who were treated with axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel) in order to provide insight into the mechanism of response or resistance to CAR-T cell therapy. METHODS We collected clinical data and formalin-fixed, paraffin embedded (FFPE) biopsy specimens from 121 DLBCL patients at the time of R/R disease after prior treatment with standard chemoimmunotherapy across 12 US academic medical centers who subsequently received commercial CAR-T cell treatment. Whole exome and transcriptome sequencing was performed on all cases to measure gene expression and gene copy number alterations. Genetic analysis was done on 96 patients with pre-treatment biopsies that passed sequencing quality filters, and expression analysis on 93 patients. Progression-free and overall survival (PFS, OS) measured from the day of CAR-T cell infusion were estimated using the Kaplan-Meier method and compared with the log-rank test. RESULTS Baseline demographics and treatment details of the patient population are shown in the Table (Panel A). Best overall response was CR in 43% of patients and PR in 10% patients. PFS and OS were significantly different based on best response to treatment (P & lt;0,001 Figure, Panel B). At the time of R/R disease, the most commonly mutated genes were TP53 (25%), KMT2D (23%), CREBBP (23%), BCL2 (20%), BTG2 (12%), ARID1A (11%), CARD11 (11%), MYD88 (11%) and PIM1 (11%), (Panel C). Molecular subtyping based on the method of Wright, et al. revealed cases to be BN2 (N=16), A53 (N=13), EZB (N=14), MCD (N=13), N1 (N=4), ST2 (N=8) and unclassifiable (UC) in 28 cases. Cluster analysis as described by Chapuy et al. assigned cases to be C0 (N=6), C1 (N=18), C2 (N=14), C3 (N=27), C4 (N=17) and C5 (N=14). The impact of subgroups on of PFS are shown in Panels D and E. While not statistically significant different across all groups, there was a trend towards improved outcomes in C5/MCD as well as the C2/A53 subtypes and a trend towards inferior PFS in the C3/EZB subtypes. Inferior PFS was observed in patients with mutations in BCL2 (P=0.009) and MYC (P & lt;0.001), but not BTG2 (P=0.095), MYD88 (P=0.106), or CD79B (P=0.086). An unbiased model comprising mutations in MYC, BCL2, CDKN2A, and KLHL6 was strongly associated with a lack of response to CAR-T therapy and a poor prognosis (HR=3.55, P & lt;0.001, Panel F). Gene Set Enrichment Analysis (GSEA) identified a gene signature reflecting T-cell activation in the pre-treatment tumor biopsy as being associated with a higher likelihood of response to treatment (Panel G). CONCLUSIONS DLBCL patients whose tumors have molecular features that are predictive of inferior response to standard frontline treatment including the high-risk subgroups (C2/A53) and (C5/MCD) have favorable treatment outcomes with CAR-T cell therapy. In contrast, individual driver mutations including MYC and BCL2, CDKN2A, and KLHL6 are associated with inferior PFS with CAR-T cell therapy, while mutations in BTG2, MYD88, and CD79B are associated with a favorable PFS. In addition, gene expression analysis implicates a potential role for the microenvironment in modulating responses to CAR-T therapy. These findings suggest that predictive biomarkers for response to traditional chemoimmunotherapy and cellular immunotherapy are distinct. Our results provide insight into potentially targetable pathways for the development of rational treatment strategies that may augment response CAR-T cell therapy. Figure 1 Figure 1. Disclosures Hill: Celgene (BMS): Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Gentenech: Consultancy, Honoraria, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel Support, Research Funding; Beigene: Consultancy, Honoraria, Research Funding; AstraZenica: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria; Incyte/Morphysis: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding. McKinney: Novartis: Research Funding; Nordic Nanovector: Research Funding; Molecular Templates: Consultancy, Research Funding; Kite/Gilead: Honoraria, Speakers Bureau; Incyte: Research Funding; Genetech: Consultancy, Honoraria, Research Funding; Epizyme: Consultancy; Celgene: Consultancy, Research Funding; BTG: Consultancy; Beigene: Research Funding; ADC Therapeutics: Consultancy, Speakers Bureau; Pharmacyclics: Consultancy; Verastem: Consultancy. Neff: Spring Discovery: Consultancy, Ended employment in the past 24 months; EUSA Pharma: Speakers Bureau; Enzyvant: Consultancy. Reshef: BMS, Regeneron, TScan, Synthekine, Atara, Jasper, Bayer: Consultancy; ilead, BMS, Precision, Immatics, Atara, Takeda, Shire, Pharmacyclics, Incyte: Research Funding; Bayer: Consultancy; Gilead and Novartis: Honoraria. Oluwole: Janssen: Consultancy; Pfizer: Consultancy; Curio Science: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding. Ghosh: Incyte: Consultancy, Honoraria; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Speakers Bureau; TG Therapeutics: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Genmab: Consultancy, Honoraria; Epizyme: Honoraria, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; ADC Therapeutics: Consultancy, Honoraria; Adaptive Biotech: Consultancy, Honoraria; AbbVie: Honoraria, Speakers Bureau; Karyopharma: Consultancy, Honoraria; Genentech: Research Funding. Chen: Actinium Pharmaceuticals: Other: Principal Investigator, SIERRA Trial, Actinium. Hernandez-Ilizaliturri: AbbVie: Other: Advisory Boards; Incyte: Other: Advisory Boards; Celgene: Other: Advisory Boards; BMS: Other: Advisory Boards; Pharmacyclics: Other: Advisory Boards; Amgen: Other: Advisory Boards; Kite: Other: Advisory Boards; Gilead: Other: Advisory Boards; Epyzime: Other: Advisory Boards. Shah: Lily: Consultancy, Honoraria, Research Funding; Miltenyi Biotec: Consultancy, Honoraria, Research Funding; Kite: Consultancy; Epizyme: Consultancy; Legend: Consultancy; Incyte: Consultancy; Umoja: Consultancy. Stephens: Epizyme: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Innate Pharma: Membership on an entity's Board of Directors or advisory committees; Beigene: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Adaptive: Membership on an entity's Board of Directors or advisory committees; JUNO: Research Funding; Novartis: Research Funding; Abbvie: Consultancy; AstraZeneca: Consultancy; CSL Behring: Consultancy; Celgene: Consultancy; Mingsight: Research Funding; Arqule: Research Funding. Patel: Janssen: Consultancy; Kite Pharma: Consultancy, Speakers Bureau; TG Therapeutics: Consultancy, Speakers Bureau; MEI Pharma: Consultancy; Abbvie: Consultancy; Genentech: Consultancy; Bristol Myers Squibb: Consultancy, Speakers Bureau; BeiGene: Consultancy; Morphosys: Consultancy; Pharmacyclics: Consultancy; AstraZeneca: Consultancy, Research Funding, Speakers Bureau; ADC Therapeutics: Consultancy; Lilly: Consultancy. Pagel: Gilead: Consultancy; Actinium Pharmaceuticals: Consultancy; Kite, a Gilead Company: Consultancy; Incyte/MorphoSys: Consultancy; AstraZeneca: Consultancy; Pharmacyclics/AbbVie: Consultancy; Epizyme: Consultancy; BeiGene: Consultancy; MEI Pharma: Consultancy. Hsi: AbbVie Inc, Eli Lilly: Research Funding. Goy: Genentech/Hoffman la Roche: Research Funding; AbbVie/Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta: Consultancy, Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Medscape: Consultancy; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Physicians' Education Resource: Consultancy, Other: Meeting/travel support; Xcenda: Consultancy, Honoraria; Genomic Testing Cooperative: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Other: Leadership role; LLC(Targeted Oncology): Consultancy; Hoffman la Roche: Consultancy; Vincerx: Honoraria, Membership on an entity's Board of Directors or advisory committees; Rosewell Park: Consultancy; Infinity/Verastem: Research Funding; MorphoSys: Honoraria, Other; Elsevier PracticeUpdate: Oncology: Consultancy, Honoraria; Xcenda: Consultancy; Bristol Meyers Squibb: Membership on an entity's Board of Directors or advisory committees; Vincerx pharma: Membership on an entity's Board of Directors or advisory committees; OncLive Peer Exchange: Honoraria; COTA (Cancer Outcome Tracking Analysis): Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Other: Leadership role; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Elsevier's Practice Update Oncology, Intellisphere, LLC(Targeted Oncology): Consultancy; Incyte: Honoraria; AbbVie/Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Michael J Hennessey Associates INC: Consultancy; Novartis: Consultancy, Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Karyopharm: Research Funding; Bristol Meyers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Phamacyclics: Research Funding; Constellation: Research Funding; Hackensack Meridian Health, Regional Cancer Care Associates/OMI: Current Employment. Ohgami: Stemline Therapeutics: Research Funding. Andreadis: CRISPR Therapeutics: Research Funding; GenMAB: Research Funding; Novartis: Research Funding; Roche: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Epizyme: Honoraria; Incyte: Honoraria; TG Therapeutics: Honoraria; Kite: Honoraria; Karyopharm: Honoraria; Atara: Consultancy, Honoraria; BMS: Research Funding; Merck: Research Funding. Thacker: Data Driven Bioscience: Current Employment. Rozzi: Data Driven Bioscience: Current Employment. Parker: Data Driven Bioscience: Current Employment. Happ: Data Driven Bioscience: Current Employment. Dave: Data Driven Bioscience: Current equity holder in publicly-traded company.

Abstract: We describe a 4-year-old boy who presented with progressive right periorbital edema and proptosis, with no systemic symptoms, who was found to have B-lymphoblastic leukemia (B-ALL). Magnetic resonance imaging (MRI) showed an enhancing mass centered in the right superolateral extraconal orbit. Orbital biopsy was consistent with B-ALL (CD99, TdT, LCA cocktail, CD34, CD79, CD10, PAX5, MIB1 positive; CD3, CD20 negative). A subsequent bone marrow aspirate confirmed a diagnosis of B-ALL with 80% blasts by flow cytometry and haploid cytogenetic findings. The patient improved clinically after chemotherapy. There are seven cases previously reported in the literature with hematogenous orbital masses at initial presentation of childhood ALL, but all with systemic symptoms or an abnormal complete blood count (CBC) at presentation. Our case is the first report in which an orbital mass preceded detectable systemic or laboratory evidence of ALL. This patient highlights the importance of differentiating benign causes of eyelid swelling from malignant ones.

Abstract: DLBCL can be detected in the blood by immunoglobulin high-throughput sequencing (Ig-HTS) with high specificity. Although DLBCL can be detected in leukocytes or plasma by Ig-HTS, plasma has greater sensitivity and more accurately reflects disease.

Abstract: Background: Molecular characterization of tumors currently relies in large part on invasive tissue biopsies, which can often be unavailable or limiting. For example, while biological heterogeneity between diffuse large B-cell lymphoma (DLBCL) patients can be stratified using classification of cell-of-origin (COO), current methods relying on tumor gene expression profiles (GEP) or multi-parametric immunohistochemistry (IHC) require adequate tissue, and can be hampered by modest accuracy and reproducibility. Circulating tumor DNA (ctDNA) is an emerging noninvasive biomarker for tumor detection with potential for DLBCL disease monitoring. Here, we evaluated the utility ofctDNA for COO classification of patients with DLBCL. Methods: We previously built and trained a novel DLBCL COO Naive Bayesian classifier, using somatic alterations in 32 genes and associated with COO subtypes that were previously classified by Affymetrix mRNA GEP of frozen tumors (n=142 Training; Scherer et al., ASH Annual Meeting 2015 / ASCO Annual Meeting 2016). Here, we applied CAPP-Seq, a capture-based targeted high-throughput sequencing (HTS) method (Newman et al., Nat Med 2014), to genetically profile and classify 146 DLBCL patients in independent cohorts. We employed a test/validation framework (n=76 Test, n=70 Validation) to classify patients diagnosed and treated at Stanford University, MD Anderson Cancer Center, or at the University of Eastern Piedmont, Italy. We compared COO classification from pre-treatment plasma samples (n=119), tumor biopsy tissues (n=82, of which 71% were from FFPE), or both (n=41) against the current clinical standard immunohistochemistry method (Hans algorithm, n=117). Kaplan Meier analyses and Cox proportional-hazard models were used to assess clinical utility of biopsy-free and tumor genotyping for prediction of clinical outcomes from time of DLBCL diagnosis. Results: Genotyping of both test and validation cohorts using either tumor or plasma samples allowed COO classification in 100% of patients (GCB=77 / non-GCB=69) with 77% overall concordance to blinded and centralized Hans IHC classification. As expected, histologically transformed (tFL/DLBCL) and double-hit DLBCLs (MYC and BCL2/BCL6 translocated) were strongly biased toward GCB DNA subtype (26/29, 90%), while primary central nervous system lymphomas were almost invariably classified as ABC/non-GCB by ctDNA (6/7, 87%). The concordance between DNA-based COO classification from tumor vs. plasma was 88% (36/41). In the test cohort, COO classification by genotyping from either tissue or plasma was significantly associated with PFS (P=0.003 and 0.02, respectively, Cox proportional-hazard), while classification by Hans criteria failed to show a significant survival difference (P=0.25). The superior outcome of patients with GCB DNA COO subtype was validated when extended to the full cohort (P=0.02, Cox proportional-hazard; P=0.03, log-rank (Figure 1)). We observed a similar, albeit not significant, trend for overall survival. Conclusions: DLBCL COO subtypes can be accurately classified using somatic alterations detectable as circulating tumor DNA. We envision that this approach might help overcome some of the limitations of mRNA GEP and protein/IHC-based methods, including the requirement for invasive biopsies, tissue availability, and suboptimal assay performance. Furthermore, this strategy could support future clinical trials in helping to identify poor-risk groups at diagnosis, to guide future therapy selection, and to improve treatment decisions for patients with DLBCL. Figure 1. Figure 1. Disclosures Newman: Roche: Consultancy. Lovejoy:Roche: Employment. Levy:Kite Pharma: Consultancy; Five Prime Therapeutics: Consultancy; Innate Pharma: Consultancy; Beigene: Consultancy; Corvus: Consultancy; Dynavax: Research Funding; Pharmacyclics: Research Funding. Gaidano:Janssen: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Gilead: Consultancy, Honoraria, Speakers Bureau; Morphosys: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Speakers Bureau. Diehn:Roche: Consultancy; Novartis: Consultancy; Quanticel Pharmaceuticals: Consultancy; Varian Medical Systems: Research Funding. Alizadeh:Gilead: Consultancy; Celgene: Consultancy; Genentech: Consultancy; Roche: Consultancy.