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PDF file - 57KB, Supplemental Table 1. Genes differently expressed in EBV+ DLBCL vs. EBV-negative DLBCL. A. Genes upregulated in EBV+ DLBCL; B. Genes downregulated in EBV+ DLBCL

PDF file - 3781KB, Supplemental Figure 1. Morphologic subtypes of EBV+ DLBCL. A, E, I, and M. The monomorphic subtype is composed of monotonous sheets of large transformed B-cells. B, F, J and N. The polymorphic subtype, canonical large B-cell neoplasm variant contains high density of large neoplastic cells and scattered cells with HRS-like features. C, G, K and O. The polymorphic subtype, Hodgkin-like variant shows lower density of neoplastic cells with HRS-like features. D, H, L and P. The polymorphic subtype, lymphoproliferative disorder-like variant has low density of neoplastic cells without Hodgkin lymphoma-like features. By immunohistochemistry, the monomorphic variant had a GCB phenotype, but all 3 polymorphic variants showed non-GCB phenotype.

Purpose: Epstein–Barr virus–positive (EBV+) diffuse large B-cell lymphoma (DLBCL) of the elderly is a variant of DLBCL with worse outcome that occurs most often in East-Asian countries and is uncommon in the Western hemisphere. We studied the largest cohort of EBV+ DLBCL, independent of age, treated with rituximab combined with CHOP (R-CHOP) in developed Western countries.Experimental design: A large cohort (n = 732) of patients with DLBCL treated with R-CHOP chemotherapy is included from the multicenter consortium. This study group has been studied for expression of different biomarkers by immunohistochemistry, genetic abnormalities by FISH and mutation analysis, genomic information by gene expression profiling (GEP), and gene set enrichment analysis (GSEA).Results: Twenty-eight patients (4.0%) were positive for EBV with a median age of 60.5 years. No clinical characteristics distinguished patients with EBV+ DLBCL from patients with EBV-negative (EBV−) DLBCL. Genetic aberrations were rarely seen. NF-κB p50, phosphorylated STAT-3, and CD30 were more commonly expressed in EBV+ DLBCLs (P < 0.05). Significant differences in survival were not observed in patients with EBV+ DLBCL versus EBV− DLBCL. However, CD30 expression combined with EBV conferred an inferior outcome. GEP showed a unique expression signature in EBV+ DLBCL. GSEA revealed enhanced activity of the NF-κB and JAK/STAT pathways independent of molecular subtype.Conclusions: The clinical characteristics of patients with EBV+ versus EBV− DLBCL are similar and EBV infection does not predict a worse outcome. EBV+ DLBCL, however, has a unique genetic signature. CD30 expression is more common in EBV+ DLBCL and, consistent CD30 and EBV is associated with an adverse outcome. Clin Cancer Res; 20(9); 2338–49. ©2014 AACR.

International audience; Intratumoral injection of G100, a toll-like receptor 4 (TLR4) agonist, was shown pre-clinically to stimulate anti-tumor immune responses and tumor regression. This open-label, multicenter, phase 1/2 trial evaluated the safety, tolerability, and preliminary efficacy of intratumoral G100 injections following localized low-dose radiation in patients with follicular lymphoma (ClinicalTrials.gov #NCT02501473). The study was comprised of a G100 dose escalation (5 or 10 mu g/dose, or 20 mu g/dose for large tumors); a randomized component comparing G100 to G100 plus pembrolizumab; and G100 20 mu g/dose expansion. Adverse events grade >= 3 were uncommon in patients treated with G100, and no unexpected toxicities were observed when combined with pembrolizumab. G100 20 mu g (n = 18) resulted in an overall response rate of 33.3% and abscopal tumor regression in 72.2% of patients. This early-phase study provides a foundation for combining an intratumoral TLR4 agonist with agents to produce immune-mediated responses in follicular lymphoma with limited added toxicity.

We developed an integrated population pharmacokinetic model to investigate loncastuximab tesirine pharmacokinetics (PK) and exposure-response relationships for relapsed/refractory B cell non-Hodgkin lymphoma, including diffuse large B cell lymphoma (DLBCL). The model, based on the recommended dosing schedule (150 µg/kg every 3 weeks [Q3W] for 2 cycles; 75 µg/kg Q3W thereafter) and drug concentrations in phase 1 and 2 studies (DLBCL [n = 284], non-DLBCL [n = 44]), was used to characterize loncastuximab tesirine PK and evaluate exposure covariates. Relationships between exposure (pyrrolobenzodiazepine-conjugated antibody [cAb] cycle 1 average concentration) and (1) efficacy (including overall response rate [ORR; primary endpoint] and overall survival [OS]) and (2) grade ≥ 2 treatment-emergent adverse events were explored. Statistical analyses included univariate and multivariate logistic regression, Kaplan-Meier analysis, and Cox proportional hazard regression. cAb and total Ab were best described by a two-compartment linear model with time-dependent clearance. The cAb steady-state half-life increased to 20.6 days by ~ 15 weeks. cAb exposure was lower for low albumin, mild/moderate hepatic impairment, non-DLBCL subtypes, and Eastern Cooperative Oncology Group scores 1. Significant positive associations were reported between exposure and ORR (p = 3.21E-6), OS (p = 0.0016), grade ≥ 2 increased gamma-glutamyltransferase, liver function test abnormalities, pain, and skin/nail reactions (p 0.05). Low albumin, bulky disease, and mild/moderate hepatic impairment had a significant negative effect on OS (p 0.01). Modeling supports the recommended loncastuximab tesirine dosing schedule. Although reduced exposure and efficacy were predicted for specific covariates (e.g., low albumin, mild/moderate hepatic impairment), dose increases are not recommended. Trial registration: NCT02669017 and NCT03589469.

Introduction: Cutaneous T-cell lymphomas (CTCLs) are a clinically heterogeneous array of clonal neoplasms of skin-homing CD4+ T-helper lymphocytes. Mycosis fungoides (MF) is the most common subtype of CTCL. Its clinical course varies significantly. Median survival times range from over fifteen years in its mildest form to under two in its most severe. Elucidation of MF pathogenesis and drug development are hampered by the dearth of CTCL laboratory models. Models examined in the literature are largely derived from leukemic CTCL, many of which have been shown to be confounded by HTLV-1 virus positivity. Additionally, recent models demonstrate phenotypic divergence even in the context of stable TCR clonality across passages. Here we molecularly characterize patient-derived xenografts (PDX) from six MF patients, compare their features to known CTCL characteristics and examine their stability over passages. Materials and methods: We established and analyzed ten PDX lines from six MF patients. Patient tumor cells were obtained from peripheral blood or lymph node fine needle aspirate and engrafted into NSG mice (P0). Subsequent passages (P1/2) were made by engrafting cells from P0/1 spleens in naive NSG mice. Peripheral blood mononuclear cells (PBMCs) from a subset of patients were collected for comparison to PDXs. Whole exome sequencing (WES) data was used for mutational and copy number analysis. Three PDX lines were also transcriptionally characterized using RNA sequencing. Results: WES analysis demonstrates the presence of canonical CTCL driver events in all samples. In all PDXs with patient PBMCs available for comparison, we find that subsets of these driver events were maintained through grafting. Strikingly, PDXs established from tumor cells collected at later points in clinical disease progression reflect tumor evolution. We identify genomic features that may show associations with successful engraftments. Through RNA-seq analysis, we observe that PDX transcriptional phenotypes harbored similarities to primary patient samples in the literature. We also demonstrate the transcriptional stability of one PDX into P1. Conclusion: Overall, we demonstrate that we have established PDXs that faithfully retain genomic and transcriptional features of CTCL across passages. Our results have implications not only for use of the models described here, but also for development of future xenografts by similar methods. We predict that employing molecularly stable CTCL PDXs in preclinical experiments could have significant benefits for the elucidation of CTCL pathophysiology and the development of novel CTCL treatments.

Purpose: Epstein–Barr virus–positive (EBV+) diffuse large B-cell lymphoma (DLBCL) of the elderly is a variant of DLBCL with worse outcome that occurs most often in East-Asian countries and is uncommon in the Western hemisphere. We studied the largest cohort of EBV+ DLBCL, independent of age, treated with rituximab combined with CHOP (R-CHOP) in developed Western countries. Experimental design: A large cohort (n = 732) of patients with DLBCL treated with R-CHOP chemotherapy is included from the multicenter consortium. This study group has been studied for expression of different biomarkers by immunohistochemistry, genetic abnormalities by FISH and mutation analysis, genomic information by gene expression profiling (GEP), and gene set enrichment analysis (GSEA). Results: Twenty-eight patients (4.0%) were positive for EBV with a median age of 60.5 years. No clinical characteristics distinguished patients with EBV+ DLBCL from patients with EBV-negative (EBV−) DLBCL. Genetic aberrations were rarely seen. NF-κB p50, phosphorylated STAT-3, and CD30 were more commonly expressed in EBV+ DLBCLs (P < 0.05). Significant differences in survival were not observed in patients with EBV+ DLBCL versus EBV− DLBCL. However, CD30 expression combined with EBV conferred an inferior outcome. GEP showed a unique expression signature in EBV+ DLBCL. GSEA revealed enhanced activity of the NF-κB and JAK/STAT pathways independent of molecular subtype. Conclusions: The clinical characteristics of patients with EBV+ versus EBV− DLBCL are similar and EBV infection does not predict a worse outcome. EBV+ DLBCL, however, has a unique genetic signature. CD30 expression is more common in EBV+ DLBCL and, consistent CD30 and EBV is associated with an adverse outcome. Clin Cancer Res; 20(9); 2338–49. ©2014 AACR.

*701 Mutational Profile and Prognostic Significance of TP53 in Diffuse Large B-cell Lymphoma Patients Treated with Rituximab-CHOP: A Report From an International DLBCL Rituximab-CHOP Consortium Program Study Zijun Y. Xu-Monette, Lin Wu, Carlo Visco, Yu Chuan Tai, Alexander Tzankov, Wei-min Liu, Santiago Montes-Moreno, Karen Dybkaer, April Chiu, Attilio Orazi, Youli Zu, Govind Bhagat, Kristy L. Richards, Eric D. Hsi, X. Frank Zhao, William W.L. Choi, Xiaoying Zhao, J. Han van Krieken, Qin Huang, Jooryung Huh, Weiyun Ai, Maurilio Ponzoni, Andres J.M. Ferreri, Fan Zhou, Brad S. Kahl, Jane N. Winter, Wei Xu, Jianyong Li, Ronald S. Go, Yong Li, Miguel A. Piris, Michael B. Moller, Roberto N. Miranda, Lynne V. Abruzzo, L. Jeffrey Medeiros, Ken H. Young Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Roche Molecular Systems, Inc., Pleasanton, CA, USA; San Bortolo Hospital, Vicenza, Italy; University Hospital, Basel, Switzerland; Hospital Universitario Marques de Valdecilla, Santander, Spain; Aalborg Hospital, Aarhus University Hospital, Aalborg, Denmark; Memorial Sloan-Kettering Cancer Center, New York, NY, USA; Weill Medical College of Cornell University, New York, NY, USA; The Methodist Hospital, Houston, TX, USA; Columbia University Medical Center and New York Presbyterian Hospital, New York, NY, USA; University of North Carolina School of Medicine, Chapel Hill, NC, USA; Cleveland Clinic, Cleveland, OH, USA; University of Maryland School of Medicine, Baltimore, MD, USA; University of Hong Kong Li Ka Shing Faculty of Medicine, Hong Kong, China; Zhejiang University School of Medicine, Second University Hospital, Hangzhou, China; Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands; City of Hope National Medical Center, Duarte, CA, USA; Asan Medical Center, Ulsan University College of Medicine, Seoul, Korea; University of California San Francisco School of Medicine, San Francisco, CA, USA; San Raffaele H. Scientific Institute, Milan, Italy; Southwest Washington Medical Center, Vancouver, WA, USA; University of Wisconsin Hospital and Clinic, Madison, WI, USA; Feinberg School of Medicine, Northwestern University, Chicago, IL, USA; The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China; Gundersen Lutheran Health System, La Crosse, WI, USA; University of Louisville, Louisville, KY; Odense University Hospital, Odense, Denmark

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