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8th International Symposium on Hodgkin Lymphoma Cologne, Germany, October 23-26, 2010 ABSTRACT BOOK The origin of a name that reflects Europe’s cultural roots. Ancient Greek aÂma [haima] = blood a·matow [haimatos] = of blood lÒgow [logos]= reasoning Scientific Latin haematologicus (adjective) = related to blood Scientific Latin haematologica (adjective, plural and neuter, used as a noun) = hematological subjects Modern English the hematology journal 2009 JCR® Impact Factor = 6.416 Haematologica/The Hematology Journal, as the official organ of the European Hematology Association (EHA), aims not only to serve the scientific community, but also to promote European cultural identity. haematologica— Vol. 95 supplement n. 4 — October 2010 — p. S1-S52 supplement 4 - October 2010 Table of Contents 8th International Symposium on Hodgkin Lymphoma Cologne, Germany, October 23-26, 2010 Oral Communications and Posters session 1. C001-C003. Biology and Basic Research . S1 session 1. P004-P045. Biology and Basic Research . S1 session 2. C046-C048. Early Stages . S13 session 2. P049-P059. Early Stages. S13 session 3. C060-C063. Advanced Stages . S17 session 3. P064-P085. Advanced Stages . S18 session 4. C086-C091. Relapsed and Refractory . S25 session 4. P092-P110. Relapsed and Refractory . S27 session 5. C111-C113. Survivorship . S33 session 5. P114-P130. Survivorship . S34 session 6. C131-C132. Miscellaneous. S39 session 6. P133-P173. Miscellaneous. S40 Author index . a Haematologica/The Hematology Journal 2010; vol. 95; supplement 4 - October 2010 http://www.haematologica.org/ 8th International Symposium on Hodgkin Lymphoma Cologne, Germany - October 23-26, 2010 Inhibition of the anti-miR-17 seed family revealed that about 500 of the Biology and Basic Research HL miRNA-targetome were regulated by miRNAs of the miR-17 seed family. One of the cell cycle genes targeted by the miR-17 seed family C001 was CDKN1A coding for the p21 protein. We showed that CDKN1A is a valid target for this miRNA seed family although the effects on both FROM HIGH DIMENSIONAL DATA TO DISEASE MECHANISMS – NOTCH SIGNALLING protein and mRNA levels were limited. The G1-trap assay showed a IN HODGKIN LYMPHOMA clear increase in cells in the G1 phase upon inhibition of the miR-17 seed Köchert K, Kreher S, Aster JC, Kitagawa M, Jöhrens K, family in KM-H2 cells, whereas the effect was more limited in two oth- Anagnostopoulos I, Jundt F, Stein H, Janz M, Dörken B, Mathas S er HL cell lines. In conclusion, we confirmed expression of miRNAs in Max-Delbrück-Center for Molecular Medicine; Charité University Medical the HRS cells of HL tissue and identified 2,500 genes that were regulat- ed by miRNAs in HL. These genes were involved in deregulation of School; Brigham and Women’s Hospital, USA; Chiba University Graduate apoptosis, cell cycle, and NF-kB pathways. School of Medicine, Japan Inappropriate activation of the NOTCH signaling pathway, e.g. by C003 activating mutations, contributes to the pathogenesis of various human METHYLATION PROFILING OF MEDIASTINAL GRAY ZONE LYMPHOMA REVEALS A malignancies. Using a bottom up approach based on the acquisition of DISTINCTIVE SIGNATURE WITH ELEMENTS SHARED BY CLASSICAL HODGKIN’S high dimensional microarray data of classical Hodgkin lymphoma (cHL) LYMPHOMA AND PRIMARY MEDIASTINAL LARGE B-CELL LYMPHOMA and non-Hodgkin B cell lymphomas as control, we identify a cHL spe- Eberle FC,1 Rodriguez-Canales J,1 Wei L,2 Hanson JC,1 Killian JK,3 Sun cific NOTCH gene-expression signature dominated by the NOTCH H-W,4 Adams LG,3 Hewitt SM,1 Wilson WH,5 Pittaluga S,1 Meltzer PS,3 coactivator MAML2. We thus further analysed the role of MAML2 in the 5 1 1 context of aberrant NOTCH signaling in B cell lymphomas. Statistical Staudt LM, Emmert-Buck MR, Jaffe ES analyses of the acquired microarray data led to the discovery of a cHL 1Laboratory of Pathology, 3Genetics Branch, and 5Metabolism Branch, National MAML2 dominated NOTCH gene-expression signature. This set the Cancer Institute, Center for Cancer Research; 2Laboratory of Immunology, basis for demonstrating that aberrant expression of the essential NOTCH National Eye Institute; 4Biodata Mining and Discovery Section, National Insti- co-activator Mastermind-like2 (MAML2) provides an alternative mech- tute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of anism to activate NOTCH signaling in human lymphoma cells. Using Health, Bethesda, Maryland, USA immunohistochemistry we detected high-level MAML2 expression in several B cell-derived lymphoma types, including cHL cells, whereas in Mediastinal gray zone lymphoma (MGZL) is a newly recognized normal B cells no staining for MAML2 was detectable. Inhibition of entity that demonstrates transitional morphologic and phenotypic fea- MAML protein activity by a dominant negative form of MAML or by tures between classical Hodgkin’s lymphoma, nodular sclerosis sub- shRNAs targeting MAML2 in cHL cells resulted in down-regulation of type (CHLNS) and primary mediastinal large B-cell lymphoma (PMBL). the NOTCH target genes HES7 and HEY1, which we identified as over- CHLNS and PMBL differ in morphology, immunophenotype, and ther- expressed in cHL cells, and in reduced proliferation. In order to target the apeutic consequences. MGZLs present a challenge both to the pathol- NOTCH transcriptional complex directly we developed short peptide ogist and clinician, as the criteria to distinguish MGZL from CHLNS and constructs that competitively inhibit NOTCH dependent transcription- PMBL are still imprecise, and the optimal treatment approach is as yet al activity as demonstrated by NOTCH reporter assays and EMSA analy- undetermined. Epigenetic changes have been implicated in the loss of ses. We conclude that NOTCH signalling is aberrantly activated in a cell the B-cell program in CHL, and might provide a basis for the autonomous manner in cHL. This is mediated by high-level expression immunophenotypic alterations seen in MGZL. Thus, we performed a of the essential NOTCH coactivator MAML2, a protein that is only large scale DNA methylation array of MGZL, CHLNS, PMBL as well as weakly expressed in B cells from healthy donors. This high-level expres- diffuse large B-cell lymphoma (DLBCL) to investigate the biological sion is also found in other B cell associated malignancies. Using short underpinnings of MGZL and how it corresponds to the two related peptide constructs we moreover show, that this approach is promising entities CHLNS and PMBL and the less related entity DLBCL. Microdis- in regard to the development of NOTCH pathway inhibitors that will section of tumor cells was performed to identify changes in the tumor also work in NOTCH associated malignancies that are resistant to -sec- cell population, and allow comparison with the background inflamma- retase inhibition. tory and stromal milieu. Principal component analysis (PCA) demon- strated that MGZLs have a distinct epigenetic profile intermediate C002 between CHLNS and PMBL but remarkably different from that of DLB- CL. Analysis of common hypo- and hypermethylated CpG targets in THE ROLE OF MIRNAS IN HODGKIN LYMPHOMA MGZL, CHLNS, PMBL and DLBCL was performed. MGZL showed van den Berg A, Ping Tan L, Gibcus J, Kluiver J, Slezack-Prochzka I, great overlap with CHLNS (49 common targets) and PMBL (50 common Halsema N, de Jong D, Kroesen B-J, Poppema S targets). In contrast, MGZL shared only two targets with DLBCL. Based Pathology & Medical Biology, University of Groningen, University Medical Cen- on the epigenetic profiles we were able to establish class prediction models that could distinguish between MGZL, CHLNS and PMLBL ter Groningen, Groningen, the Netherlands with a final combined prediction of 100%. Pyrosequencing for select- Several studies indicate that HRS cells display a characteristic miRNA ed CpG sites from different genes confirmed the high accuracy of the expression profile. Based on cell line profiling we demonstrated a high methylation results. MGZLs share several clinical and pathological fea- expression of miR-15, miR-16, miR-29, miR-155 and miR-17~92. Using tures with CHLNS and PMBL. Our findings further underscore the close miRNA in situ hybridization (ISH) we confirmed expression of miR-17- biological relationship between MGZL, CHLNS and PMBL, and ready 5p, miR-24, miR-106a, miR-146a, miR-155, miR-181b and miR-210 in distinction from DLBCL. However, MGZL has a distinct epigenetic the HRS cells in HL tissue. In contrast to the HL cell lines, expression of identity that shares elements of both parent disorders. As the first bio- miR-21 was low in HRS cells of HL tissue, whereas expression level of logical study of MGZL, our results provide not only novel insights into miR-150 was very high. To investigate the role of miRNAs in the patho- MGZL pathogenesis, but also reveal potentially useful targets for MGZL genesis of HL we identified miRNA target genes in two HL cell lines by diagnosis and future therapies. immunoprecipitation (IP) of the Ago2 containing RISC and the subse- quent microarray analysis of the co-immunoprecipitated target genes. P004 The miRNA-targetome of HL comprises about 2,500 genes. Gene ontol- ABSENCE OF HLA-DM PREVENTS HLA CLASS II ANTIGEN PRESENTATION IN A SUBSET OF ogy (GO) analysis for the total miRNA-targetome of HL showed a sig- HODGKIN LYMPHOMA PATIENTS nificant enrichment of genes involved in the regulation of apoptosis, immune system development, the NF-kB cascade and cell cycle. The Diepstra A, Xu C, Visser L, Kluiver J, Plattel W, Poppema S, van den miRNA-targetome of HL contained several genes known to be mutated Berg A in HRS cells, including A20, FAS, NFKB1A, NFKB1E, PERP and SOCS1. Department of Pathology and Medical Biology, University Medical Center Only two (i.e. MYBL1 and CXCR4) of the loss-of-B-cell-phenotype sig- Groningen, University of Groningen, the Netherlands nature genes were enriched in the IP-fraction suggesting that miRNAs do not play an important role in the downregulation of these genes.
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    19 July 2012 EMA/702390/2012 Committee for Medicinal Products for Human Use (CHMP) Assessment report Adcetris International non-proprietary name: brentuximab vedotin Procedure No. EMEA/H/C/002455 Note Assessment report as adopted by the CHMP with all information of a commercially confidential nature deleted. 7 Westferry Circus ● Canary Wharf ● London E14 4HB ● United Kingdom Telephone +44 (0)20 7418 8400 Facsimile +44 (0)20 7523 7455 E -mail [email protected] Website www.ema.europa.eu An agency of the European Union Product information Name of the medicinal product: Adcetris Applicant: Takeda Global Research and Development Centre (Europe) Ltd. 61 Aldwych London WC2B 4AE United Kingdom Active substance: brentuximab vedotin International Nonproprietary Name/Common Name: brentuximab vedotin Pharmaco-therapeutic group Monoclonal antibodies (ATC Code): (L01XC12) ADCETRIS is indicated for the treatment of adult Therapeutic indication(s): patients with relapsed or refractory CD30+ Hodgkin lymphoma (HL): 1. following autologous stem cell transplant (ASCT) or 2. following at least two prior therapies when ASCT or multi-agent chemotherpay are not a treatment option ADCETRIS is indicated for the treatment of adult patients with relapsed or refractory systemic anaplastic large cell lymphoma (sALCL). Pharmaceutical form(s): Powder for concentrate for solution for infusion Strength(s): 50 mg Route(s) of administration: Intravenous use Packaging: vial (glass) Package size(s): 1 vial Adcetris CHMP assessment report Page 2/102 Rev10.11 Table of contents 1. Background information on the procedure .............................................. 9 1.1. Submission of the dossier ...................................................................................... 9 1.2. Steps taken for the assessment of the product ....................................................... 10 2. Scientific discussion .............................................................................