TY - JOUR A1 - Aukema, Sietse M. A1 - Kreuz, Markus A1 - Kohler, Christian W. A1 - Rosolowski, Maciej A1 - Hasenclever, Dirk A1 - Hummel, Michael A1 - Küppers, Ralf A1 - Lenze, Diddo A1 - Ott, German A1 - Pott, Christiane A1 - Richter, Julia A1 - Rosenwald, Andreas A1 - Szczepanowski, Monika A1 - Schwaenen, Carsten A1 - Stein, Harald A1 - Trautmann, Heiko A1 - Wessendorf, Swen A1 - Trümper, Lorenz A1 - Loeffler, Markus A1 - Spang, Rainer A1 - Kluin, Philip M. A1 - Klapper, Wolfram A1 - Siebert, Reiner T1 - Biological characterization of adult MYC-translocation-positive mature B-cell lymphomas other than molecular Burkitt lymphoma JF - Haematologica N2 - Chromosomal translocations affecting the MYC oncogene are the biological hallmark of Burkitt lymphomas but also occur in a subset of other mature B-cell lymphomas. If accompanied by a chromosomal break targeting the BCL2 and/or BCL6 oncogene these MYC translocation-positive (MYC+) lymphomas are called double-hit lymphomas, otherwise the term single-hit lymphomas is applied. In order to characterize the biological features of these MYC+ lymphomas other than Burkitt lymphoma we explored, after exclusion of molecular Burkitt lymphoma as defined by gene expression profiling, the molecular, pathological and clinical aspects of 80 MYC-translocation-positive lymphomas (31 single-hit, 46 double-hit and 3 MYC+-lymphomas with unknown BCL6 status). Comparison of single-hit and double-hit lymphomas revealed no difference in MYC partner (IG/non-IG), genomic complexity, MYC expression or gene expression profile. Double-hit lymphomas more frequently showed a germinal center B-cell-like gene expression profile and had higher IGH and MYC mutation frequencies. Gene expression profiling revealed 130 differentially expressed genes between BCL6(+)/MYC+ and BCL2(+)/MYC+ double-hit lymphomas. BCL2(+)/MYC+ double-hit lymphomas more frequently showed a germinal center B-like gene expression profile. Analysis of all lymphomas according to MYC partner (IG/non-IG) revealed no substantial differences. In this series of lymphomas, in which immunochemotherapy was administered in only a minority of cases, single-hit and double-hit lymphomas had a similar poor outcome in contrast to the outcome of molecular Burkitt lymphoma and lymphomas without the MYC break. Our data suggest that, after excluding molecular Burkitt lymphoma and pediatric cases, MYC+ lymphomas are biologically quite homogeneous with single-hit and double-hit lymphomas as well as IG-MYC and non-IG-MYC+ lymphomas sharing various molecular characteristics. KW - Rituximab plus KW - cyclophsophamide KW - c-myc KW - gene expression KW - genomic aberrations KW - follicular lymphoma KW - prognostic factor KW - poor prognosis KW - grade 3B KW - distinct Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-116882 SN - 1592-8721 VL - 99 IS - 4 ER - TY - JOUR A1 - Loeffler-Wirth, Henry A1 - Kreuz, Markus A1 - Hopp, Lydia A1 - Arakelyan, Arsen A1 - Haake, Andrea A1 - Cogliatti, Sergio B. A1 - Feller, Alfred C. A1 - Hansmann, Martin-Leo A1 - Lenze, Dido A1 - Möller, Peter A1 - Müller-Hermelink, Hans Konrad A1 - Fortenbacher, Erik A1 - Willscher, Edith A1 - Ott, German A1 - Rosenwald, Andreas A1 - Pott, Christiane A1 - Schwaenen, Carsten A1 - Trautmann, Heiko A1 - Wessendorf, Swen A1 - Stein, Harald A1 - Szczepanowski, Monika A1 - Trümper, Lorenz A1 - Hummel, Michael A1 - Klapper, Wolfram A1 - Siebert, Reiner A1 - Loeffler, Markus A1 - Binder, Hans T1 - A modular transcriptome map of mature B cell lymphomas JF - Genome Medicine N2 - Background Germinal center-derived B cell lymphomas are tumors of the lymphoid tissues representing one of the most heterogeneous malignancies. Here we characterize the variety of transcriptomic phenotypes of this disease based on 873 biopsy specimens collected in the German Cancer Aid MMML (Molecular Mechanisms in Malignant Lymphoma) consortium. They include diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL), Burkitt’s lymphoma, mixed FL/DLBCL lymphomas, primary mediastinal large B cell lymphoma, multiple myeloma, IRF4-rearranged large cell lymphoma, MYC-negative Burkitt-like lymphoma with chr. 11q aberration and mantle cell lymphoma. Methods We apply self-organizing map (SOM) machine learning to microarray-derived expression data to generate a holistic view on the transcriptome landscape of lymphomas, to describe the multidimensional nature of gene regulation and to pursue a modular view on co-expression. Expression data were complemented by pathological, genetic and clinical characteristics. Results We present a transcriptome map of B cell lymphomas that allows visual comparison between the SOM portraits of different lymphoma strata and individual cases. It decomposes into one dozen modules of co-expressed genes related to different functional categories, to genetic defects and to the pathogenesis of lymphomas. On a molecular level, this disease rather forms a continuum of expression states than clearly separated phenotypes. We introduced the concept of combinatorial pattern types (PATs) that stratifies the lymphomas into nine PAT groups and, on a coarser level, into five prominent cancer hallmark types with proliferation, inflammation and stroma signatures. Inflammation signatures in combination with healthy B cell and tonsil characteristics associate with better overall survival rates, while proliferation in combination with inflammation and plasma cell characteristics worsens it. A phenotypic similarity tree is presented that reveals possible progression paths along the transcriptional dimensions. Our analysis provided a novel look on the transition range between FL and DLBCL, on DLBCL with poor prognosis showing expression patterns resembling that of Burkitt’s lymphoma and particularly on ‘double-hit’ MYC and BCL2 transformed lymphomas. Conclusions The transcriptome map provides a tool that aggregates, refines and visualizes the data collected in the MMML study and interprets them in the light of previous knowledge to provide orientation and support in current and future studies on lymphomas and on other cancer entities. KW - tumor heterogeneity KW - B cell malignancies KW - gene regulation KW - molecular subtypes KW - machine learning Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-237262 VL - 11 ER - TY - JOUR A1 - Liebers, Nora A1 - Duell, Johannes A1 - Fitzgerald, Donnacha A1 - Kerkhoff, Andrea A1 - Noerenberg, Daniel A1 - Kaebisch, Eva A1 - Acker, Fabian A1 - Fuhrmann, Stephan A1 - Leng, Corinna A1 - Welslau, Manfred A1 - Chemnitz, Jens A1 - Middeke, Jan-Moritz A1 - Weber, Thomas A1 - Holtick, Udo A1 - Trappe, Ralf A1 - Pfannes, Roald A1 - Liersch, Ruediger A1 - Spoer, Christian A1 - Fuxius, Stefan A1 - Gebauer, Niklas A1 - Caillé, Léandra A1 - Geer, Thomas A1 - Koenecke, Christian A1 - Keller, Ulrich A1 - Claus, Rainer A1 - Mougiakakos, Dimitrios A1 - Mayer, Stephanie A1 - Huettmann, Andreas A1 - Pott, Christiane A1 - Trummer, Arne A1 - Wulf, Gerald A1 - Brunnberg, Uta A1 - Bullinger, Lars A1 - Hess, Georg A1 - Mueller-Tidow, Carsten A1 - Glass, Bertram A1 - Lenz, Georg A1 - Dreger, Peter A1 - Dietrich, Sascha T1 - Polatuzumab vedotin as a salvage and bridging treatment in relapsed or refractory large B-cell lymphomas JF - Blood Advances N2 - The antibody-drug conjugate polatuzumab vedotin (pola) has recently been approved in combination with bendamustine and rituximab (pola-BR) for patients with refractory or relapsed (r/r) large B-cell lymphoma (LBCL). To investigate the efficacy of pola-BR in a real-world setting, we retrospectively analyzed 105 patients with LBCL who were treated in 26 German centers under the national compassionate use program. Fifty-four patients received pola as a salvage treatment and 51 patients were treated with pola with the intention to bridge to chimeric antigen receptor (CAR) T-cell therapy (n = 41) or allogeneic hematopoietic cell transplantation (n = 10). Notably, patients in the salvage and bridging cohort had received a median of 3 prior treatment lines. In the salvage cohort, the best overall response rate was 48.1%. The 6-month progression-free survival and overall survival (OS) was 27.7% and 49.6%, respectively. In the bridging cohort, 51.2% of patients could be successfully bridged with pola to the intended CAR T-cell therapy. The combination of pola bridging and successful CAR T-cell therapy resulted in a 6-month OS of 77.9% calculated from pola initiation. Pola vedotin-rituximab without a chemotherapy backbone demonstrated encouraging overall response rates up to 40%, highlighting both an appropriate alternative for patients unsuitable for chemotherapy and a new treatment option for bridging before leukapheresis in patients intended for CAR T-cell therapy. Furthermore, 7 of 12 patients with previous failure of CAR T-cell therapy responded to a pola-containing regimen. These findings suggest that pola may serve as effective salvage and bridging treatment of r/r LBCL patients. Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-369173 VL - 5 ER -