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J Clin Oncol. 2017 Aug 1;35(22):2515-2526. doi: 10.1200/JCO.2016.70.3660. Epub 2017 May 19.

Clinical Impact of the Cell-of-Origin Classification and the MYC/ BCL2 Dual Expresser Status in Diffuse Large B-Cell Lymphoma Treated Within Prospective Clinical Trials of the German High-Grade Non-Hodgkin's Lymphoma Study Group.

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Annette M. Staiger, Heike Horn, and German Ott, Institute of Clinical Pathology, Robert-Bosch-Krankenhaus, Stuttgart; Annette M. Staiger and Heike Horn, Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart; Annette M. Staiger and Heike Horn, University of Tuebingen, Tuebingen; Marita Ziepert and Markus Löffler, Institute for Medical Informatics, Statistics and Epidemiology, Universität Leipzig, Leipzig; Thomas F.E. Barth and Peter Möller, Institute of Pathology, Universitätsklinikum Ulm, Ulm; Heinz-Wolfram Bernd and Alfred C. Feller, Haematopathologie Luebeck, Luebeck; Wolfram Klapper and Monika Szczepanowski, Institute of Pathology, Universitätsklinikum Schleswig-Holstein, Campus Kiel, Kiel; Monika Szczepanowski, Universitätsklinikum Schleswig-Holstein, Campus Kiel, Kiel; Michael Hummel and Dido Lenze, Institute of Pathology, Campus Benjamin Franklin, Charité Universitätsmedizin; Harald Stein, Pathodiagnostik Berlin, Berlin; Martin-Leo Hansmann and Sylvia Hartmann, Dr. Senckenberg Institute of Pathology, Goethe University Hospital, Frankfurt; Georg Lenz, Translational Oncology, Albert-Schweitzer-Campus 1, University Hospital Münster, and Cluster of Excellence EXC 1003, Cells in Motion, Münster; Lorenz Trümper, Georg-August Universität, Göttingen; Norbert Schmitz, Asklepios Klinik St Georg, Hamburg; Michael Pfreundschuh, Saarland University Medical School, Homburg/Saar; Andreas Rosenwald, Institute of Pathology, Universität Würzburg and Comprehensive Cancer Center Mainfranken, Würzburg, Germany; David W. Scott, Centre for Lymphoid Cancer, British Columbia Cancer Agency, Vancouver, British Columbia, Canada; and Sergio Cogliatti, Institute of Pathology, Kantonal Hospital St Gallen, St Gallen, Switzerland.


Purpose To explore the prognostic impact and interdependence of the cell-of-origin (COO) classification, dual expression (DE) of MYC and BCL2 proteins, and MYC, BCL2, and BCL6 translocations in two prospectively randomized clinical trials of patients with diffuse large B-cell lymphoma (DLBCL). Patients and Methods Overall, 452 formalin-fixed paraffin-embedded samples from two prospective, randomized DLBCL trials (RICOVER-60, prospective, randomized study for patients > 60 years, all IPI groups; and R-MegaCHOEP, prospective, randomized study for patients ≤ 60 years with age-adjusted IPI 2,3) of the German High-Grade Non-Hodgkin Lymphoma Study Group were analyzed with the Lymph2Cx assay for COO classification, with immunohistochemistry for MYC and BCL2, and with fluorescent in situ hybridization for MYC, BCL2, and BCL6 rearrangements. Results COO classification was successful in 414 of 452 samples. No significant differences with respect to COO (activated B-cell [ABC]-like DLBCL v germinal center B-cell [GCB]-like DLBCL) were observed in event-free survival, progression-free survival, and overall survival in patients treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in the RICOVER-60 trial. Also, no differences with respect to COO were observed in multivariable analyses adjusted for International Prognostic Index factors in event-free survival (hazard ratio [HR] of ABC-like disease v GCB-like disease, 1.0; 95% CI, 0.6 to 1.6; P = .93), progression-free survival (HR, 1.1; 95% CI, 0.6 to 1.8; P = .82), and overall survival (HR, 1.0; 95% CI, 0.6 to 1.8; P = .96). Similar results were observed in the R-MegaCHOEP trial. In patients treated with R-CHOP, DE status was associated with significantly inferior survival compared with nonDE within the GCB, but not within the ABC subgroup. DE status was associated with significantly inferior outcome compared with patients with ABC-like DLBCL without DE (5-year PFS rate, 39% [95% CI,19% to 59%] v 68% [95% CI, 52% to 85%]; P = .03) and compared with patients with GCB-like DLBCL without DE. When data from patients with nonDE were analyzed separately, the outcome of patients in the ABC subgroup was inferior to that of patients in the GCB subgroup (5-year PFS rate, 68% [95% CI, 52% to 85%] v 85% [95% CI, 74% to 96%]; P = .04). Conclusion COO profiling in two prospective randomized DLBCL trials failed to identify prognostic subgroups, whereas dual expression of MYC and BCL2 was predictive of poor survival. Evaluation of prognostic or predictive biomarkers in the management of DLBCL, such as the COO, within prospective clinical trials will be important in the future.

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