Gene Expression Signatures Predict Overall Survial in Diffuse Large B Cell Lymphoma Treated with Rituximab and Chop-Like Chemotherapy.
Authors: Lenz Georg , Wright George , Dave Sandeep , Kohlmann Alexander , Xiao Wenming , Powell John , Zhao Hong , Xu Weihong , Gascoyne Randy D. , Connors Joseph M. , May Lorraine , Weisenburger Dennis D. , Greiner Tim , Vose Julie , Armitage James O. , Iqbal Javeed , Bast Martin , Fu Kai , Campo Elias , Montserrat Emili , Lopez-Guillermo Armando , Jares Pedro , Martinez Antonio , Gibbs Betty , Rimsza Lisa M. , Fisher Richard I. , Braziel Rita M. , Tubbs Ray , Cook James , Pohlman Brad , Sweetenham John , Troen Gunhild , Smeland Erlend B. , Delabie Jan , Kvaloy Stein , Holte Harald , Jaffe Elaine S. , Wilson Wyndham H. , Grant Nicole , Hartmann Elena , Rosenwald Andreas , Ott German , Muller-Hermelink Hans-Konrad , Lister T. Andrew , Williams Mickey , Wieczorek Lothar , Chan Wing C. , Staudt Louis M. 
Published: October 2019

Abstract
Gene expression profiling has been used to distinguish two major subtypes of diffuse large B cell lymphoma (DLBCL), termed germinal center B cell-like (GCB) DLBCL and activated B cell-like (ABC) DLBCL. Following CHOP-like chemotherapy, GCB and ABC DLBCLs had distinct 5-year survival rates of ∼60% and ∼30%, respectively. Prognostic gene expression signatures in CHOP-treated DLBCL include the lymph node signature, which reflects a non-malignant host response, the MHC class II signature, both favorable when expressed and the proliferation signature which is adverse when expressed. The addition of rituximab to CHOP chemotherapy (R-CHOP) has significantly improved the outcome for DLBCL patients. We therefore investigated, if gene expression signatures that predicted survival among DLBCL patients treated with CHOP remained predictive for DLBCL patients treated with R-CHOP. Gene expression profiling was performed on 156 samples from previously untreated patients with DLBCL using Affymetrix U133 plus arrays. All patients received rituximab and CHOP-like chemotherapy. Samples were classified as GCB DLBCL, ABC DLBCL, or unclassified, and were assessed for expression of the lymph node and proliferation signatures. A Cox-proportional hazards model was used to determine the association of these gene expression features with overall survival (OS). 71 DLBCL samples were classified as GCB DLBCL, 63 as ABC DLBCL, and 22 were unclassified. The addition of rituximab improved OS for both GCB and ABC DLBCL compared to historical controls treated with CHOP-like chemotherapy alone. After a median follow-up of 2.3 years, GCB DLBCL had a more favorable OS than ABC DLBCL, with 3-year OS rates of 86% vs. 68% (p = 0.014). The 3-year OS rate of unclassified DLBCLs was 69%. The lymph node signature was associated with favorable OS (p = 0.023) and the proliferation signature with inferior OS (p = 0.009), whereas the MHC class II signature was not associated with OS (p = 0.44). In summary, addition of rituximab to CHOP-like chemotherapy improved OS for both GCB and ABC DLBCL but ABC DLBCL remained inferior to GCB DLBCL. The prognostic value of the lymph node and proliferation signatures were maintained in the context of R-CHOP therapy. An understanding of the biological attributes of DLBCL tumors that are reflected in these gene expression signatures remains critical to our ability to improve survival of these patients.