Differential efficacy of bortezomib plus chemotherapy within molecular subtypes of diffuse large B cell lymphoma Export

@article{citeulike:4371197, abstract = {Gene expression profiling of diffuse large B-cell lymphoma (DLBCL) has revealed distinct molecular subtypes that include germinal center B cell-like (GCB) and activated B cell-like (ABC) DLBCL. ABC DLBCL has a worse survival following upfront chemotherapy and is characterized by constitutive activation of the anti-apoptotic nuclear factor-kappa B (NF-{kappa}B) pathway, which can inhibit chemotherapy. We hypothesized that inhibition of NF-{kappa}B might sensitize ABC but not GCB DLBCL to chemotherapy and improve outcome. As the proteasome inhibitor bortezomib can inhibit NF-{kappa}B through blocking I{kappa}B{alpha} degradation, we investigated bortezomib alone followed by bortezomib and doxorubicin-based chemotherapy in recurrent DLBCL. Tumor tissue was analyzed by gene expression profiling and/or immunohistochemistry to identify molecular DLBCL subtypes. As a control, we showed that relapsed/refractory ABC and GCB DLBCL have equally poor survivals following upfront chemotherapy. Bortezomib alone had no activity in DLBCL, but when combined with chemotherapy, it demonstrated a significantly higher response (83\% versus 13\%; P = 0.0004) and median overall survival (10.8 versus 3.4 months; P = 0.0026) in ABC compared to GCB DLBCL, respectively. These results suggest bortezomib enhances the activity of chemotherapy in ABC but not GCB DLBCL, and provide a rational therapeutic approach based on genetically distinct DLBCL subtypes. This trial is registered with http://www.clinicaltrials.gov under identifier: NCT00057902. 10.1182/blood-2009-01-199679}, author = {Dunleavy, Kieron and Pittaluga, Stefania and Czuczman, Myron S. and Dave, Sandeep and Wright, George and Grant, Nicole and Shovlin, Margaret and Jaffe, Elaine S. and Janik, John E. and Staudt, Louis M. and Wilson, Wyndham H.}, citeulike-article-id = {4371197}, citeulike-linkout-0 = {http://dx.doi.org/10.1182/blood-2009-01-199679}, day = {20}, doi = {10.1182/blood-2009-01-199679}, journal = {Blood}, keywords = {clinical\_trial, dlbcl, gene\_expression}, month = {April}, pages = {blood-2009-01-199679+}, posted-at = {2009-04-21 06:36:27}, priority = {2}, title = {Differential efficacy of bortezomib plus chemotherapy within molecular subtypes of diffuse large B cell lymphoma}, url = {http://dx.doi.org/10.1182/blood-2009-01-199679}, year = {2009} }

TY - JOUR ID - citeulike:4371197 L3 - citeulike-article-id:4371197 N2 - Gene expression profiling of diffuse large B-cell lymphoma (DLBCL) has revealed distinct molecular subtypes that include germinal center B cell-like (GCB) and activated B cell-like (ABC) DLBCL. ABC DLBCL has a worse survival following upfront chemotherapy and is characterized by constitutive activation of the anti-apoptotic nuclear factor-kappa B (NF-{kappa}B) pathway, which can inhibit chemotherapy. We hypothesized that inhibition of NF-{kappa}B might sensitize ABC but not GCB DLBCL to chemotherapy and improve outcome. As the proteasome inhibitor bortezomib can inhibit NF-{kappa}B through blocking I{kappa}B{alpha} degradation, we investigated bortezomib alone followed by bortezomib and doxorubicin-based chemotherapy in recurrent DLBCL. Tumor tissue was analyzed by gene expression profiling and/or immunohistochemistry to identify molecular DLBCL subtypes. As a control, we showed that relapsed/refractory ABC and GCB DLBCL have equally poor survivals following upfront chemotherapy. Bortezomib alone had no activity in DLBCL, but when combined with chemotherapy, it demonstrated a significantly higher response (83% versus 13%; P = 0.0004) and median overall survival (10.8 versus 3.4 months; P = 0.0026) in ABC compared to GCB DLBCL, respectively. These results suggest bortezomib enhances the activity of chemotherapy in ABC but not GCB DLBCL, and provide a rational therapeutic approach based on genetically distinct DLBCL subtypes. This trial is registered with http://www.clinicaltrials.gov under identifier: NCT00057902. 10.1182/blood-2009-01-199679 JF - Blood TI - Differential efficacy of bortezomib plus chemotherapy within molecular subtypes of diffuse large B cell lymphoma SP - blood-2009-01-199679 KW - clinical_trial KW - dlbcl KW - gene_expression AU - Dunleavy, Kieron AU - Pittaluga, Stefania AU - Czuczman, Myron AU - Dave, Sandeep AU - Wright, George AU - Grant, Nicole AU - Shovlin, Margaret AU - Jaffe, Elaine AU - Janik, John AU - Staudt, Louis AU - Wilson, Wyndham PY - 2009/04/20/ UR - http://dx.doi.org/10.1182/blood-2009-01-199679 ER -