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Blood, 11 June 2009, Vol. 113, No. 24, pp. 6069-6076.
Prepublished online as a Blood First Edition Paper on April 20, 2009; DOI 10.1182/blood-2009-01-199679.
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Submitted January 15, 2009
Accepted April 10, 2009
Differential efficacy of bortezomib plus chemotherapy within molecular subtypes of diffuse large B cell lymphoma
Kieron Dunleavy, Stefania Pittaluga, Myron S. Czuczman, Sandeep Dave, George Wright, Nicole Grant, Margaret Shovlin, Elaine S. Jaffe, John E. Janik, Louis M. Staudt, and Wyndham H. Wilson*
Center for Cancer Research, National Cancer Institute, Bethesda, MD, United States
Roswell Park Cancer Institute, Buffalo, NY, United States
* Corresponding author; email: wilsonw{at}mail.nih.gov.
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- B) pathway, which can inhibit chemotherapy. We hypothesized that inhibition of NF-B might sensitize ABC but not GCB DLBCL to chemotherapy and improve outcome. As the proteasome inhibitor bortezomib can inhibit NF-B through blocking IB 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.
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