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

Kieron Dunleavy, Stefania Pittaluga, Myron S. Czuczman, Sandeep S. Dave, George Wright, Nicole Grant, Margaret Shovlin, Elaine S. Jaffe, John Edward Janik, Louis M. Staudt, Wyndham H. Wilson

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382 Scopus citations

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 after upfront chemotherapy and is characterized by constitutive activation of the antiapoptotic nuclear factor-kappa B (NF-κB) pathway, which can inhibit chemotherapy. We hypothesized that inhibition of NF-κB might sensitize ABC but not GCB DLBCL to chemotherapy and improve outcome. As the proteasome inhibitor bortezomib can inhibit NF-κB through blocking IκBα 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 after upfront chemotherapy. Bortezomib alone had no activity in DLBCL, but when combined with chemotherapy, it demonstrated a significantly higher response (83% vs 13%; P < .001) and median overall survival (10.8 vs 3.4 months; P = .003) in ABC compared with 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.

Original languageEnglish (US)
Pages (from-to)6069-6076
Number of pages8
JournalBlood
Volume113
Issue number24
DOIs
StatePublished - Nov 19 2009

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ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Dunleavy, K., Pittaluga, S., Czuczman, M. S., Dave, S. S., Wright, G., Grant, N., Shovlin, M., Jaffe, E. S., Janik, J. E., Staudt, L. M., & Wilson, W. H. (2009). Differential efficacy of bortezomib plus chemotherapy within molecular subtypes of diffuse large B-cell lymphoma. Blood, 113(24), 6069-6076. https://doi.org/10.1182/blood-2009-01-199679