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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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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Chemotherapy
Lymphoma, Large B-Cell, Diffuse
Cells
Drug Therapy
B-Lymphocytes
NF-kappa B
Gene expression
Gene Expression Profiling
Proteasome Inhibitors
Bortezomib
Refractory materials
Doxorubicin
Tumors
Germinal Center
Chemical activation
Tissue
Degradation
Immunohistochemistry

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., ... 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

Differential efficacy of bortezomib plus chemotherapy within molecular subtypes of diffuse large B-cell lymphoma. / Dunleavy, Kieron; Pittaluga, Stefania; Czuczman, Myron S.; Dave, Sandeep S.; Wright, George; Grant, Nicole; Shovlin, Margaret; Jaffe, Elaine S.; Janik, John Edward; Staudt, Louis M.; Wilson, Wyndham H.

In: Blood, Vol. 113, No. 24, 19.11.2009, p. 6069-6076.

Research output: Contribution to journalArticle

Dunleavy, K, Pittaluga, S, Czuczman, MS, Dave, SS, Wright, G, Grant, N, Shovlin, M, Jaffe, ES, Janik, JE, Staudt, LM & Wilson, WH 2009, 'Differential efficacy of bortezomib plus chemotherapy within molecular subtypes of diffuse large B-cell lymphoma', Blood, vol. 113, no. 24, pp. 6069-6076. https://doi.org/10.1182/blood-2009-01-199679
Dunleavy, Kieron ; Pittaluga, Stefania ; Czuczman, Myron S. ; Dave, Sandeep S. ; Wright, George ; Grant, Nicole ; Shovlin, Margaret ; Jaffe, Elaine S. ; Janik, John Edward ; Staudt, Louis M. ; Wilson, Wyndham H. / Differential efficacy of bortezomib plus chemotherapy within molecular subtypes of diffuse large B-cell lymphoma. In: Blood. 2009 ; Vol. 113, No. 24. pp. 6069-6076.
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AU - Dave, Sandeep S.

AU - Wright, George

AU - Grant, Nicole

AU - Shovlin, Margaret

AU - Jaffe, Elaine S.

AU - Janik, John Edward

AU - Staudt, Louis M.

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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 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.

AB - 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.

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