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

Publication ,  Journal Article
Dunleavy, K; Pittaluga, S; Czuczman, MS; Dave, SS; Wright, G; Grant, N; Shovlin, M; Jaffe, ES; Janik, JE; Staudt, LM; Wilson, WH
Published in: Blood
June 11, 2009

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-kappaB) pathway, which can inhibit chemotherapy. We hypothesized that inhibition of NF-kappaB might sensitize ABC but not GCB DLBCL to chemotherapy and improve outcome. As the proteasome inhibitor bortezomib can inhibit NF-kappaB through blocking IkappaBalpha 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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Published In

Blood

DOI

EISSN

1528-0020

Publication Date

June 11, 2009

Volume

113

Issue

24

Start / End Page

6069 / 6076

Location

United States

Related Subject Headings

  • Young Adult
  • Treatment Outcome
  • Survival Rate
  • Pyrazines
  • Prognosis
  • Oligonucleotide Array Sequence Analysis
  • Neoplasm Recurrence, Local
  • Middle Aged
  • Male
  • Lymphoma, Large B-Cell, Diffuse
 

Citation

APA
Chicago
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MLA
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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
Dunleavy, Kieron, Stefania Pittaluga, Myron S. Czuczman, Sandeep S. Dave, George Wright, Nicole Grant, Margaret Shovlin, et al. “Differential efficacy of bortezomib plus chemotherapy within molecular subtypes of diffuse large B-cell lymphoma.Blood 113, no. 24 (June 11, 2009): 6069–76. https://doi.org/10.1182/blood-2009-01-199679.
Dunleavy K, Pittaluga S, Czuczman MS, Dave SS, Wright G, Grant N, et al. Differential efficacy of bortezomib plus chemotherapy within molecular subtypes of diffuse large B-cell lymphoma. Blood. 2009 Jun 11;113(24):6069–76.
Dunleavy, Kieron, et al. “Differential efficacy of bortezomib plus chemotherapy within molecular subtypes of diffuse large B-cell lymphoma.Blood, vol. 113, no. 24, June 2009, pp. 6069–76. Pubmed, doi:10.1182/blood-2009-01-199679.
Dunleavy K, Pittaluga S, Czuczman MS, Dave SS, Wright G, Grant N, Shovlin M, Jaffe ES, Janik JE, Staudt LM, Wilson WH. Differential efficacy of bortezomib plus chemotherapy within molecular subtypes of diffuse large B-cell lymphoma. Blood. 2009 Jun 11;113(24):6069–6076.

Published In

Blood

DOI

EISSN

1528-0020

Publication Date

June 11, 2009

Volume

113

Issue

24

Start / End Page

6069 / 6076

Location

United States

Related Subject Headings

  • Young Adult
  • Treatment Outcome
  • Survival Rate
  • Pyrazines
  • Prognosis
  • Oligonucleotide Array Sequence Analysis
  • Neoplasm Recurrence, Local
  • Middle Aged
  • Male
  • Lymphoma, Large B-Cell, Diffuse