Differential efficacy of bortezomib plus chemotherapy within molecular subtypes of diffuse large B-cell lymphoma.
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.
Dunleavy
Kieron
K
Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
Pittaluga
Stefania
S
Czuczman
Myron S
MS
Dave
Sandeep S
SS
Wright
George
G
Grant
Nicole
N
Shovlin
Margaret
M
Jaffe
Elaine S
ES
Janik
John E
JE
Staudt
Louis M
LM
Wilson
Wyndham H
WH
D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001402:B-Lymphocytes / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D001897:Boronic Acids / Q000008:administration & dosage; D000069286:Bortezomib; D004317:Doxorubicin / Q000008:administration & dosage; D005260:Female; D020869:Gene Expression Profiling; D018858:Germinal Center / Q000187:drug effects; D006801:Humans; D007124:Immunoenzyme Techniques; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D011719:Pyrazines / Q000008:administration & dosage; D015996:Survival Rate; D016896:Treatment Outcome; D055815:Young Adult
D014408:Biomarkers, Tumor; D001897:Boronic Acids; D011719:Pyrazines; D000069286:Bortezomib; D004317:Doxorubicin