title: BCL2 predicts survival in germinal center B-cell-like diffuse large B-cell lymphoma treated with CHOP-like therapy and rituximab.
abstract: OBJECTIVE
  We have previously shown the prognostic significance of BCL2 expression in the activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL) patients treated with cyclophosphamide-Adriamycin-vincristine-prednisone (CHOP) or CHOP-like therapy. However, after the inclusion of rituximab (R) in the CHOP regimen, several conflicting observations about the prognostic value of BCL2 expression have been reported.
  
  
  METHODS
  We evaluated the R-CHOP cohort of 221 DLBCL cases with gene expression profiling data. BCL2 protein (n = 169), mRNA (n = 221) expression, and t(14;18) (n = 144) were correlated with clinical outcome. The CHOP cohort (n = 181) was used for comparative analysis.
  
  
  RESULTS
  BCL2 protein expression has significant impact on overall survival (OS) and event-free survival (EFS) in DLBCL (OS, P = 0.009; EFS, P = 0.001) and GCB-DLBCL (OS, P = 0.03; EFS, P = 0.002) but not in ABC-DLBCL in the R-CHOP cohort. The survival differences for EFS in GCB-DLBCL were still observed in multivariate analysis. At the mRNA level, this correlation was observed in EFS in DLBCL (P = 0.006), but only a trend was observed in GCB-DLBCL (P = 0.09). The t(14;18) was detected in 34% of GCB-DLBCL but was not associated with significant differences in survival. Gene enrichment analysis identified significant enrichment of the DLBCL "stromal-1" signatures and hypoxia-inducible factor 1 (HIF1-α) signature in BCL2(-)GCB-DLBCL, whereas T(FH) cell signatures were enriched in BCL2(+)GCB-DLBCL.
  
  
  CONCLUSIONS
  The prognostic significance of BCL2 has changed after inclusion of rituximab in the treatment protocol and is observed in the GCB-DLBCL rather than the ABC-DLBCL. Although rituximab has benefited patients in both DLBCL subgroups, the BCL2(+)GCB-DLBCL seems to receive less benefit from this treatment and may require other novel therapeutic intervention.
authors.affiliation: Departments of Pathology and Microbiology and Hematology/Oncology and College of Public Health, Department of Biostatistics, University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors.forename: Javeed
authors.initials: J
authors.lastname: Iqbal
authors.forename: Paul N
authors.initials: PN
authors.lastname: Meyer
authors.forename: Lynette M
authors.initials: LM
authors.lastname: Smith
authors.forename: Nathalie A
authors.initials: NA
authors.lastname: Johnson
authors.forename: Julie M
authors.initials: JM
authors.lastname: Vose
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Greiner
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Connors
authors.forename: Louis M
authors.initials: LM
authors.lastname: Staudt
authors.forename: Lisa
authors.initials: L
authors.lastname: Rimsza
authors.forename: Elaine
authors.initials: E
authors.lastname: Jaffe
authors.forename: Andreas
authors.initials: A
authors.lastname: Rosenwald
authors.forename: German
authors.initials: G
authors.lastname: Ott
authors.forename: Jan
authors.initials: J
authors.lastname: Delabie
authors.forename: Elias
authors.initials: E
authors.lastname: Campo
authors.forename: Rita M
authors.initials: RM
authors.lastname: Braziel
authors.forename: James R
authors.initials: JR
authors.lastname: Cook
authors.forename: Raymond R
authors.initials: RR
authors.lastname: Tubbs
authors.forename: Randy D
authors.initials: RD
authors.lastname: Gascoyne
authors.forename: James O
authors.initials: JO
authors.lastname: Armitage
authors.forename: Dennis D
authors.initials: DD
authors.lastname: Weisenburger
authors.forename: Wing C
authors.initials: WC
authors.lastname: Chan
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D058846:Antibodies, Monoclonal, Murine-Derived / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology; D003520:Cyclophosphamide / Q000008:administration & dosage; D018572:Disease-Free Survival; D004317:Doxorubicin / Q000008:administration & dosage; D005260:Female; D020869:Gene Expression Profiling; D018858:Germinal Center / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D011239:Prednisolone / Q000008:administration & dosage; D011379:Prognosis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics* / Q000378:metabolism; D000069283:Rituximab; D014178:Translocation, Genetic; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D019253:Proto-Oncogene Proteins c-bcl-2; D000069283:Rituximab; D004317:Doxorubicin; D003520:Cyclophosphamide; D011239:Prednisolone