BCL2 predicts survival in germinal center B-cell-like diffuse large B-cell lymphoma treated with CHOP-like therapy and rituximab

Javeed Iqbal, Paul N. Meyer, Lynette M Smith, Nathalie A. Johnson, Julie Marie Vose, Timothy Charles Greiner, Joseph M. Connors, Louis M. Staudt, Lisa Rimsza, Elaine Jaffe, Andreas Rosenwald, German Ott, Jan Delabie, Elias Campo, Rita M. Braziel, James R. Cook, Raymond R. Tubbs, Randy D. Gascoyne, James Olen Armitage, Dennis D. WeisenburgerWing C. Chan

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Abstract

Purpose: 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. Experimental Design: 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. Conclusion: 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.

Original languageEnglish (US)
Pages (from-to)7785-7795
Number of pages11
JournalClinical Cancer Research
Volume17
Issue number24
DOIs
StatePublished - Dec 15 2011

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Germinal Center
Lymphoma, Large B-Cell, Diffuse
Vincristine
Prednisone
Doxorubicin
Cyclophosphamide
B-Lymphocytes
Disease-Free Survival
Proto-Oncogene Proteins c-bcl-2
Survival
Therapeutics
Hypoxia-Inducible Factor 1
Messenger RNA
Gene Expression Profiling
Clinical Protocols
Rituximab
Research Design
Multivariate Analysis
Genes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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BCL2 predicts survival in germinal center B-cell-like diffuse large B-cell lymphoma treated with CHOP-like therapy and rituximab. / Iqbal, Javeed; Meyer, Paul N.; Smith, Lynette M; Johnson, Nathalie A.; Vose, Julie Marie; Greiner, Timothy Charles; Connors, Joseph M.; Staudt, Louis M.; Rimsza, Lisa; Jaffe, Elaine; Rosenwald, Andreas; Ott, German; Delabie, Jan; Campo, Elias; Braziel, Rita M.; Cook, James R.; Tubbs, Raymond R.; Gascoyne, Randy D.; Armitage, James Olen; Weisenburger, Dennis D.; Chan, Wing C.

In: Clinical Cancer Research, Vol. 17, No. 24, 15.12.2011, p. 7785-7795.

Research output: Contribution to journalArticle

Iqbal, J, Meyer, PN, Smith, LM, Johnson, NA, Vose, JM, Greiner, TC, Connors, JM, Staudt, LM, Rimsza, L, Jaffe, E, Rosenwald, A, Ott, G, Delabie, J, Campo, E, Braziel, RM, Cook, JR, Tubbs, RR, Gascoyne, RD, Armitage, JO, Weisenburger, DD & Chan, WC 2011, 'BCL2 predicts survival in germinal center B-cell-like diffuse large B-cell lymphoma treated with CHOP-like therapy and rituximab', Clinical Cancer Research, vol. 17, no. 24, pp. 7785-7795. https://doi.org/10.1158/1078-0432.CCR-11-0267
Iqbal, Javeed ; Meyer, Paul N. ; Smith, Lynette M ; Johnson, Nathalie A. ; Vose, Julie Marie ; Greiner, Timothy Charles ; Connors, Joseph M. ; Staudt, Louis M. ; Rimsza, Lisa ; Jaffe, Elaine ; Rosenwald, Andreas ; Ott, German ; Delabie, Jan ; Campo, Elias ; Braziel, Rita M. ; Cook, James R. ; Tubbs, Raymond R. ; Gascoyne, Randy D. ; Armitage, James Olen ; Weisenburger, Dennis D. ; Chan, Wing C. / BCL2 predicts survival in germinal center B-cell-like diffuse large B-cell lymphoma treated with CHOP-like therapy and rituximab. In: Clinical Cancer Research. 2011 ; Vol. 17, No. 24. pp. 7785-7795.
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title = "BCL2 predicts survival in germinal center B-cell-like diffuse large B-cell lymphoma treated with CHOP-like therapy and rituximab",
abstract = "Purpose: 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. Experimental Design: 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. Conclusion: 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.",
author = "Javeed Iqbal and Meyer, {Paul N.} and Smith, {Lynette M} and Johnson, {Nathalie A.} and Vose, {Julie Marie} and Greiner, {Timothy Charles} and Connors, {Joseph M.} and Staudt, {Louis M.} and Lisa Rimsza and Elaine Jaffe and Andreas Rosenwald and German Ott and Jan Delabie and Elias Campo and Braziel, {Rita M.} and Cook, {James R.} and Tubbs, {Raymond R.} and Gascoyne, {Randy D.} and Armitage, {James Olen} and Weisenburger, {Dennis D.} and Chan, {Wing C.}",
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TY - JOUR

T1 - BCL2 predicts survival in germinal center B-cell-like diffuse large B-cell lymphoma treated with CHOP-like therapy and rituximab

AU - Iqbal, Javeed

AU - Meyer, Paul N.

AU - Smith, Lynette M

AU - Johnson, Nathalie A.

AU - Vose, Julie Marie

AU - Greiner, Timothy Charles

AU - Connors, Joseph M.

AU - Staudt, Louis M.

AU - Rimsza, Lisa

AU - Jaffe, Elaine

AU - Rosenwald, Andreas

AU - Ott, German

AU - Delabie, Jan

AU - Campo, Elias

AU - Braziel, Rita M.

AU - Cook, James R.

AU - Tubbs, Raymond R.

AU - Gascoyne, Randy D.

AU - Armitage, James Olen

AU - Weisenburger, Dennis D.

AU - Chan, Wing C.

PY - 2011/12/15

Y1 - 2011/12/15

N2 - Purpose: 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. Experimental Design: 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. Conclusion: 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.

AB - Purpose: 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. Experimental Design: 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. Conclusion: 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.

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