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. 2011 Dec 15;17(24):7785-95.
doi: 10.1158/1078-0432.CCR-11-0267. Epub 2011 Sep 20.

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

Javeed Iqbal  1 , Paul N Meyer, Lynette M Smith, Nathalie A Johnson, Julie M Vose, Timothy C 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 O Armitage, Dennis D Weisenburger, Wing C Chan
Affiliations

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

Javeed Iqbal et al. Clin Cancer Res. .

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.

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Conflict of interest statement

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Figures

Figure 1.
Figure 1.
Flowchart outlining the number of patients in each analysis.
Figure 2.
Figure 2.
Correlation of BCL2 protein expression with OS and EFS in R-CHOP cohort. BCL2 protein expression is significantly correlated with OS and EFS in the R-CHOP cohort.
Figure 3.
Figure 3.
Correlation of BCL2 mRNA with OS and EFS in R-CHOP cohort. BCL2 mRNA shows significant correlation with EFS in DLBCL (A) cases divided into 2 halves and (B) cases divided into quartiles according to BCL2 mRNA expression.
Figure 4.
Figure 4.
Association of BCL2 protein and mRNA with OS and EFS in ABC-DLBCL. No significant correlation at (A) protein level or (B) mRNA level.
Figure 5.
Figure 5.
Correlation of BCL2 protein and mRNA with OS and EFS in GCB-DLBCL. Significant correlation in at (A) protein level and (B) marginally at mRNA level in EFS.
Figure 6.
Figure 6.
Differential expression of genes (A) and GSEA (B) between BCL2 protein–positive and -negative groups in GCB-DLBCL. GSEA identified enrichment of gene signatures (P < 0.01) in BCL2-positive and -negative GCB-DLBCL groups. The enrichment score curves were obtained from GSEA software. Vertical black lines indicate the position of the enriched genes (Hit) comprising the gene set. The graph on the bottom of each panel shows the ranked list metric (signal-to-noise ratio) for each gene as a function of the rank in the ordered data set (see Subramanian and colleagues for more details; ref. 32). IHC, immunohistochemistry.
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