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.
Clin Cancer Res. 2011 Dec 15;17(24):7785-95. doi: 10.1158/1078-0432.CCR-11-0267. Epub 2011 Sep 20.
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.
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.
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.
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.
我们之前已经证明了在接受环磷酰胺-阿霉素-长春新碱-泼尼松（CHOP）或 CHOP 样治疗的活化 B 细胞样弥漫性大 B 细胞淋巴瘤（ABC-DLBCL）患者中，BCL2 表达的预后意义。然而，在利妥昔单抗（R）纳入 CHOP 方案后，关于 BCL2 表达的预后价值已经有了一些相互矛盾的观察结果。
我们评估了 221 例接受基因表达谱数据分析的 DLBCL 病例的 R-CHOP 队列。BCL2 蛋白（n = 169）、mRNA（n = 221）表达和 t（14；18）（n = 144）与临床结局相关。CHOP 队列（n = 181）用于比较分析。
在 R-CHOP 队列中，BCL2 蛋白表达对总体生存（OS）和无事件生存（EFS）具有显著影响（OS，P = 0.009；EFS，P = 0.001）和 GCB-DLBCL（OS，P = 0.03；EFS，P = 0.002），但在 ABC-DLBCL 中则不然。在多变量分析中，仍观察到 GCB-DLBCL 中 EFS 生存差异。在 mRNA 水平上，这种相关性在 DLBCL 中 EFS 中也有观察到（P = 0.006），但在 GCB-DLBCL 中仅观察到趋势（P = 0.09）。在 34%的 GCB-DLBCL 中检测到 t（14；18），但与生存无显著差异相关。基因富集分析表明，在 BCL2（-）GCB-DLBCL 中存在明显的 DLBCL“基质-1”特征和缺氧诱导因子 1（HIF1-α）特征富集，而 T（FH）细胞特征在 BCL2（+）GCB-DLBCL 中富集。
在利妥昔单抗纳入治疗方案后，BCL2 的预后意义发生了变化，并且仅在 GCB-DLBCL 中观察到，而不是在 ABC-DLBCL 中观察到。尽管利妥昔单抗使两个 DLBCL 亚组的患者都受益，但 BCL2（+）GCB-DLBCL 似乎从这种治疗中获益较少，可能需要其他新的治疗干预。
