Program: Oral and Poster Abstracts
Session: 622. Non-Hodgkin Lymphoma: Biology, excluding Therapy: Poster I
Methods: In a two-step strategy, we have challenged this hypothesis; first, by clinical data analysis of the prognostic impact of CXCR4 gene expression in clinical DLBCL datasets and, secondly, by laboratory analysis in a preclinical model of 14 DLBCL cell lines, studying, in vitro, the effect of CXCR4 in rituximab-mediated complement-dependent cytotoxicity.
Results: Our results document that the normal expression pattern of centroblasts having higher CXCR4 membrane expression levels than centrocytes, is maintained in the malignant condition of DLBCL when individual patient samples at time of diagnosis are associated to normal B-cell subset phenotypes using the expression based “B-cell associated gene signature” (BAGS) classification system (2). The prognostic impact of CXCR4 gene expression is significant in R-CHOP but not in CHOP treated patients and independent of both the international prognostic index (IPI) scoring system as well as the (BAGS)-defined classification. Experimental in vitro studies of rituximab-induced complement-dependent cytotoxicity in systematic dose response screens of 14 CD20+ DLBCL cell lines using growth inhibition as out-read parameter resulted in very heterogeneous responses ranging from fully resistance to hypersensitivity. An inverse correlation between rituximab sensitivity and the level of gene- as well as membrane-located CXCR4 expression was documented, but exclusively in sensitive cell lines. In addition, rituximab induced membrane-located CXCR4 expression in a complement-independent manner in DLBCL cell lines. Combining rituximab and the CXCR4-antagonist plerixafor increased the cytotoxic effect of rituximab in cell lines supporting that CXCR4 has negative impact on the function of rituximab.
Conclusion: This study supports that CXCR4 expression is a pathogenic variable, reflecting the reminiscent state of normal B-cell differentiation of the malignant DLBCL cells. In addition, CXCR4 provides additional and independent prognostic information in DLBCL patients treated with R-CHOP, and plays a role in rituximab-mediated CDC sensitivity in DLBCL cell lines.
Disclosures: No relevant conflicts of interest to declare.
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