Background: The cell of origin (COO) distinction provides a prognostic and biologically relevant subclassification of DLBCL. Germinal center B cell (GCB) and non-GCB subtypes were originally characterized by gene expression studies and subsequently validated at the protein level by Hans et al., Blood 193: 275–82 (2004). The addition of R to CHOP chemotherapy has been shown to improve the outcome of patients with DLBCL. The underlying mechanism(s) responsible for this effect is largely unknown. However, it is known that R may preferentially prevent chemotherapy failure in DLBCLs that express Bcl-2 protein or fail to express Bcl-6 (

Mounier et al., Blood 101: 4279–84 2003
,
Winter et al., Blood 107: 4207–13 2006
). Bcl-2 over-expression and absence of Bcl-6 is more common in the non-GCB subtype. Thus, R may benefit mostly non-GCB lymphomas. To test this hypothesis we assessed the clinical impact of CHOP-R vs CHOP in DLBCL distinguished by COO subtypes.

Method: We identified 163 patients with DLBCL treated with either CHOP or CHOP-R with available paraffin blocks and interpretable immuno-staining. All were de novo DLBCL cases diagnosed between 1999 and 2002 at the BCCA. The two treatment cohorts represent consecutive eras of therapy (

Sehn et al., JCO 2005; 23: 5027–33
), and thus the median follow-up of living patients was 5.1 and 4.0 y for CHOP and CHOP-R, respectively. HIV+ patients or those with active secondary malignancies were excluded. Tissue microarrays (TMA) were built using duplicate 0.6mm cores from paraffin embedded formalin fixed (FFPE) tissues and stained with antibodies against CD10, Bcl-6, MUM1, and Bcl-2. The COO distinction was determined using the method of Hans.

Results: Patients were treated with either CHOP (81) or CHOP-R (82). Their clinical characteristics, including the IPI, were evenly matched. The median follow-up of living patients was 4.4 y. The IPI was predictive of overall survival (OS) (p<0.0001) for the entire study population. Six cases had uninterpretable immunostains resulting in 74 cases with a GCB phenotype and 83 with a non-GCB phenotype (n = 157). Overall, 71% and 75% of the cases over-expressed Bcl-2 and Bcl-6, respectively. Bcl-2 protein was expressed in 70% GCB cases and 73% non-GCB (p= 0.72). Bcl-6 was expressed in 96% GCB cases and 63% non-GCB cases (p<0.0001). In univariate analysis, the addition of R was associated with a better prognosis in the non-GCB cases (p=0.02), but not in the GCB cases (p=0.3). This survival difference was not solely explained by either Bcl-2 or Bcl-6 expression. The addition of R to CHOP chemotherapy and IPI were independent predictors of OS in non-GCB DLBCL (p=0.02; p=0.016, respectively). The addition of R was also of prognostic importance in the lymphomas over-expressing Bcl-2 (p=0.0081).

Conclusion: Immuno-chemotherapy using CHOP-R is associated with better OS in DLBCL, due largely to its effect on the non-GCB subgroup. Although Bcl-2 expression does not contribute to the determination of COO distinctions, the OS of Bcl-2-positive DLBCL patients is significantly improved by the addition of R. These results provide insight into the possible mechanisms by which R exerts its beneficial therapeutic effect.

Overall Survival for 157 DLBCL Based on Cell of Origin
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Overall Survival for 157 DLBCL Based on Cell of Origin

Overall Survival for 157 DLBCL Based on Cell of Origin
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Overall Survival for 157 DLBCL Based on Cell of Origin

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Topics:
cyclophosphamide, doxorubicin, prednisone, and vincristine, diffuse large b-cell lymphoma, rituximab, r-chop, chemotherapy regimen, bcl-2 protein, follow-up, lymphoma, paraffin, tissue microarray

Disclosures: Basic and fellowship funding from Roche Canada.; Honoraria from Genentech, Roche, Genitope, Biogen Idec.; Ad Board member for Roche, Genentech, Lilly, Genitope and Biogen Idec.

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2006, The American Society of Hematology
2006
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