Hexokinase II Expression As a Prognosis Marker in Diffuse Large B-Cell Lymphoma (DLBCL) Pre- and Post- the Incorporation of Rituximab to Standard CHOP Chemotherapy

Purpose: The results of the prospective multicenter phase III Collaborative trial in relapsed aggressive lymphoma (CORAL) study stressed the need to identify cellular pathways associated with poor clinical outcomes and to develop novel therapeutic strategies for DLBCL. We previously demonstrated that over-expression of HKII contribute to the acquirement of resistance to rituximab and chemotherapy agents in DLBCL B-cell lymphoma in pre-clinical models. Using gene expression profiling, we also demonstrated that higher mRNA levels of HKII correlated with a shorter progression free survival (PFS) and overall survival (OS) in previously untreated DLBCL in the pre- and post-rituximab era. In current study, we aimed to assess HKII expression by immunohistochemistry (IHC) and analyze the prognostic significance in 97 diffuse large B cell lymphoma patients pre- and post-rituximab era treated in a different Country/Institution. Methods: We retrospectively identified 97 newly diagnosed DLBCL treated at Fudan University Shanghai Cancer Center, Shanghai, China from March 2009 to December 2012. Clinical, demographic and pathological characteristics for each patient were collected. Patients were treated with standard doses of CHOP (N=41) or rituximab and CHOP (N=56). Pathological archived material was submitted for immunohistochemistry (IHC) for the determination of cell of origin (COO) (Han's algorithm) and HKII levels. Co-relation between HKII expression and COO or impact on overall response rate (ORR), PFS and OS were analyzed. Result: Demographic and clinical characteristic of gender, stage and IPI score distribution were similar between patients treated with CHOP or R+CHOP. As expected, the clinical outcome of DLBCL patients treated with R+CHOP was superior than those treated with CHOP. HKII expression was observed in 62 DLBCL patients (63.9%). There was a correlation between HKII expression and COO. Expression of HKII was observer in 84.6% of non-germinal center B-cell (non-GCB) DLBCL and 60% of GCB DLBCL (P=0.027). There was no correlation between HKII expression and ORR or PFS in DLBCL patients treated with CHOP or R-CHOP. In patients treated with CHOP chemotherapy, HKII expression was associated with an inferior OS, 100% (HKII negative) vs. 67% (HKII positive) (P=0.025). In rituximab era, additionally rituximab to CHOP results significantly improved OS in HKII positive patient compared to CHOP only patients (91% vs 67%, P=0.05), but R+CHOP did not change OS between HKII negative patients. Conclusion: As previously observed, HKII expression is more prevalent in non-GCB DLBCL patients. In pre-rituximab era, HKII expression was associated with a poor clinical outcome after CHOP chemotherapy. The negative effect of HKII expression appears to be overcome by the addition of rituximab to CHOP. (This work was supported by National Natural Science Foundation of China (81670177 and 81773203)).