LMO2 Protein Expression Predicts Survival in Patients with Diffuse Large B-Cell Lymphoma in the Pre- and Post-Rituximab Treatment Eras.

Finding new prognostic markers in diffuse large B-cell lymphoma (DLBCL) is of importance because the disease is heterogeneous and current therapies fail to cure many affected patients. Previously, we showed that the expression of LMO2 mRNA was the strongest single predictor of superior outcome in patients with DLBCL in a multivariate model based on the expression of six genes (Lossos et al, NEJM 2004). Subsequently, we generated an anti-LMO2 monoclonal antibody and showed that LMO2 protein is expressed in a subset of germinal center-derived B-cell lymphomas including DLBCL, and that its expression predicted a superior outcome in DLBCL patients who were treated with anthracycline-based regimens (Natkunam et al, Blood 2006 & 2007). We have now expanded this cohort to include DLBCL patients treated at five international medical centers and have also tested the prognostic impact of LMO2 in patients treated with the addition of rituximab to CHOP (R-CHOP), a regimen which was recently demonstrated to improve the outcome of DLBCL patients (Coiffier et al, NEJM 2002; Sehn et al, JCO 2005; Habermann et al, JCO 2006; Pfreundschuh et al, Lancet Oncol 2006). Immunohistochemistry for LMO2 was performed on tissue microarrays containing cores of diagnostic biopsy specimens from patients with de novo DLBCL treated with anthracycline-based chemotherapy (280 patients) or with R-CHOP (80 patients) who had been followed for clinical outcome. The results show that in the pre-rituximab group staining for LMO2 was strongly correlated with overall survival (OS) and progression-free survival (PFS) (p=0.0018 and p=0.00071, respectively). Similarly, in the post-rituximab group LMO2 protein expression was associated with a significantly longer OS (p=0.0048) and PFS (p=0.0087). In multivariate Cox regression analyses, the expression of the LMO2 protein was found to be independent of the clinical IPI and most strikingly, was more robust than the conventional IPI in predicting OS and PFS, particularly in the post-rituximab DLBCL group of patients (OS p = 0.03, PFS p = 0.01). The capacity of LMO2 protein to identify DLBCL patients with improved outcome in an IPI-independent manner indicates its potential role in risk stratification of this disease. We conclude that the prognostic value of LMO2 protein expression remains significant in the era of R-CHOP treatment and recommend its assessment in all newly diagnosed DLBCL patients to confirm these results and eventually to optimize patient management.