Prognostic Significance and Phenotypic Manifestations of MYC/BCL2 Protein Expression in Diffuse Large B-Cell Lymphoma (DLBCL) with Extranodal Organ Involvement: A Report of the International DLBCL Rituximab-CHOP Consortium Program Study

Abstract 544 Background: In DLBCL, multiple extranodal sites of involvement and MYC/BCL2 translocations (double hit lymphoma) are associated with a poor clinical outcome. The association between the pattern of extranodal involvement and MYC and BCL2 protein expression, as well as the prognostic significance of expression, are unknown. Methods: We analyzed the clinical data of 487 DLBCL patients treated with R-CHOP. Immunohistochemical (IHC) studies were performed on paraffin-embedded tissue samples for MYC and BCL2. A double-hit score (DHS) of 0, 1, or 2 was assigned to all patients based on protein expression of MYC and BCL2. Those with both MYC and BCL2 expression were DHS 2, with MYC or BCL2 was DHS 1, and neither was DHS 0. Cell-of-origin classification was achieved by combining gene expression profiling (GEP) and IHC data with GEP as the gold standard. Patient characteristics were compared using Fisher9s exact test. Survival analyses were performed using Kaplan-Meier curves and compared using log-rank test. The Cox proportional regression model was used for multivariate analysis. Results: Approximately half of the patients (n = 251; 51.5%) had at least 1 extranodal site of involvement. In this group, the clinical features were: median age of 63 years (range, 12–88), male (58.6%), stage III/IV (63.2%), elevated serum LDH (66.8%), and International Prognostic Index (IPI) of 3–5 (48.5%). IHC features were: non-germinal center B-cell like (non-GCB) (53%), MYC+ (64.9%), BCL2+ (49.8%), MYC-/BCL2- (DHS 0; 20.3%), MYC+/BCL2- or MYC-/BCL2+ (DHS 1; 44.6%) and MYC+/BCL2+ (DHS 2; 35.1%). The common extranodal sites of involvement were genitourinary tract (18.3%), gastrointestinal tract (15.1%), sinonasal (14.3%), bones (13.9 %), lung (11.6 %), skin/soft tissues (9.9%), liver (9.1%), and bone marrow (8.4%). MYC+ was associated with bone marrow (odds ratio [OR]: 5.67; P = 0.009) and skin (OR: 3.11; P = 0.045) involvement, BCL2+ with sinonasal (OR: 2.26; P = 0.032) involvement, and MYC+/BCL2+ with skin/soft tissue (OR: 2.38; P = 0.049) and lung (OR: 2.37; P = 0.04) involvement. Non-GCB subtype was associated with genitourinary tract (OR: 1.47; P = 0.005) and bone marrow involvement (OR: 1.5; P = 0.038). The DHS 2 subgroup was significantly associated with lower complete response rate (62.5% vs 76.1%; P = 0.023), shorter progression-free-survival (PFS) (median 23.1 months vs 80.7 months; P Conclusions: In DLBCL with extranodal disease, MYC and BCL2 protein expressions and cell-of-origin are associated with distinct patterns of organ involvement. Patients with DLBCL expressing both MYC and BCL2 (score DHS 2; double hit biology) have a poor outcome independent of IPI and cell-of-origin. Disclosures: No relevant conflicts of interest to declare.