Gene Expression Signatures Predict Overall Survial in Diffuse Large B Cell Lymphoma Treated with Rituximab and Chop-Like Chemotherapy.

Abstract

Gene expression profiling has been used to distinguish two major subtypes of diffuse large B cell lymphoma (DLBCL), termed germinal center B cell-like (GCB) DLBCL and activated B cell-like (ABC) DLBCL. Following CHOP-like chemotherapy, GCB and ABC DLBCLs had distinct 5-year survival rates of ∼60% and ∼30%, respectively. Prognostic gene expression signatures in CHOP-treated DLBCL include the lymph node signature, which reflects a non-malignant host response, the MHC class II signature, both favorable when expressed and the proliferation signature which is adverse when expressed. The addition of rituximab to CHOP chemotherapy (R-CHOP) has significantly improved the outcome for DLBCL patients. We therefore investigated, if gene expression signatures that predicted survival among DLBCL patients treated with CHOP remained predictive for DLBCL patients treated with R-CHOP. Gene expression profiling was performed on 156 samples from previously untreated patients with DLBCL using Affymetrix U133 plus arrays. All patients received rituximab and CHOP-like chemotherapy. Samples were classified as GCB DLBCL, ABC DLBCL, or unclassified, and were assessed for expression of the lymph node and proliferation signatures. A Cox-proportional hazards model was used to determine the association of these gene expression features with overall survival (OS). 71 DLBCL samples were classified as GCB DLBCL, 63 as ABC DLBCL, and 22 were unclassified. The addition of rituximab improved OS for both GCB and ABC DLBCL compared to historical controls treated with CHOP-like chemotherapy alone. After a median follow-up of 2.3 years, GCB DLBCL had a more favorable OS than ABC DLBCL, with 3-year OS rates of 86% vs. 68% (p = 0.014). The 3-year OS rate of unclassified DLBCLs was 69%. The lymph node signature was associated with favorable OS (p = 0.023) and the proliferation signature with inferior OS (p = 0.009), whereas the MHC class II signature was not associated with OS (p = 0.44). In summary, addition of rituximab to CHOP-like chemotherapy improved OS for both GCB and ABC DLBCL but ABC DLBCL remained inferior to GCB DLBCL. The prognostic value of the lymph node and proliferation signatures were maintained in the context of R-CHOP therapy. An understanding of the biological attributes of DLBCL tumors that are reflected in these gene expression signatures remains critical to our ability to improve survival of these patients.

Primary diffuse large B‐cell lymphoma of the breast: An aggressive subgroup with nongerminal center B‐cell‐like phenotype

“…In nodal DLBCL these features are usually associated with poor prognosis [2,15]. Altogether these results indicate the need for a specific management for primary DLBCL of the breast [13,16] taking into account of the recent results obtained in clinical and molecular subtypes of CD20 positive DLBCL [17,18]. Furthermore, a more precise knowledge of the clinical behavior of lymphomas arising in extranodal sites is necessary, since the optimal management of DLBCL might vary by the primary site of involvement (nodal versus extranodal DLBCL; primary DLBCL of the breast versus other primary extranodal DLBCL).…”

Primary malignant non-Hodgkin’s lymphoma of the breast: a study of seven cases and literature review

“…Although the combination of anthracycline-based chemotherapy with rituximab should be considered standard, it appears that the addition of rituximab improves the outcome of all clinical and molecular subtypes of CD20-positive diffuse large B-cell lymphoma [ 22 - 24 ].…”

Genomic Analysis of Lymphoma: Potential for Clinical Application

“…2 The addition of rituximab has improved the outcome in both groups, although patients with the GCB subtype still have superior survival. 12 An unusual subtype of diffuse large B-cell lymphoma presents with a mediastinal mass and occurs disproportionately in young women. When gene expression profiling was studied in these patients, the pattern was found to be different from that in other DLBCL, and in many ways similar to the pattern of gene expression seen in cell lines derived from classical Hodgkin lymphoma.…”