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Hematologic Malignancies Individualized Treatment of Diffuse Large B-cell Lymphoma— The Evolving Role of Molecular-subtype-specific Therapy Gita Thanarajasingam, MD, 1 Nabila Bennani-Baiti, MD 1 and Grzegorz S Nowakowski, MD 2 1. Advanced Fellow in Hematology; 2. Consulant in Hematology, Division of Hematology, Mayo Clinic, Rochester, Minnesota, US Abstract Individualized treatment of patients with diffuse large B cell lymphoma (DLBCL) is within reach given advancements in molecular techniques and the development of novel, targeted drugs. Two biologically distinct subtypes, germinal center B-cell (GCB) DLBCL and activated B-cell (ABC) DLBCL, display differences in outcome and response to therapy. ABC-DLBCL confers poorer prognosis. Several targeted agents show promising activity in this group. Molecular-subtype is a prognostic and therapy-related biomarker that can guide personalized frontline therapy to improve outcomes in DLBCL. Keywords Diffuse large B-cell lymphoma (DLBCL), cell of origin (COO), outcomes, therapy Disclosure: Gita Thanarajasingam, MD, and Nabila Bennani-Baiti, MD, have no conflicts of interests to declare. Grzegorz S Nowakowski, MD, receives research funding support from Celgene. No funding was received in the publication of this article. Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any noncommercial use, distribution, adaptation, and reproduction provided the original author(s) and source are given appropriate credit. Received: September 2, 2015 Published Online: November 10, 2015 Citation: Oncology & Hematology Review, 2015;11(2):113–4 Correspondence: Gita Thanarajasingam, MD, Division of Hematology Mayo Clinic, 200 First Street SW, Rochester, MN 55905. E: Individualized treatment of patients with malignancy is feasible in modern oncology due to improved molecular techniques and the development of novel, targeted agents. Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma (NHL). Standard frontline therapy consists of combined immunochemotherapy with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Although outcomes for patients with DLBCL improved significantly with the addition of rituximab to the standard cytotoxic chemotherapy backbone over a decade ago, they have largely remained stable since that time. Approximately 40  % of DLBCL patients will develop relapsed or refractory disease. 1,2 Most patients in this setting succumb to their disease despite salvage treatments, suggesting that the highest impact area for improvement is first-line therapy. 3 Recent advances in molecular characterization techniques have deepened the understanding of the biology of DLBCL and paved the way for personalized therapies aimed at improving outcomes in this disease. Gene expression profiling of DLBCL has identified two distinct subtypes classified by the malignant cell of origin (COO): germinal center B-cell (GCB) and non-GCB DLBCL, the latter of which is further categorized into activated B-cell (ABC) DLBCL and primary mediastinal B-cell lymphoma. 4 ABC-DLBCL displays chronic active B-cell receptor (BCR) signaling and is associated with inferior clinical outcome, while GCB-DLBCL is associated with better outcomes and a pathogenesis that may involve epigenetic Tou ch MEd ica l MEdia changes and the anti-apoptotic B-cell lymphoma-2 (BCL-2) family of proteins. 5,6 Immunohistochemical and gene expression profiling methods that permit real-time assessment of COO on paraffin-embedded tissue are now available, and therefore molecular subtyping of DLBCL is increasingly feasible in the clinic. Additionally, increased understanding of signaling pathways, genetic mutations, and biomarkers in lymphomagenesis has driven a rapid expansion of novel, biologically targeted therapies with differential activity in specific DLBCL subtypes, particularly in ABC-DLBCL. Molecular subtype in DLBCL is therefore both a prognostic and a therapy- related biomarker. Multiple classes of novel agents targeting the BCR pathway or its downstream constituents have been investigated in clinical trials, with emphasis on efficacy in ABC-DLBCL. These include immunomodulatory drugs (IMiDs), proteasome inhibitors, and BCR signaling pathway inhibitors. IMiDs such as lenalidomide may enhance antibody-dependent cell-mediated cytotoxicity (ADCC), inhibit production of inflammatory cytokines, and decrease nuclear transcription factor kappa B (NFκB) activity. 7,8 Phase II studies have demonstrated the efficacy of single-agent lenalidomide in relapsed/refractory NHL, with significantly improved response rates and progression-free survival observed in non-GCB- DLBCL. 9 Proteasome inhibitors, such as bortezomib, suppress the NFκB pathway, which is constitutively activated in ABC-DLBCL. Bortezomib was one of the first agents to show promising results in relapsed and 113