In the modern era of rituximab-based therapy as the first-line treatment, the prognoses of patients who require salvage therapy are poor and most will eventually succumb to their disease. this molecular era of disease definition will be the identification of combinations of novel brokers that target the oncogenic drivers of these subsets. Well-conducted clinical trials, with translational molecular investigations, will be essential to achieve the goal of precision medicine and expand the number of patients with DLBCL who achieve a cure. Introduction Diffuse large B-cell lymphoma (DLBCL) is the most common B-cell non-Hodgkin lymphoma (NHL) throughout the world, comprising 30C35% of all NHLs.1 DLBCL is biologically aggressive, but can be cured in 50% of cases, even in advanced stages.2 However, up to one-third of patients have refractory disease or relapse after treatment.3 The standard salvage treatment for patients with relapsed or refractory DLBCL that remains sensitive to chemotherapy is autologous stem cell transplantation (ASCT), but success rates are poor in the current era,4 highlighting the urgent need for novel therapeutic approaches for these patients. DLBCL was first cured with combination chemotherapy in the 1970s with anthracycline-based regimens.5 Cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) chemotherapy E3 ligase Ligand 14 has been the standard of care for patients with DLBCL since the landmark randomized phase III study of 899 patients with advanced intermediate-grade and high-grade lymphomas. In that study, equivalent response rates and survival were exhibited, but with lower toxicity for CHOP compared with third-generation anthracycline-based regimens.6 The most recent breakthrough in the treatment of DLBCL has been the development of rituximab, a chimeric monoclonal antibody targeting the CD20 receptor, which has shown benefit for all those DLBCL subgroups.7C11 The first study to show the benefit of rituximab was performed by Croupe dEtude des Lymphomes de FAdulte (GELA), in which patients 60 years of age were randomly assigned to receive CHOP plus rituximab (R-CHOP) or E3 ligase Ligand 14 CHOP alone. 7 In this study, the complete remission rate (76% versus 63%, = 0.005) and 2-year event-free survival (EFS) rate (57% versus 39%, = 0.005).9 R-CHOP also demonstrated an almost 20% improvement in the 6-year EFS rate compared with CHOP alone when administered to younger patients with DLBCL who had good prognostic features (74.3% versus 55.8%, standard of care in patients of all ages with DLBCL. The development of other more-effective chemotherapy platforms has been limited. For example, randomized studies of ASCT in first remission12 and dose-dense strategies13 have failed to demonstrate improvement over R-CHOP. A randomized study from GELA in 380 patients between the ages of 18C59 years with newly diagnosed DLBCL and with low-risk features showed that rituximab, doxorubicin, cyclophosphamide, vindesine, bleomycin and prednisone (R-ACVBP) was superior to R-CHOP in terms of both 3-year EFS rates (81% versus 67%, = 0.0035) and overall survival (92% versus 84%, = 0.007).14 However, the haematological toxicity of R-ACVBP E3 ligase Ligand 14 limits its use in older patients.14 The pharmaco-dynamically derived infusional regimen of dose-adjusted etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone and rituximab (DA-EPOCH-R) has proven to be highly effective for certain molecular subtypes of DLBCL,15,16 and is currently being compared with R-CHOP in a randomized E3 ligase Ligand 14 phase III study that has completed accrual.17 Overall, R-CHOP remains the most commonly used regimen CCNB2 for newly diagnosed DLBCL. DLBCL has significant molecular heterogeneity within morphologically indistinguishable tumours and can be subdivided by gene-expression profiling (GEP) into three distinct molecular cell-of-origin subtypes: germinal centre B-cell (GCB), activated B-cell (ABC) and primary mediastinal B-cell lymphoma (PMBL)18C22 (Figure E3 ligase Ligand 14 1). We are currently in the molecular era of disease definition, and discovery of new signalling pathwaysthrough GEP, transcriptome sequencing, RNA interference screens and DNA sequencinghas identified an array of new therapeutic targets in DLBCL (Table 1). Targeting specific oncogene addictions within the DLBCL subgroups offers a more-precise approach to therapy23 compared with the standard chemotherapy-based approaches. Analysis of DLBCL primary tumour samples using whole-genome and exome sequencing has revealed tremendous molecular complexity,24C27 indicating that the development of precision personalized medicine in DLBCL will not only require identification of mutations that drive tumorigenesis and disease progression, but will also involve characterization of cooperating mutations that confer drug resistance in patients. It is likely that the next major breakthrough in DLBCL therapy will spawn from a principled understanding of how to manage the subgroups at highest risk of initial treatment failure. In this Review, we describe.
In the modern era of rituximab-based therapy as the first-line treatment, the prognoses of patients who require salvage therapy are poor and most will eventually succumb to their disease