Diffuse large B-cell lymphoma: can genomics improve treatment options for a curable cancer?

Abstract

Gene-expression profiling and next-generation sequencing have defined diffuse large B-cell lymphoma (DLBCL), the most common lymphoma diagnosis, as a heterogeneous group of subentities. Despite ongoing explosions of data illuminating disparate pathogenic mechanisms, however, the five-drug chemoimmunotherapy combination R-CHOP remains the frontline standard treatment. This has not changed in 15 years, since the anti-CD20 monoclonal antibody rituximab was added to the CHOP backbone, which first entered use in the 1970s. At least a third of patients are not cured by R-CHOP, and relapsed or refractory DLBCL is fatal in ∼90%. Targeted small-molecule inhibitors against distinct molecular pathways activated in different subgroups of DLBCL have so far translated poorly into the clinic, justifying the ongoing reliance on R-CHOP and other long-established chemotherapy-driven combinations. New drugs and improved identification of biomarkers in real time, however, show potential to change the situation eventually, despite some recent setbacks. Here, we review established and putative molecular drivers of DLBCL identified through large-scale genomics, highlighting among other things the care that must be taken when differentiating drivers from passengers, which is influenced by the promiscuity of activation-induced cytidine deaminase. Furthermore, we discuss why, despite having so much genomic data available, it has been difficult to move toward personalized medicine for this umbrella disorder and some steps that may be taken to hasten the process.

Epigenetic inhibitors sensitize DLBCL cells to rituximab and doxorubicin

“…The standard of care therapy given to previously untreated DLBCL patients of all ages and subtypes is an immunochemotherapy combination consisting of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) ( 1 ), which cures approximately 60% of the DLBCL patients ( 1 ). Even though several genes, such as TP53, STAT3/6, CDKN2A, and EZH2, have been suggested to confer resistance to R-CHOP ( 2, 3 ), there is no clinically effective treatment available for R-CHOP resistant patients. Given patients who do not respond to R-CHOP or relapse after primary therapy have dismal prognosis, novel strategies to overcome R-CHOP resistance are needed.…”

Systematic Review of Therapy Used in Relapsed Or Refractory Diffuse Large B-Cell Lymphoma and Follicular Lymphoma

“…Since the addition of rituximab to the CHOP regimen approximately 15 years ago, there have been no additional approvals for any novel front-line therapies for either DLBCL or FL, nor any meaningful improvements to the R-CHOP survival rates [ 6 ]. With approximately a third of DLBCL patients experiencing R/R disease, many of whom are ineligible for SCT, there exists an unmet need, and the development of more effective therapies for these patients remains an important objective.…”

Past, Present, and Future of Rituximab—The World’s First Oncology Monoclonal Antibody Therapy

“…Because germline genetic markers can be easily probed with current technologies, they remain the most attractive potential biomarkers to facilitate personalized medicine choices. However, somatic mutations that arise in cancer tend to make more accurate predictions, although limitations such as biopsy requirements and tumor heterogeneity as well as distinguishing driver and passenger mutations, still need to be fully overcome ( 147 ). TP53 mutations are the most common de novo mutation in nearly all cancer types and are also common in lymphomas.…”