Debating Molecular Markers in the Treatment of DLBCL
Jonathon B. Cohen, MD, MS
Despite the current ‘one-size-fits-all’ approach to treating patients with diffuse large B-cell lymphoma (DLBCL), advances in molecular diagnostics have allowed for a greater understanding of the biology and pathology of DLBCL, leading to the identification of subgroups according to genetic lesions that may be targetable in the treatment of the disease.
Whether or not these genetic variants should be used to determine treatment options for patients with DLBCL was the subject of a debate held at the 2016 Debates and Didactics in Hematology and Oncology meeting in Sea Island, Georgia.
Two oncologists from Emory University School of Medicine faced off to determine if molecular markers should play a role in the treatment of subgroups of patients with DLBCL.
The standard of care for DLBCL has been rituximab, a monoclonal antibody directed against the CD20 antigen, used in combination with an anthracycline-based chemotherapy regimen consisting of cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). While R-CHOP can lead to remission and possible cure in a sizable portion of DLBCL patients, a subgroup of patients remain that will ultimately relapse, at which time their therapeutic options will be limited and prognosis is poor.1
A substantive heterogeneity in the clinical presentation, biology, and pathology of DLBCL has been recognized though, suggesting that a more individualized approach to treatment may be warranted.
Advances in molecular diagnostic methods are beginning to unravel the complexity of DLBCL at the molecular level, lead- ing to the identification of subsets of DLBCLs based upon the patterns of genes that they express.
Genetic lesions, including somatic mutations, chromosomal rearrangements, and copy number alterations are common in DLBCL. Some of the most common genes to be impacted (>15% of cases) are KMT2D (MLL2), BCL2, TP53, MYD88, and CREBBP. Rearrangement of the MYC oncogene, which leads to aberrant growth and proliferation, is also observed in roughly 10% of DLBCLs. MYC rearrangement along with a translocation of the anti-apoptosis BCL2 gene is one example of a “double-hit” lymphoma that is observed in the minority of patients and is associated with a poor prognosis.2
In order to identify appropriate targeted therapies that may outperform R-CHOP in high-risk subgroups, such as those with double-hit lymphoma, the patients most likely to benefit from these agents need to be identified using predictive molecular biomarkers.