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While the majority of patients diagnosed with diffuse large B-cell lymphoma (DLBCL) can be cured with front-line chemoimmunotherapy, a subset of patients with high-risk disease remain challenging to treat. Identification of high-risk DLBCL is important as future therapy options are explored. We discuss the clinical, pathologic, and molecular risk stratification in DLBCL and how these factors are incorporated into the decision making for the front-line therapy. Clinical and pathological risk stratification has long been the standard for identifying likelihood of future disease progression and overall survival; however, these prediction models lack the granularity of individual patient pathology and response to therapy. Molecular subtypes defined through whole exome sequencing have independent prognostic significance. While identifying molecular drivers of aggressive disease has provided the opportunity to analyze novel therapy combinations with front-line chemoimmunotherapy, only modest benefit has been observed when targeting DLBCL subtypes. Combining clinical, pathologic, and molecular data will likely result in significant improvement in our ability to identify the most aggressive DLBCL subsets. Novel therapies and trial designs will continue to play an important role as we target these at-risk populations in the future.

Identifying aggressive subsets within diffuse large B-cell lymphoma: implications for treatment approach