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

ABSTRACT

Introduction

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.

Areas covered

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.

Expert opinion

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.

KEYWORDS:

• High-risk DLBCL
• novel therapy
• molecular subtypes
• clinical risk
• targeted therapy

Article highlights

• DLBCL is a heterogeneous clinical, pathologic, and molecular diagnosis.

• Clinical risk models continue to perform well with respect to long-term outcomes as compared to novel approaches to identifying high-risk disease.

• Cell-of-origin, MYC and BCL2 overexpression, MYC rearrangements, CD5 expression, metabolic tumor volume, and CD79B, MYD88^L265P, TP53 mutations have independent prognostic value.

• Polatuzumab + R-CHP is the first phase III randomized study (combining conventional cytotoxic chemotherapy with targeted therapy) that showed superior outcomes with similar toxicity profile compared to R-CHOP for patients with DLBCL in the front-line setting.

Author contributions

Both authors have read and agree to the published version of the manuscript. Conceptualization, T.J.V. and N.E.; resources, T.J.V. and N.E.; data curation, N.E.; writing—original draft preparation T.J.V. and N.E.; writing—review and editing, T.J.V. and N.E.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

The authors have no funding to report.