In DLBCL, Refining Patient Stratification an Ongoing Project

The methods of subtyping diffuse large B-cell lymphoma (DLBCL) have changed over time, and the greater refinement of those categories should create better opportunities for precision medicine and superior outcomes, according to a new review.

Investigators reviewed the various approaches to classifying patients with DLBCL in the journal Seminars in Hematology. They also laid out future directions they said could help better classify individual cases.

Patients with DLBCL face a stark set of outcomes, the authors noted. Most patients will achieve long-term remission with standard-of-care chemoimmunotherapy, they said. However, 30% to 40% of patients will experience a relapse or have refractory disease.

“Making meaningful improvements will require better understanding of DLBCL biology,” they wrote. “Specifically, understanding the underlying factors that influence biological heterogeneity in DLBCL will provide opportunities to implement precision medicine approaches, enabling the application of therapies that target the distinct biology of each patient's disease.”

Data analytics | Image Credit: NicoElNino - stock.adobe.com

The investigators began by outlining the current classification systems. For instance, the World Health Organization’s most recent HAEM5 classification and the latest International Consensus Classification—both released in 2022—subdivide DLBCL based on primary site of involvement, clinical presentation, the presence of virus in the malignant cells, and recurrent chromosomal arrangements, the authors noted.

Still, they pointed out that “the most common lymphoma category worldwide” is “DLBCL, not otherwise specified” (DLBCL, NOS), the catch-all classification for tumors that do not fall into any of the other categories.

“Studies of the mutational and gene expression landscapes of extranodal entities show substantial homogeneity of tumors in each of these categories, while DLBCL, NOS represents a very heterogeneous group that can be further divided based on molecular substructure,” the study authors wrote.

The investigators then examined some of the more recent developments in categorizing DLBCL. They said gene expression profiling and genetics-based subtypes have helped to provide additional answers about biological heterogeneity in DLBCL.

“Recent studies of tumor evolution challenge the notion that these subgroups are arbitrary divisions; instead, DLBCL appears to be made up of discrete entities each evolved from distinct [common precursor cell] populations,” they wrote.

Still, because genetic subgroupings are a relatively new advancement, they said data are limited so far on the role such classifications might play in treatment stratification. They added that another factor that appears to play an important role in cases of DLBCL is the tumor microenvironment (TME).

“Qualities of the TME have prognostic and likely therapeutic significance and, with the addition of spatial arrangement, may contribute to diagnostic categories in the future,” they wrote.

They said it is not yet clear exactly how different tumor-based subtypes and TME features interact, but they said investigating those links could help increase scientists’ understanding of the disease and its variations.

“The most comprehensive view of biological heterogeneity in DLBCL will need to look beyond the genome and transcriptome, incorporating features of the TME and the epigenome through techniques such as single-cell multiomics, spatial transcriptomics and proteomics, and methylation analyses,” they concluded.

They said future trials need to have sufficient molecular data from patient samples, along with high-quality clinical assays to subtype patients most accurately, and that incorporating such measures will enable a new era of precision medicine in DLBCL and ultimately improve patient outcomes.

Reference

Hilton LK, Scott DW, Morin RD. Biological heterogeneity in diffuse large B-cell lymphoma. Semin Hematol. Published online December 1, 2023. doi:10.1053/j.seminhematol.2023.11.006