Results from a new study led by researchers in the Center for Cancer Research (CCR) at the National Cancer Institute (NCI) could potentially explain why some patients with diffuse large B-cell lymphoma (DLBCL) respond to treatment and others don’t.
In the study, the team comprised by the National Institutes of Health (NIH) identified critical genetic subtypes of the most common type of lymphoma. Results were published in an article titled, “Genetics and Pathogenesis of Diffuse Large B-Cell Lymphoma
,” in the New England Journal of Medicine
DLBCL, known for how aggressive it can be, is still believed to be curable. In some patients, treatment eliminates the disease. In others, however, the standard treatment (chemotherapy plus rituximab combination) has no effect. Researchers have been left trying to understand why.
Several years ago, researchers defined 2 major subgroups of DLBCL that arise from different cells of origin and that have different patterns of gene activity. It was uncovered that patients with activated B-cell-like (ABC) DLBCL have approximately a 40% average survival rate. Comparatively, those with germinal center B-cell-like (GCB) DLBCL have an estimated 75% average survival rate.
Even in the GCB subgroup, most patients experienced disease relapse after treatment.
“These findings are the culmination of two decades of research at NCI and elsewhere, advancing our understanding of the effect of DNA mutations and gene expression on lymphoma biology and outcome,” said NCI Director Ned Sharpless, MD in a press release. “This refined molecular classification will be instrumental in predicting prognosis and tailoring therapy for patients with DLBCL going forward.”2
In the study, investigators performed a multi-platform analysis of genomic alterations and gene expression on tumor samples from 574 patients with DLBCL. The hope of the researchers was to define whether there were other molecular features of the tumors that could assist in the explanation why some people were well-served by chemotherapy.
Louis M. Staudt, M.D., Ph.D., of NCI’s CCR, who led the new study, explained: “If we could understand who was not responding well to treatment, could we understand the genetics of these tumors to suggest new potential therapies beyond chemotherapy? The answer to both questions was ‘yes.’”
The analysis identified 4 prominent genetic subtypes, each of which share a group of genetic deviations. Patients with 2 of the 4 subtypes – BN2 and EZB – respond well to treatment, while those with the other 2 – MCD and N1 – do not. Some of these subtypes can be found in both ABC and GCB subgroups, meaning a patient could have the gene expression with the lower survival rate (ABC DLBCL), but the disease could also have the genetic subtype (BN2) that responds well to chemotherapy.
“This shows we’ve gone beyond where we were,” said Dr Staudt. “Before, even with our most advanced molecular diagnosis, we would have said all ABC tumors are the ‘bad’ type and they need to be treated aggressively. Now we can implement this kind of classification and say that even if a patient has the ‘bad’ ABC type, they have the ‘good’ genetic type, BN2. So, there’s a much better chance of chemotherapy curing the disease.”
These findings pertain to current treatment, however, Dr Staudt and his team of researchers hope that the new molecular classification will be used in future clinical trials. With this, eventually, treatments might be able to move away from chemotherapy and toward more targeted therapies with fewer side effects.
Research is already being conducted in this area. Results from historical clinical trials have shown that patients with GCB DLBCL were less likely to respond to ibrutinib, a targeted therapy, than those with ABC DLBCL.
By understanding these genetic subtypes, patients can be assigned to appropriate treatment arms based on tumor classification.
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- Schmitz R, Wright GW, et al; Genetics and Pathogenesis of Diffuse Large B-Cell Lymphoma. New England Journal of Medicine. 2018;378:1396-1407. doi: 10.1056/NEJMoa1801445.
- NIH study revises molecular classification for most common type of lymphoma [news release]. Bethesda, MD: National Institutes of Health; April 11, 2018. https://www.nih.gov/news-events/news-releases/nih-study-revises-molecular-classification-most-common-type-lymphoma