'Landmark' Study Revises Molecular Classification of Most Common Lymphoma

Megan Brooks

April 11, 2018

Researchers have identified four genetic subtypes of diffuse large B-cell lymphoma (DLBCL) that may explain why some patients respond to treatment and others don't and provide a path toward precision medicine treatment strategies for DLBCL, the most common type of lymphoma.

The study, led by researchers at the National Cancer Institute (NCI), Bethesda, Maryland, was published online April 11 in The New England Journal of Medicine.

"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," NCI Director Ned Sharpless, MD, said in a statement.  "This refined molecular classification will be instrumental in predicting prognosis and tailoring therapy for patients with DLBCL going forward."

There are two major subgroups of DLBCL that arise from different cells of origin: activated B-cell-like (ABC) DLBCL and germinal-center B-cell-like (GCB) DLBCL. "It has long been known that DLBCL is a catch-all diagnostic classification and that patients with this diagnosis can have dramatically different responses to chemotherapy," Louis Staudt, MD, from NCI's Center for Cancer Research, who led the study, told Medscape Medical News.

Using multiple advanced techniques, the researchers analyzed genomic alterations and gene expression on tumor samples from 574 patients with DLBCL. They identified four prominent genetic subtypes, which they are calling MCD (based on the co-occurrence of MYD88 L265P and CD79B mutations), BN2 (based on BCL6 fusions and NOTCH2 mutations), N1 (based on NOTCH1 mutations), and EZB (based on EZH2 mutations and BCL2 translocations).

The genetic classification of DLBCL that we describe revealed striking differences in 5-year overall survival. Dr Louis Staudt

Their observations suggest that patients with the BN2 and EZB subtypes respond well to treatment, while those with the MCD and N1 subtypes do not. It's noteworthy, they say, that some of these subtypes are present in both ABC and GCB subgroups. Therefore, a patient could have ABC DLBCL, which is associated with the lower survival rate, but the disease could also have the BN2 genetic subtype that responds well to chemotherapy.

Notably, said Staudt, "The genetic classification of DLBCL that we describe revealed striking differences in 5-year overall survival, ranging from 26% in the worst subtype to 68% in the best."

"Moreover, we showed that this classification identified clinical differences beyond what was captured by gene expression profiling, which is the current standard for molecular diagnosis of DLBCL. Beyond this, the genetic abnormalities in each genetic subtype predict that they will respond differently to targeted therapies," such as drugs that inhibit the B-cell receptor signaling pathway like ibrutinib (Imbruvica, Pharmacyclics and Janssen) and acalabrutinib (Calquence, AstraZeneca), Staudt explained.

This is a landmark study in DLBCL. Dr Pallawi Torka

Data from this study will be shared through NCI's Genomic Data Commons to make them available for future research.

"Precision medicine treatment strategies for DLBCL is our goal," Staudt said.

"In the immediate term," he noted, "clinical trials in DLBCL should investigate the response to investigational agents in these genetic subtypes of DLBCL. Over time, we will learn how these genetic subtypes of DLBCL respond to chemotherapy and to targeted therapies. When up-front genetic profiling of cancer becomes routine, this genetic classification will allow doctors to choose an optimal therapy for a patient with DLBCL," said Staudt.

Reached for comment, Beth Christian, MD, from The Ohio State University Comprehensive Cancer Center in Columbus, called the study a "significant advance in the understanding of the diverse biology" of DLBCL.

"These findings can potentially lead to more personalized therapy in the treatment of diffuse large B-cell lymphoma, both by identifying high-risk patients and incorporating rationale targeted novel therapies," Christian told Medscape Medical News.

Pallawi Torka, MD, from the Lymphoma & Myeloma Division, Department of Medicine, Roswell Park Comprehensive Cancer Center in Buffalo, New York, called it a "landmark study" in DLBCL, adding that the NCI group "has been pioneers in classifying DLBCL into clinically relevant subtypes. With this study, we move one step closer to understanding what drives the response heterogeneity in DLBCL."

Torka said discerning genetic subtypes will also help identify the most appropriate targeted therapy for a particular patient, based on what gene expression signature their lymphoma carries.

"For example, in an elderly patient with MCD subtype of DLBCL, now knowing that they have inferior outcomes with chemotherapy such as R-CHOP [rituximab, cyclosporine, doxorubicin, vincristine, and prednisolone], considering their older age and presence of targetable mutations such as MYD88L265P, I would offer enrollment in a clinical trial using an agent such as ibrutinib, rather than upfront conventional chemotherapy," Torka told Medscape Medical News.

"The vital next step," she said, is translation of the advanced sequencing techniques used in this study to a simpler platform so that it can be used in clinical practice.

This research was supported by the Intramural Research Program of the National Institutes of Health (NIH), the Center for Cancer Research of the NCI, and an NCI Strategic Partnering to Evaluate Cancer Signatures grant. Disclosures for authors are available with the full text of the article at NEJM.org. Christian and Torka have disclosed no relevant financial relationships.

N Engl J Med. Published online April 11, 2018. Abstract

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