Gene Signature Identifies New Subgroup of DLBCL

A new study has identified a clinically and biologically distinct subgroup of diffuse large B-cell lymphoma (DLBCL) tumors that have worse outcomes when treated with standard of care chemoimmunotherapy.

Researchers led by Daisuke Ennishi, PhD, of British Columbia Cancer Centre for Lymphoid Cancer, Vancouver, Canada, used RNA sequencing from 157 germinal center B-cell-like (GCB) DLBCL to develop a gene expression signature that distinguishes high-grade B-cell lymphoma (HGBL) with MYC and BCL2 and/or BCL6 rearrangements (HGBL-DH/TH) with BCL2 rearrangements from other GCB DLBCLs.

The 104-gene double-hit signature classified 27% of GCB-DLBCLs to a double-hit signature-positive (DHITsig) group. Only half of the patients classified as DHITsig-positive harbored MYC and BCL2 rearrangements, but MYC and BCL2 translocations and protein expression of MYC and BCL2 were more frequent in those patients classified as DHITsig-positive (P < .001).

“This new DHITsig-positive subgroup of GCB-DLBCL roughly doubles the number of DLBCL tumors that would be classified as HGBL on the basis of FISH testing,” Ennishi and colleagues wrote in The Journal of Clinical Oncology. “We envision that this will afford an immediate clinical impact because the signature identifies a large group of DHITsig-negative patients with GCB-DLBCL in whom R-CHOP is sufficient to effect cure, obviating the need for therapy escalation in this group.”

Those patients that were DHITsig-positive had worse outcomes after chemoimmunotherapy with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone compared with DHITsig-negative patients (5-year time to progression rate 57% vs 81%; P < .001). DHITsig-positive patients also had significantly shorter disease-specific survival and overall survival compared with DHITsig-negative patients, with outcomes comparable to those of patients with activated B-cell-like DLBCL. These inferior outcomes occurred regardless of HGBL-DH/TH-BCL2 status. The researchers confirmed the prognostic value of their gene expression signature in an independent validation cohort.

The researchers reduced the 104 gene panel to a 30-gene module to provide an assay applicable to routinely available biopsy samples. The NanoString-based assay, which they named DLBCL90, can assign tumors into DHITsig-positive or negative groups, or to an intermediate group if the tumor could not be classified as positive or negative.

“As genomic testing gains adoption in clinical practice, this signature could form the basis of a more inclusive category that encompasses DLBCLs both with and without these rearrangements,” the researchers wrote. “This system would classify tumors with shared biology together while significantly expanding a group of patients with an established need for dose-intensive regimens or alternative therapies and may drive acceleration of clinical trials aimed at improving outcomes.”

In an accompanying editorial, Wing C. Chan, MD, of City of Hope Medical Center, Duarte, California wrote that the results should not come as a surprise “because the MYC/BCL2 double-hit concept is an oversimplification.”

He also noted that although Ennishi and colleagues developed a diagnostic signature that can be performed on the NanoString platform, “it would be of interest to perform additional analyses of the data…and translate that to a platform that others can use in the clinical setting.”

“Although the identification of this high-risk group of patients with tumor gene expression signature similar to MYC/BCL2 double hit lymphomas is valuable, heterogeneity still exists in survival within this group, which probably reflects biologic differences that need to be deciphered,” Chen concluded. “Additional molecular information may provide insight into how best to target at least some of these tumors.”