The disease formerly known as double-hit diffuse large B-cell lymphoma (DH DLBCL), now called high-grade B cell lymphoma with MYC and BCL2/BCL6 rearrangements, may be more common than previously thought. The entity is currently defined by the detection of rearrangements of the relevant genes using fluorescence in situ hybridization (FISH) probes, and most series estimate the incidence to be approximately 8 percent of all DLBCL cases.1 The cell of origin for DH DLBCL is almost exclusively germinal center B (GCB), which is ironically also the entity with a better prognosis (compared to activated B cell DLBCL). Having GCB DLBCL is good, unless your patient has the DH version.
Dr. Daisuke Ennishi and colleagues investigated the biologic differences between garden variety GCB DLBCL and DH DLBCL by analyzing cases through targeted resequencing, whole-exome sequencing, RNA sequencing, and immunohistochemistry data. In the process, they uncovered a group of patients who did not meet the classical definition of DH DLBCL but who had gene expression signatures very similar to DH DLBCL and clinical outcomes very similar to DH DLBCL. By this broader definition, the proportion of patients with a DH signature approximately doubles.
So, what are the biologic underpinnings of this new entity? The authors noted a distinct mutational landscape that comprises several genes associated with chromatin remodeling. They also noted overexpression of MYC and E2F target genes, as well as genes associated with oxidative phosphorylation, suggesting high proliferation and high metabolism. They observed low expression of genes associated with immune signatures and inflammatory signatures. Despite the MYC signatures by gene expression profiles and mutational analysts, MYC rearrangements were not present by FISH testing, suggesting other mechanisms for MYC dysregulation. Embedded in this biology are some suggestions of therapeutic strategies to exploit (histone modifying agents) and avoid (immunotherapy).
Prognostic association of double-hit signature (DHITsig) in patients with diffuse large B-cell lymphoma (DLBCL) treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. Kaplan-Meier curves of the DHITsig-positive (DHITsig-pos) germinal center B-cell-like (GCB-) DLBCL versus DHITsig-negative GCB-DLBCL versus activated B-cell-like (ABC-) DLBCL for disease-specific survival (DSS) in the BC Cancer cohort. *P < .001. HR, hazard ratio. From Ennishi D et al: J Clin Oncol 37 (3), 2019: 190-201. Reprinted with permission. © 2019 American Society of Clinical Oncology. All rights reserved.
Prognostic association of double-hit signature (DHITsig) in patients with diffuse large B-cell lymphoma (DLBCL) treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. Kaplan-Meier curves of the DHITsig-positive (DHITsig-pos) germinal center B-cell-like (GCB-) DLBCL versus DHITsig-negative GCB-DLBCL versus activated B-cell-like (ABC-) DLBCL for disease-specific survival (DSS) in the BC Cancer cohort. *P < .001. HR, hazard ratio. From Ennishi D et al: J Clin Oncol 37 (3), 2019: 190-201. Reprinted with permission. © 2019 American Society of Clinical Oncology. All rights reserved.
In Brief
So, should the definition of this poor-prognosis DLBCL be revised from “DH DLBCL” to “DH signature DLBCL?” This change would create a new, larger category with about half of the cases harboring traditional DH rearrangements by FISH. Presumably, validation by other groups is needed before such a proposal can be adopted. If this broader category is the future, then most of the high-risk patients with GCB fit under this definition. The remaining GCB DLBCL cases (the ones without a DH signature) have an outstanding prognosis of greater than 90 percent cured with standard R-CHOP (rituximab + cyclophosphamide, doxorubicin, vincristine, and prednisone) and perhaps do not require the same attention for novel drug development and clinical trials (Figure).
