Molecular High-Grade B-Cell Lymphoma: Defining a Poor-Risk Group That Requires Different Approaches to Therapy

Abstract

Purpose Biologic heterogeneity is a feature of diffuse large B-cell lymphoma (DLBCL), and the existence of a subgroup with poor prognosis and phenotypic proximity to Burkitt lymphoma is well known. Conventional cytogenetics identifies some patients with rearrangements of MYC and BCL2 and/or BCL6 (double-hit lymphomas) who are increasingly treated with more intensive chemotherapy, but a more biologically coherent and clinically useful definition of this group is required. Patients and Methods We defined a molecular high-grade (MHG) group by applying a gene expression–based classifier to 928 patients with DLBCL from a clinical trial that investigated the addition of bortezomib to standard rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) therapy. The prognostic significance of MHG was compared with existing biomarkers. We performed targeted sequencing of 70 genes in 400 patients and explored molecular pathology using gene expression signature databases. Findings were validated in an independent data set. Results The MHG group comprised 83 patients (9%), with 75 in the cell-of-origin germinal center B-cell-like group. MYC rearranged and double-hit groups were strongly over-represented in MHG but comprised only one half of the total. Gene expression analysis revealed a proliferative phenotype with a relationship to centroblasts. Progression-free survival rate at 36 months after R-CHOP in the MHG group was 37% (95% CI, 24% to 55%) compared with 72% (95% CI, 68% to 77%) for others, and an analysis of treatment effects suggested a possible positive effect of bortezomib. Double-hit lymphomas lacking the MHG signature showed no evidence of worse outcome than other germinal center B-cell-like cases. Conclusion MHG defines a biologically coherent high-grade B-cell lymphoma group with distinct molecular features and clinical outcomes that effectively doubles the size of the poor-prognosis, double-hit group. Patients with MHG may benefit from intensified chemotherapy or novel targeted therapies.

New prognosis score including absolute lymphocyte/monocyte ratio, red blood cell distribution width and beta‐2 microglobulin in patients with diffuse large B‐cell lymphoma treated with R‐CHOP: Spanish Lymphoma Group Experience (GELTAMO)

“…The adverse prognostic effect of MYC translocation seems to increase in the presence of an additional chromosomal breakpoint involving the BCL2 or BCL6 loci. These 'double-hit' lymphomas seem to have an extremely aggressive clinical course and poor response to standard chemotherapy (Sha et al, 2019). Besides, gene expression profiling for the cell of origin is a genomics tool that utilizes DNA microarray to assess gene expression and at least three molecularly distinct forms of DLBCL have been identified: the germinal centre Bcell, activated B-cell and primary mediastinal B-cell subtypes (Alizadeh et al, 2000).…”

Double‐hit lymphoma: So what?

“…Through the use of gene expression profiling, recognition of high‐risk disease has recently moved beyond FISH identification of the three described translocations. Two groups used independent data sets to look either for a Burkitt‐like gene expression signature or a signature associated with the known presence of DHL in large cohorts of patients with DLBCL. This approach identified most DHL patients but also many non–double‐hit lymphomas, representing over half of the group, cosegregated with the same gene expression signatures.…”

Clinical Interest of LMO2 Testing for the Diagnosis of Aggressive Large B-Cell Lymphomas

“…Favorable outcomes of DH-FL were also observed in other studies in patients treated with conventional or intensive schemes [25][26][27]. Recent studies have defined the molecular high-grade B-cell lymphoma profile (MGH) by gene expression and mutational analysis [28,29]. These studies identified cases that did not carry MYC rearrangements and behaved aggressively.…”