Molecular High-Grade B-Cell Lymphoma: Defining a Poor-Risk Group That Requires Different Approaches to Therapy.
Bentley, Michael A
Care, Matthew A
Thompson, Joe S
van Hoppe, Moniek
Johnson, Peter WM
Westhead, David R
Journal of Clinical Oncology
American Society of Clinical Oncology
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Sha, C., Barrans, S., Cucco, F., Bentley, M. A., Care, M. A., Cummin, T., Kennedy, H., et al. (2018). Molecular High-Grade B-Cell Lymphoma: Defining a Poor-Risk Group That Requires Different Approaches to Therapy.. Journal of Clinical Oncology https://doi.org/10.1200/JCO.18.01314
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.
Supported by Bloodwise grant number 15002: Precision Medicine for Aggressive Lymphoma. The Randomized Evaluation of Molecular-Guided Therapy for DLBCL With Bortezomib (REMoDL-B) trial was endorsed by Cancer Research UK, reference number CRUKE/10/024, and Janssen-Cillag provided funding. A.S. is partly funded by the National Institute for Health Research Oxford Biomedical Research Centre. D.R.W. acknowledges UK Medical Research Council grant MR/L01629X/1 for infrastructure support.
External DOI: https://doi.org/10.1200/JCO.18.01314
This record's URL: https://www.repository.cam.ac.uk/handle/1810/288672
Attribution 4.0 International
Licence URL: http://creativecommons.org/licenses/by/4.0/
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