Molecular High-Grade B-Cell Lymphoma: Defining a Poor-Risk Group That Requires Different Approaches to Therapy
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...
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Published in | Journal of clinical oncology Vol. 37; no. 3; pp. 202 - 212 |
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Main Authors | , , , , , , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
American Society of Clinical Oncology
20.01.2019
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Abstract | 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.
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.
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.
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. |
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AbstractList | 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.
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.
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.
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. |
Author | Tooze, Reuben Kennedy, Hannah Worrillow, Lisa Caddy, Josh Westhead, David R Mamot, Christoph Davies, Andrew Barrans, Sharon Cucco, Francesco van Hoppe, Moniek Sha, Chulin Johnson, Peter W M Burton, Catherine Maishman, Tom Thompson, Joe S Bentley, Michael A Care, Matthew A Chalkley, Rebecca Cummin, Thomas Ahmed, Sophia Du, Ming-Qing Uddin, Rahman Schuh, Anna |
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Cites_doi | 10.1056/NEJM199309303291402 10.1111/j.0105-2896.2006.00373.x 10.1182/blood-2016-01-643569 10.18632/oncotarget.653 10.1146/annurev-immunol-020711-075027 10.1016/j.blre.2016.09.004 10.1038/nature11378 10.1038/s41591-018-0016-8 10.1038/leu.2015.299 10.1002/hon.2437_120 10.1038/ng.892 10.1182/blood-2015-05-647602 10.1056/NEJMoa055351 10.1186/s13073-015-0187-6 10.1056/NEJMoa1801445 10.1038/nm.3943 10.1038/35000501 10.1097/PAS.0b013e3181cd3aeb 10.1002/cncr.27396 10.1200/JCO.2016.70.3660 10.1073/pnas.1205299110 10.1038/bjc.2015.94 10.1073/pnas.0506580102 10.1038/nrclinonc.2014.137 10.1371/journal.pone.0055895 10.1038/ng.2468 10.1080/10428194.2016.1228932 10.1038/leu.2015.34 10.1093/bioinformatics/btr260 10.1056/NEJMoa055759 10.1182/blood-2012-03-415380 |
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SubjectTerms | Antibodies, Monoclonal, Murine-Derived - administration & dosage Antineoplastic Combined Chemotherapy Protocols - administration & dosage Antineoplastic Combined Chemotherapy Protocols - therapeutic use Biomarkers, Tumor - genetics Biomarkers, Tumor - metabolism Bortezomib - administration & dosage Cyclophosphamide - administration & dosage Databases, Genetic Doxorubicin - administration & dosage Female Humans Lymphoma, Large B-Cell, Diffuse - drug therapy Lymphoma, Large B-Cell, Diffuse - genetics Lymphoma, Large B-Cell, Diffuse - metabolism Lymphoma, Large B-Cell, Diffuse - pathology Male Middle Aged Neoplasm Grading ORIGINAL REPORTS Prednisone - administration & dosage Proportional Hazards Models Randomized Controlled Trials as Topic Retrospective Studies Rituximab - administration & dosage Transcriptome Vincristine - administration & dosage |
Title | Molecular High-Grade B-Cell Lymphoma: Defining a Poor-Risk Group That Requires Different Approaches to Therapy |
URI | https://www.ncbi.nlm.nih.gov/pubmed/30523719 https://pubmed.ncbi.nlm.nih.gov/PMC6338391 |
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