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Molecular high-grade B-Cell lymphoma: defining a poor-risk group that requires different approaches to therapy

Molecular high-grade B-Cell lymphoma: defining a poor-risk group that requires different approaches to therapy
Molecular high-grade B-Cell lymphoma: defining a poor-risk group that requires different approaches to therapy
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.
1527-7755
202-213
Sha, Chulin
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Barrans, Sharon
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Cucco, Francesco
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Bentley, Michael A.
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Care, Matthew A.
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Cummin, Thomas
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Kennedy, Hannah
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Sneath Thompson, Joe
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Uddin, Rahman
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Worrillow, Lisa
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Chalkley, Rebecca
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van Hoppe, Moniek
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Ahmed, Sophia
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Maishman, Tom
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Caddy, Joshua
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Schuh, Anna
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Mamot, Christoph
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Burton, Catherine
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Tooze, Reuben
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Davies, Andrew
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Du, Ming-Qing
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Johnson, Peter W.M.
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Westhead, David R.
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Sha, Chulin
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Barrans, Sharon
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Cucco, Francesco
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Bentley, Michael A.
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Care, Matthew A.
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Cummin, Thomas
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Kennedy, Hannah
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Sneath Thompson, Joe
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Uddin, Rahman
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Worrillow, Lisa
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Chalkley, Rebecca
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van Hoppe, Moniek
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Ahmed, Sophia
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Maishman, Tom
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Caddy, Joshua
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Schuh, Anna
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Mamot, Christoph
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Burton, Catherine
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Tooze, Reuben
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Davies, Andrew
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Du, Ming-Qing
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Johnson, Peter W.M.
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Westhead, David R.
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Sha, Chulin, Barrans, Sharon, Cucco, Francesco, Bentley, Michael A., Care, Matthew A., Cummin, Thomas, Kennedy, Hannah, Sneath Thompson, Joe, Uddin, Rahman, Worrillow, Lisa, Chalkley, Rebecca, van Hoppe, Moniek, Ahmed, Sophia, Maishman, Tom, Caddy, Joshua, Schuh, Anna, Mamot, Christoph, Burton, Catherine, Tooze, Reuben, Davies, Andrew, Du, Ming-Qing, Johnson, Peter W.M. and Westhead, David R. (2018) Molecular high-grade B-Cell lymphoma: defining a poor-risk group that requires different approaches to therapy. Journal of Clinical Oncology, 37 (3), 202-213, [37]. (doi:10.1200/JCO.18.01314).

Record type: Article

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.

Text
jco.18.01314 - Version of Record
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More information

Accepted/In Press date: 1 November 2018
e-pub ahead of print date: 3 December 2018
Published date: 3 December 2018

Identifiers

Local EPrints ID: 426755
URI: http://eprints.soton.ac.uk/id/eprint/426755
ISSN: 1527-7755
PURE UUID: 7e6b1deb-99fc-4e9b-bb4d-68ed74234ece
ORCID for Andrew Davies: ORCID iD orcid.org/0000-0002-7517-6938
ORCID for Peter W.M. Johnson: ORCID iD orcid.org/0000-0003-2306-4974

Catalogue record

Date deposited: 11 Dec 2018 17:30
Last modified: 26 Nov 2021 02:53

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Contributors

Author: Chulin Sha
Author: Sharon Barrans
Author: Francesco Cucco
Author: Michael A. Bentley
Author: Matthew A. Care
Author: Thomas Cummin
Author: Hannah Kennedy
Author: Joe Sneath Thompson
Author: Rahman Uddin
Author: Lisa Worrillow
Author: Rebecca Chalkley
Author: Moniek van Hoppe
Author: Sophia Ahmed
Author: Tom Maishman
Author: Joshua Caddy
Author: Anna Schuh
Author: Christoph Mamot
Author: Catherine Burton
Author: Reuben Tooze
Author: Andrew Davies ORCID iD
Author: Ming-Qing Du
Author: David R. Westhead

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