Targeting of inflammatory pathways with R2CHOP in high-risk DLBCL
Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma, and front line therapies have not improved overall outcomes since the advent of immunochemotherapy. By pairing DNA and gene expression data with clinical response data, we identified a high-risk subset of non-GCB DLBCL patients chara...
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Published in | Leukemia Vol. 35; no. 2; pp. 522 - 533 |
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Main Authors | , , , , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
London
Nature Publishing Group UK
01.02.2021
Nature Publishing Group |
Subjects | |
Online Access | Get full text |
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Summary: | Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma, and front line therapies have not improved overall outcomes since the advent of immunochemotherapy. By pairing DNA and gene expression data with clinical response data, we identified a high-risk subset of non-GCB DLBCL patients characterized by genomic alterations and expression signatures capable of sustaining an inflammatory environment. These mutational alterations (
PIM1
,
SPEN
, and
MYD88
[L265P]) and expression signatures (NF-κB, IRF4, and JAK-STAT engagement) were associated with proliferative signaling, and were found to be enriched in patients treated with RCHOP that experienced unfavorable outcomes. However, patients with these high-risk mutations had more favorable outcomes when the immunomodulatory agent lenalidomide was added to RCHOP (R2CHOP). We are the first to report the genomic validation of a high-risk phenotype with a preferential response towards R2CHOP therapy in non-GCB DLBCL patients. These conclusions could be translated to a clinical setting to identify the ~38% of non-GCB patients that could be considered high-risk, and would benefit from alternative therapies to standard RCHOP based on personalized genomic data. |
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Bibliography: | Co-Senior Authors K.T.H., T.E.W., G.S.N, and A.J.N. collected, analyzed and interpreted the data, and drafted the paper. T.E.W., S.M.A., T.M.H., and G.S.N participated in the clinical studies. W.R.M, R.L.K, and A.L.F performed pathologic review of the cases. K.T.H., K.W., J.K., M.M., V.S., Y.A., M.J.M, and M.L. performed experiments, bioinformatic and statistical analyses. A.K.G. and J.C. helped design the study and edited the manuscript. Author Contributions |
ISSN: | 0887-6924 1476-5551 |
DOI: | 10.1038/s41375-020-0766-4 |