Targeting of inflammatory pathways with R2CHOP in high-risk DLBCL

• Published in: Leukemia Vol. 35; no. 2; pp. 522 - 533
• Main Authors: Hartert, Keenan T., Wenzl, Kerstin, Krull, Jordan E., Manske, Michelle, Sarangi, Vivekananda, Asmann, Yan, Larson, Melissa C., Maurer, Matthew J., Slager, Susan, Macon, William R., King, Rebecca L., Feldman, Andrew L., Gandhi, Anita K., Link, Brian K., Habermann, Thomas M., Yang, Zhi-Zhang, Ansell, Stephen M., Cerhan, James R., Witzig, Thomas E., Nowakowski, Grzegorz S., Novak, Anne J.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.02.2021; Nature Publishing Group
• Subjects: 38/39; 45/23; 631/67/1990/291/1621/1915; 631/67/69; 692/308/575; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; B-cell lymphoma; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Cancer Research; Care and treatment; Critical Care Medicine; Cyclophosphamide - administration & dosage; Deoxyribonucleic acid; Development and progression; DNA; Doxorubicin - administration & dosage; Female; Follow-Up Studies; Gene expression; Gene Expression Regulation, Neoplastic - drug effects; Gene mutations; Genetic aspects; Genomics; Health aspects; Hematology; Humans; Immunomodulation; Inflammation; Intensive; Interferon regulatory factor 4; Internal Medicine; Lenalidomide - administration & dosage; Lymphocytes B; Lymphoma; Lymphoma, Large B-Cell, Diffuse - drug therapy; Lymphoma, Large B-Cell, Diffuse - immunology; Lymphoma, Large B-Cell, Diffuse - pathology; Lymphomas; Male; Medicine; Medicine & Public Health; Middle Aged; Mutation; MyD88 protein; NF-κB protein; Oncology; Phenotypes; Prednisone - administration & dosage; Prognosis; Retrospective Studies; Risk; Rituximab - administration & dosage; Signatures; Survival Rate; Vincristine - administration & dosage; Young Adult; United States
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/s41375-020-0766-4

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.