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 characterized by genomic alterations and expression signatures capable of sustaining an inflammatory environment. These mutational alterations (PIM1,SPEN, andMYD88[L265P]) and expression signatures (NF-kappa B, 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 similar to 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.

Automated summary

A study identified a high-risk subset of non-GCB DLBCL patients with genomic alterations and expression signatures affecting treatment outcomes, showing unfavorable prognoses with RCHOP therapy. However, these high-risk patients had better outcomes when lenalidomide was added to RCHOP treatment.