Neoplastic cell expression of CD30 in DLBCL, NOS is a favorable prognostic indicator; in these cases, brentuximab vedotin may be a useful addition to chemotherapy treatment protocols. This agent is a CD30-targeting antibody that delivers a toxin, monomethyl auristatin E, to CD30-expressing cells, has therapeutic efficacy against other CD30-expressing lymphomas, and may prove useful in treating the 10–15% of DLBCL, NOS cases expressing this protein. The neoplastic cells in the GBC variant of DLBCL, NOS often have mutations in the "EZH2, BCL2" and "CREBBP" genes and overactive PI3K/AKT/mTOR and JAK-STAT signaling pathways while neoplastic cells in the ABC variant often have mutations in the "MYD88, CD79A" and "CD79B" genes and overactive B-cell receptor, toll-like receptor, and NF-κB signaling pathways. These different gene mutations and dysregulated signaling pathways are also being studied as potential therapeutic targets for the individualized treatment of GBC and ABC/non-GBC cases. CUDC-907, an inhibitor of PI3K and histone deacetylases, is being evaluated in two separate clinical trials for the treatment of refractory and/or relapsed DLBCL, NOS including cases with alterations in the "MYC gene". GSK525762, an inhibitor of the BET family of proteins, suppresses expression of the "MYC" gene and is undergoing a phase I clinical trial for the treatment of high-grade B-cell lymphoma with "MYC, BL2," and/or "BL6" rearrangements (i.e. DH/THL). RO6870810, another BET inhibitor, in combination with Venetoclax, an inhibitor of the Bcl-2 protein, is likewise in a phase I clinical trial for the treatment of DH/THL.