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 (polatuzumab vedotin) 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. Pharmacological inhibition of BCL-2 is effective in most B cell lymphomas, but often leads to acquired resistance due to the expression of other major anti-apoptotic BCL-2 family proteins like BCL-XL and MCL-1. Combined therapy using MCL-1 inhibitor (S63845) or BCL-XL inhibitor (A-1331852) in addition to Venetoclax can be a solution to overcome this issue.
Patients refractory to first-line therapy or who relapse within 12 months of receiving salvage therapy (including bone marrow transplant) for recurrent disease have had poor prognoses with median overall survival rates of 3.3 and 6.3 months, respectively. The prognosis of these patients appears to be improved by using CAR-T therapy. Chimeric antigen receptor T cell (i.e. CAR-T) adoptive cellular immunotherapy has emerged as a recent advance in treating refractory and relapsed DLBCL, NOS (tisagenlecleucel, axicabtagene ciloleucel, lisocabtagene maraleucel). Chimeric antigen receptor T cells are genetically engineered to express: 1) an artificial T-cell receptor consisting of antigen-recognition and attached hinge domains expressed on their surface membranes; 2) a surface membrane-spanning domain; 3) an intracellular domain which, when the antigen-recognition domain binds its targeted antigen, activates signaling pathways that cause the T-cell to attack and kill cells that bear the recognized antigen on their surface membranes; and 4), in more recently devised second generation CAR-T strategies, an associated intracellular co-stimulating molecule (e.g. CD28 or 4-1BB) which augments activation of the cell-killing signaling pathways. CAR-T therapy, as it pertains to DLBCL, NOS, kills a patients neoplastic B-cells by isolating this patients T-cells; genetically engineering these cells to express an artificial T-cell receptor designed to bind an antigen expressed on the surface of their neoplastic B-cells; and infusing these cells back into the donor patient. The targeted antigen has usually been CD19, a surface membrane protein expressed on virtually all B-cells including the neoplastic cells in DLBCL, NOS.