burkitt lymphoma" (i.e. bclu) but were separated into dh/thl and hgbc, nos by the world health organization, 2016. the neoplastic cells in a related variant, double expresser lymphoma (i.e. del), express the products of myc and bcl2 genes, i.e. c-myc and bcl-2 proteins, respectively, but do not have translocations in either of their genes. del, which represents about one-third of all dlbcl, nos cases, has a poorer prognosis than standard dlbcl, nos but not as poor as dh/thl cases. cases in which the neoplastic cells have alterations in the myc gene or its expression without changes in blc2 or blc6 also have a poor prognosis, particularly in cases where the myc gene translocates (i.e. rearranges) with one of the immunoglobulin gene loci. dlbcl that begin in the testicles are a variant of dlbcl, nos that some authors suggest should be classified as a distinct dlbcl subtype. this variant, termed primary testicular diffuse large b-cell lymphoma (pt-dlbcl), is a dlbcl, nos that in >75% of cases involves activated b-cells, i.e. abc. these cells, which typically have a centroblast-like morphology, infiltrate one or, in ~6% of cases, both testicles. pt-dlbcl is an aggressive disease that often spreads to the central nervous system and has median overall survival and progression-free survival times of 96 and 49 months, respectively. the neoplastic cells in almost all cases of dlbcl, nos express cd20. commercially available anti-cd20 antibody agents such as rituximab or obinutuzumab (which is sometimes used in place of rituximab) kill cells that express high levels of cd20 by binding to this cell-surface protein and thereby targeting them for attack by the hosts adaptive immune system. the addition of one of these immunotherapy agents to chemotherapy protocols has greatly improved the prognosis of most dlbcl, nos variants. neoplastic cell expression of cd30, found in 10–15% of dlbcl, nos cases is a favorable prognostic indicator. as indicated in the following treatments and prognoses section, expression of the cd20 and cd30 proteins as well as the cd19, cd20 cd22, cd30, cd79a, cd79b, and d-l1 proteins, expression of the myc, bcl2, myd88nd, and crebbp genes, and expression of the pi3k/akt/mtor, jak-stat, b-cell receptor, toll-like receptor, and nf-κb signaling pathways are being studied as potential therapeutic targets for the individualized treatment of gbc and abc/non-gbc dlbcl, nos cases. first-line therapy first-line therapy for patients with the gbc variant of dlbcl, nos is r-chop. r-chop consists of rituximab, three chemotherapy drugs (cyclophosphamide, doxorubicin, and vincristine) and a glucocorticoid (either prednisone or prednisolone). the regimen achieves cure, relapse following remission, and unresponsive rates of 60–70%, 30–40% and <10%, respectively, in gbc variant cases. relapses generally occur within the first 3 years of diagnosis with few cases doing so after 5 years. patients who are refractory to, relapse within 1 year of diagnosis before starting, relapse within 6 months after completing, or progress within 2 years of starting r-chop have poorer prognoses. r-chop is less effective and not recommended for patients who have myc, bl2, and/or bl6 rearrangements regardless of their gbc, abc, or non-gbc type. one recommendation for treating these dh/thl cases is the da-r-epoch regimen (dose-adjusted rituximab, etoposide, prednisolone, oncovin, cyclophosphamide, and hydroxydaunorubicin). s-r-epoch achieves 2 year survival rates of 40–67% compared to a ~25% survival rate for r-chop in these cases. da-r-epoch has also been recommended for patients with double expresser lymphoma although some experts recommend treating this variant more like a typical dlcbl, nos. first-line therapy for patients with the abc, undetermined, or non-gbc variants has been the da-r-epoch regimen. patients with these variants (including those with double expresser lymphoma) have had a ~40% cure rate when treated with it. a randomized clinical trial conducted in france reported that a r-acvbp chemotherapy regimen (rituximab, adriamycin, cyclophosphamide, vindesine, bleomycin, and cytarabine followed by sequential consolidation therapy with systemic methotrexate, ifosfamide, and etoposide, and then cytarabine) achieved significantly better response rates than r-chop in abc/ngc variant cases lymphoma. in dlbcl, nos variants which trend to spread or to the central nervous system, methotrexate has been recommended to be added to regimens not containing it for use as prophylaxis to reduce the incidence of this complication. the role of autologous stem-cell transplantation as an addition to first-line therapy in the treatment of dlbcl, nos, including cases with a poor prognosis, is unclear. a phase i clinical research trial found that the addition of lenalidomide to the r-chop regimen produce an ~80% complete response rate in gbc as well as non- gbc dlbcl, nos variants. two phase iii clinical research trials are underway to confirm these results and determine if the r-chop + lenalidomide regimen is superior to r-chop in the up-front treatment of gbc and/or non-gbc variants. treatment of recurrent and refractory dlbcl, nos patients with dlbcl, nos who relapse or progress following first-line therapy have been treated with "salvage regimens" consisting of high-dose (also termed high-intensity) chemotherapy conditioning drugs followed by autologous stem cell transplantation. this regimen has attained 3-year progression-free survival rates of 21–37%. relapse following this treatment carries a very poor prognosis with median overall survival times of ~10 months. patients who have failed or because of health issues are ineligible for autologous stem cell transplantation have been treated with low-dose (i.e. low-intensity) chemotherapy conditioning regimens followed by allogeneic stem cell transplantation. this regimen has achieved 3 year progression-free and overall survival rates of 41% and 52%, respectively. further studies are underway to determine the best treatment regimens for these cases. 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 patient's neoplastic b-cells by isolating this patient's 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. however, design of cars as well as the antigens chosen to be their targets are constantly being changed in order to improve the efficacy of this therapeutic strategy. car-t therapy for dlbcl, nos has been used on patients who are refractory to and/or have progressed on first-line as well as salvage (including autologous stem cell transplantation) treatment regimens. patients are treated first with a conditioning chemotherapy regimen, usually cyclophosphamide and fludarabine, and then infused with their own t-cells that have been engineered to attack cd19-bearing or, rarely, cd20-bearing cells. a meta-analysis of 17 studies using this or very similar approaches to treat dlbcl, nos found the treatments gave complete and partial responses rates of 61% and 43%, respectively. while these studies did not have control groups and were too recent for meaningful estimates of remission durations, the remission rates were higher than expected using other treatment approaches. significant and potentially lethal therapeutic complications of this therapy included development of the cytokine release syndrome (21% of cases), neurotoxicity, i.e. the car-t cell-related encephalopathy syndrome (9% of cases), and the hemophagocytic lymphohistiocytosis/macrophage-activation syndrome (i.e. a form of hemophagocytic lymphohistiocytosis). individual studies within and outside of this meta-analysis have reported remissions lasting >2 years but also lethal cytokine release syndrome and neurotoxicity responses to this therapy. as a consequence of these studies, the committee for advanced therapies and the committee for medicinal products for human use of the european medicines agency recommend granting marketing authorization for tisagenlecleucel (i.e. chimeric antigen receptor t cells directed against cd19) in adult patients with dlbcl, nos who have relapsed after or are refractory to two or more lines of systemic therapy. the committee for orphan medicinal products of the european medicines agency recommends tisagenlecleucel retain its orphan drug designation. the usa food and drug administration (fda) has also approved the use of this drug for relapsed or refractory dlbcl of the large b-cell lymphoma subtype in patients who have failed after two or more lines of systemic therapy. monoclonal antibodies directed against cd19, cd22, cd30, and pd-l1 have been developed for use as immunotherapeutic agents in other hematological malignancies and are being or plan to be tested for their usefulness in dlbcl, nos. in august 2020, the fda approved the humanized fc-modified cytolytic cd19 targeting monoclonal antibody tafasitamab in combination with lenalidomide as a treatment for adult patients with relapsed or refractory dlbcl. in april 2021, the fda approved the cd19-directed antibody-drug conjugate loncastuximab tesirine as a treatment for adult patients with relapsed or refractory dlbcl after systemic therapy. glofitamab (columvi) is a bispecific monoclonal antibody that was approved for medical use in canada in march 2023. emerging therapies 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 (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. subtypes of diffuse large b-cell lymphoma dlbcl subtypes have been sorted into groups based on their distinctive morphology or immunophenotype, distinctive clinical issues, and distinctive virus-driven etiology. the prognoses and treatment of these subtypes varies with their severity. most subtypes are aggressive diseases and consequently treated in a manner similar to dlbcl, nos. further details on these subtypes, including their treatments, can be found in their respective main article linkages. t cell/histiocyte-rich large b-cell lymphoma main article: t cell/histiocyte-rich large b-cell lymphoma t-cell/histiocyte-rich large b-cell lymphoma (thrlbcl) is a dlbcl in which tumors containing small numbers of usually large neoplastic b-cells embedded in a background of reactive t-cells and histiocytes develop in the liver, spleen, bone marrow and/or, rarely other sites. patients usually present with advanced disease; their overall 3 year survival rates in different studies range between 46% and 72%. alk+ large b-cell lymphoma main article: alk+ large b-cell lymphoma alk+ large b-cell lymphoma (alk+ lbcl) is a dlbcl in