DLBCL patients are at higher risk when they relapse early after R-CHOP chemotherapy and have a poor response to second-line rituximab-containing treatments even when these regimens involve high-dose therapy and autologous stem<unk>  transplant. Approximately half of DLBCL patients develop CHOP-resistant<unk> s. A study of DLBCL<unk>  lines indicated that 14-3-3ζ proteins may play a role in mediating resistance of DLBCL<unk> s to CHOP. 14-3-3 proteins exert anti-apoptotic activity by interfering with the function of BH3-only proteins and has been validated as a potential molecular target for anticancer therapeutic development in other types of cancers. Monoclonal antibodies Monoclonal antibodies are made by injecting human cancer<unk> s into mice so that their immune systems create antibodies against foreign antigens. Monoclonal antibodies target specific antigens on cancer<unk> s and may enhance the patient's immune response. They can be administered alone or be linked (conjugated) to anticancer drugs, radioisotopes, or other biologic response modifiers. There are several therapeutic mechanisms for monoclonal antibodies: # Directly initiates apoptosis in the targeted<unk> s # Antibody-dependent<unk> -mediated cytotoxicity (ADCC) -- Recruits monocytes, macrophages, and natural killer<unk> s to destroy the targeted<unk> s # Complement-dependent cytotoxicity (CDC)-- Initiates the complement system which activates the membrane attack complex causing<unk>  lysis and death. # Delivers chemotherapy or radiation in a targeted manner which allows higher concentrations to be administered Monoclonal antibodies for treatment of B-cell malignancies * CD20. Approximately 95% of B-cell lymphomas express CD20, but CD20 is not critical for B-cell survival. Clonal B-cells spontaneously mutate the idiotypic region of their immunoglobulin. This high mutation rate makes them prone to the selection of B-cells lacking the CD20 antigen following treatment with CD20-targeting monoclonal antibodies. As a result, CD20 may lose its effectiveness as a target after as little as one or two treatments with monoclonal antibodies such as rituximab. A study in Japan found that approximately 26% of relapsed B-cell lymphoma patients lost CD20 expression during treatment with rituximab. Lab tests involving 5-Aza showed that CD20 expression and rituximab sensitivity could be restored in some cases using epigenetic drug treatment. * Rituximab (Rituxan. The mechanism of action of Rituximab against DLBCL is not fully understood, but studies suggest that rituximab modulates<unk> ular and molecular signal transduction pathways that regulate bcl-2-expression. Interaction between bcl-2 expression and IL-10 growth factors may contribute to the resistance mechanisms of DLBCL to chemotherapy. * Tositumomab (Bexxar). Anti-CD20 conjugated with radionuclide iodine-131 * Ibritumomab tiuxetan (Zevalin). Anti-CD20 conjugated with radioactive isotope (either yttrium-90 or indium-111) * CD22. Approximately 85% of DLBCLs express CD22. It is expressed on pre-B and mature B<unk> s, and expression is lost upon maturation to plasma<unk> s. * Epratuzumab (Lymphocide). After binding epratuzumab, CD22 is rapidly internalized.<unk>  death does not appear to be mediated by complement, but modest antibody-dependent<unk> ular cytotoxicity and direct killing effects have been demonstrated. * CD70. In normal lymphoid tissues CD27 and its ligand CD70 have a restricted expression pattern, but a 1999 study found CD70 on 71% of large B-cell lymphomas. * Vorsetuzumab mafodotin (antibody conjugated to monomethyl auristatin F). Monomethyl auristatin F is a mitotic inhibitor. Preliminary data from a phase I clinical trial of vorsetuzumab mafodotin showed that of the 7 patients with non-Hodgkin lymphoma, one achieved complete remission, four were stable, one experienced progressive disease, and one was not evaluable. Bcl-2 inhibitors Apoptosis is one of the major mechanisms of<unk>  death targeted by cancer therapies. Reduced susceptibility to apoptosis increases the resistance of cancer<unk> s to radiation and cytotoxic agents. B-cell lymphoma-2 (Bcl-2) family members create a balance between pro and anti-apoptotic proteins. Pro-apoptotic proteins include Bax and Bak. Anti-apoptotic proteins include Bcl-2, Bcl-XL, Bcl-w, Mcl-1. When anti-apoptotic family members are overexpressed, apoptotic<unk>  death becomes less<unk> ly. * Oblimersen sodium (G3139, Genasense) targets BCL-2 mRNA * ABT-737 (oral form navitoclax, ABT-263). A small molecule that targets anti-apoptotic Bcl-2 family proteins (Bcl-2, Bcl-XL and Bcl-w). ABT-737 binds anti-apoptotic Bcl-2 proteins with an affinity two or three orders of magnitude more potent than previously reported compounds. High basal levels of Mcl-1 expression are associated with resistance to ABT-737. Combining ABT-737 with second agents that inactivate Mcl-1 may reduce this effect. ABT-737 has demonstrated single-agent efficacy against<unk>  lines from lymphoid malignancies known to express high levels of Bcl-2, including DLBCL. It has also been found to be synergistic with proteasome inhibitors. * Fenretinide. A synthetic retinoid that induces apoptosis of cancer<unk> s and acts synergistically with chemotherapeutic drugs by triggering the activation of 12-Lox (12-lipoxygenase) leading to oxidative stress and apoptosis via the induction of the transcription factor Gadd153 and the Bcl-2-family member protein Bak. mTOR (mammalian target of rapamycin) inhibitors mTOR inhibitors : * Everolimus * Temsirolimus mTOR is a kinase enzyme inside the<unk>  that regulates<unk>  growth, proliferation, and survival. mTOR inhibitors lead to<unk>  cycle arrest in the G1 phase and also inhibits tumor angiogenesis by reducing synthesis of VEGF. A Phase II trial of Evorolimus on relapsed DLBCL patients showed a 30% Overall Response Rate (ORR). Syk (Spleen Tyrosine Kinase) inhibitors Syk inhibitors include : * Fostamatinib * Tamatinib Chronic signaling through the B-cell receptor appears to contribute to the survival of DLBCL. These survival signals can be blocked by Syk inhibitors. However, since the BCR signaling pathway is not as important to the GCB DLBCL as it is to the ABC subtype, Syk inhibitors may not be effective against GCB DLBCL Proteasome inhibitors * Bortezomib (Velcade) Proteasome inhibitors inhibit the NF-κB pathway. Since this pathway is not a significant factor in GCB DLBCL, proteasome inhibitors have not been found to be effective against GCB DLBCL. A clinical trial of bortezomib showed that bortezomib alone had no activity in DLBCL, but when combined with chemotherapy, it demonstrated an ORR of 83% in ABC DLBCL and 13% in GCB DLBCL, suggesting that bortezomib enhances the activity of chemotherapy for ABC but not GCB DLBCL when combined with conventional chemotherapy.
Germinal center B-cell like diffuse large B-cell lymphoma
Diffuse large B-cell lymphoma associated with chronic inflammation
Epstein–Barr virus positive diffuse large B-cell lymphoma, not otherwise specified
T cell/histiocyte-rich large B-cell lymphoma
Nodular lymphocyte predominant Hodgkin lymphoma
Extranodal NK/T-cell lymphoma, nasal type
Large B-cell lymphoma arising in HHV8-associated multicentric Castleman's disease
Pediatric-type follicular lymphoma