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.
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.