First, the conclusion: R-CHOP is sufficient for germinal center type, and clinical trials of R-CHOP plus other drugs are recommended for non-germinal center type (non-specialists may not read the detailed description below). Because: Diffuse large B-cell lymphoma (DLBCL) is divided into anaplastic and anaplastic (or ABC) according to WHO. If there is C-MYC positivity by FISH with BCL-2 or BCL-6 positivity, WHO calls this type of lymphoma a two- or three-hit lymphoma, which cannot be classified as a diffuse large B-cell lymphoma, and the prognosis of these patients is poor, and they often relapse very quickly after autologous transplantation. Immunohistochemistry with C-MYC positivity with BCL-2 or BCL-6 positivity is called double- or triple-expression lymphoma. These lymphomas are still classified as diffuse large B-cell lymphomas, and the prognosis is variable, but it is generally agreed that the prognosis may be worse than that of the germinal center type. Previous studies have concluded that DA-EPOCH chemotherapy with increased chemotherapy doses is as efficacious as R-CHOP. However, with the gradual subdivision of diffuse large B-cell lymphoma, it was found that increasing the chemotherapy dose for the germinal center type did not improve overall survival, with RCHOP treating the germinal center type with a disease-free survival and overall survival rate of 70% and 75%, respectively, at 5 years [1]. da-EPOCH-R versus R-CHOP A multicenter trial reported no difference in remission or disease-free survival and overall survival at two years in 491 patients randomly assigned to da-EPOCH-R versus R-CHOP [2]. grade ≥3 adverse events were more common with da-EPOCH-R, including infections (17% versus 11%), neutropenia fever (35% vs. 18%), mucositis (8% vs. 2%), and neuropathy (19% vs. 3%). R-CHOP-14 (14 days of chemotherapy) versus R-CHOP-21 (28 days of chemotherapy) A trial of 1,080 patients with newly diagnosed DLBCL was randomly assigned to eight cycles of R-CHOP-21 versus six cycles of R-CHOP-14 therapy followed by two additional doses of rituximab [3]. At a median follow-up of 46 months, there was no significant difference in disease-free survival or overall survival between the two treatment groups. Another trial randomized 600 older adults with DLBCL to eight cycles of R-CHOP-14 and eight cycles of R-CHOP-21 and reported similar rates of complete remission, disease-free production period, and overall survival between the two regimens [4].CHOP-14 has been associated with increased toxicity, including an increased risk of Pneumocystis pneumonia [5]. R-CEOP Some clinicians believe that CEOP (with epirubicin instead of adriamycin) has the same efficacy as CHOP, but this has not been confirmed. Only one trial that randomly assigned 217 patients with aggressive lymphoma to R-CEOP-14 versus R-CEOP-21 reported no significant differences in complete remission rates, overall remission rates, or overall survival rates [6]. However (generally but followed by koan yo), patients with ABC-type DLBCL or double-strike DLBCL have unacceptably high relapse rates and poor survival rates after treatment with R-CHOP. Patients with double/triple strike DLBCL have an even worse prognosis [7]. For the non-growth center type, participation in clinical trials is encouraged (the guidelines are not currently available and it is expected that they may be changed in the future). The 5-year disease-free survival and overall survival rates for such patients using standard treatment with R-CHOP are 45% and 50%, respectively [8].A chemotherapy regimen of R-CHOP plus an additional agent may correct the poor prognostic outcome of such patients, with conclusions based on the following studies. R-ACVBP: plus bleomycin Disease-free survival and overall survival were superior to R-CHOP when used in younger patients in a prospective randomized trial [9]. The trial randomly assigned 379 young patients (<60 years) with newly diagnosed DLBCL to one of eight cycles of R-ACVBP (four cycles of rituximab, adriamycin, cyclophosphamide, vincristine, bleomycin, and prednisone followed by combined methotrexate and folinic acid) or R-CHOP-21. R-ACVBP was associated with similar rates of complete remission (83% versus 80%) and higher rates of three-year disease-free productive period (81% versus 67%) and overall survival (92% versus 84%) compared with R-CHOP-21. r-ACVBP was associated with more hematologic and non-hematologic toxicities. Further analysis of this study suggests that the superiority of R-ACVBP over R-CHOP is limited to tumors with immunohistochemical profiles indicating a non-growth center B-cell-like phenotype (CD10- and BCL6- or CD10-/BCL6+/MUM1+ to benefit) [10]. R-CHOP plus lenalidomide (R2-CHOP) An open-label, single-arm, multicenter trial (REAL07) evaluated the use of R-CHOP plus lenalidomide (R2-CHOP) in 49 older adults (60 to 80 years of age) with previously untreated advanced DLBCL or grade 3b follicular lymphoma [8]. Treatment consisted of six cycles of oral lenalidomide (15 mg on days 1 to 14) in combination with standard R-CHOP-21. The overall response and CR rates were 92% and 86%, respectively. Severe (grade 3/4) toxicities included neutropenia (31%), leukopenia (28%), and thrombocytopenia (13%). After a median follow-up of 28 months, the estimated two-year disease-free and overall survival rates were 80% and 92%, respectively. The prognosis was similar for the germinal-neutral and non-germinal-centered types. In another phase II trial of R2-CHOP, 64 patients with previously untreated advanced DLBCL were treated with oral lenalidomide (25 mg on days 1 through 10) plus standard dose R-CHOP-21 administered for six cycles [11]. Of the 60 patients available for response assessment, the overall response rate was 98% (80% completion rate).Estimated progression-free and overall survival rates at 24 months were 59% and 78%, respectively.Progression-free survival rates were similar for GCB and ABC subtypes. Hematologic toxicity was common. 25% of patients experienced severe (grade 3/4) nonhematologic toxicity. One patient died of sepsis following intestinal perforation at the site of DLBCL involvement after the first cycle of R2-CHOP. Three patients developed second malignancies (acute myeloid leukemia, glioblastoma, and metastatic colon cancer). R-CHOP plus ibrutinib A multicenter trial reported no difference in progression-free survival and overall survival after a median of 35 months in 838 non-GCBDLBCL patients (76% ABC subtype) who were randomly assigned to the R-CHOP plus ibrutinib group versus the R-CHOP group alone [12]. In patients <60 years of age, ibrutinib plus R-CHOP was associated with improved progression-free survival, disease-free survival, and overall survival with manageable toxicity, but side effects were increased in patients over 60 years of age plus ibrutinib. R-CHOP plus bortezomib A single-arm phase II trial evaluated the use of R-CHOP plus bortezomib in 40 patients with previously untreated DLBCL [13]. 88% of patients had a partial or better response, and 75% achieved near complete remission. At a median follow-up of 51 months, the two-year disease-free and overall survival rates were 64% and 70%, respectively. The addition of bortezomib was associated with a higher than usual incidence of peripheral neuropathy. However, it resulted in a consistent prognosis between germinal center and non-germinal center types. In a randomized trial of 164 non-GCBDLBCL patients, no benefit was found by replacing vincristine in R-CHOP with bortezomib (VR-CAP).