Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin’s lymphoma (NHL), accounting for 30% to 40% of NHL. In the last decade, landmark advances in the treatment of DLBCL have been made with the use of the anti-CD20 monoclonal antibody rituximab(R). Several international multicenter clinical trials of rituximab in combination with chemotherapy have established strategies to stratify the treatment of DLBCL based on the International Prognostic Index (IPI) risk, age, and other factors. These studies show that the treatment of DLBCL is becoming increasingly refined and precise, with an emphasis on stratified and moderate treatment. However, the tremendous progress has also raised many new issues, the resolution of which undoubtedly still requires multicenter prospective clinical trials. In addition, the results of these studies originated from abroad, and given the genetic differences between Eastern and Western populations, it is necessary to conduct multicenter prospective clinical trials for domestic DLBCL patients to establish the best treatment strategy for DLBCL in the national population.
First-line treatment of DLBCL Sun Zhiqiang, Department of Hematology, Affiliated Hospital of Guizhou Medical University
For patients with primary treatment, three different levels of DLBCL are treated, mainly based on age and IPI risk, including elderly (>60 years old), young low-risk [corrected age IPI (aaIPI) score 0-1] and young high-risk (aaIPI score 2-3) DLBCL.
Aged DLBCL Several international multicenter prospective randomized clinical trials have established the first-line treatment status of the R-CHOP regimen. For example, the GELA study in France and the RICOVER-60 study in the German Highly Malignant Non-Hodgkin’s Lymphoma (DSHNHL) Study Group have shown that the R-CHOP group had better event-free survival (EFS), progression-free survival (PFS), disease-free survival (DFS), and overall survival (OS) than the CHOP group. In addition, the RICOVER-60 study suggests that 6 courses of R-CHOP-14 are optimal for older primary DLBCL.
The 34-month follow-up data from the MInT study of young low-risk DLBCL showed that the rituximab combined with chemotherapy group (413 cases) had significantly better 3-year EFS (79% vs. 59%, P < 0.0001) and OS (93% vs. 84%, P = 0.0001) than the chemotherapy alone group (411 cases). Comparing the different chemotherapy regimens, the 3-year EFS and OS were comparable in the R-CHOP-21 and R-CHOEP-21 groups, and therefore the 6-course R-CHOP-21 regimen is recommended for young low-risk primary DLBCL patients.
Young high-risk DLBCL There is no accepted treatment option for young patients with aaIPI score of 2 to 3. The main treatment strategy is rituximab combined with high-dose or highly intensive chemotherapy and autologous hematopoietic stem cell transplantation (ASCT) after remission. The results of the Italian GIMURELL study showed that the 4-year FFS and OS of this treatment were 73% and 80%, respectively, significantly better than historical controls (44% and 54%, P=0.001 and 0.002) and well tolerated by patients.
Maintenance therapy The ECOG 4494 study suggested that CHOP + rituximab maintenance (MR) therapy significantly improved 2-year FFS compared with the CHOP regimen alone (74% versus 45%, P < 0.001), whereas there was no significant difference between the R-CHOP and R-CHOP + MR groups (77% versus 79%, P = 0.81). Therefore, patients after rituximab+chemotherapy-induced remission may not receive rituximab maintenance therapy.
Treatment of relapsed refractory DLBCL
The main treatment strategy for relapsed refractory DLBCL is ASCT after rituximab combined with chemotherapy-induced remission.
The prospective randomized clinical trial HOVON confirmed that for patients with CD20-positive relapsed progressive aggressive lymphoma (89% to 91% of DLBCL patients), the objective remission rate (ORR) for R-DHAP treatment was 75%, significantly higher than that of 54% in the DHAP-only group (p=0.01). At a median follow-up of 24 months, EFS and PFS in the R-DHAP group were 50% and 52%, respectively, also significantly better than 24% (P<0.001) and 31% (P< 0.002) in the DHAP group. The addition of rituximab to induction chemotherapy was also beneficial in relapse-refractory patients who were proposed for ASCT. A retrospective study showed that 22 patients who received R-DHAP + ASCT had significantly higher 2-year OS than historical controls (74% versus 33%, P=0.0424).
With the widespread use of rituximab in the first-line treatment of DLBCL, salvage therapy for relapse-refractory patients after rituximab+chemotherapy has become another current research focus. In the GELA LNH 98-5 study, rituximab combined with salvage therapy did not improve 2-year survival in patients who relapsed after receiving R-CHOP chemotherapy (P=0.23). However, Palacios et al. reported that patients with lymphoma who had received R-CHOP or R-CHOP-like chemotherapy and then progressed to relapse had better outcomes with rituximab-containing regimens.
Therapeutic status of radiotherapy in DLBCL
The role of radiotherapy in DLBCL has historically been controversial. In the pre-rituximab era, the SWOG 8736 study suggested that CHOP combined with involved field radiotherapy (IFRT) reduced the number of chemotherapy sessions in patients with stage I or II without a large mass, while the GELA LNH 93-1 study showed that strong chemotherapy such as the ACVBP regimen was superior to CHOP + IFRT.The ECOG 1484 study showed that 8 courses of CHOP therapy given after achieving CR The ECOG 1484 study showed that IFRT consolidation after 8 courses of CHOP to achieve CR improved DFS and controlled local symptoms, while the GELA 93-4 study showed that 4 courses of CHOP with and without IFRT were comparable in terms of EFS and OS.
After the introduction of rituximab, the SWOG 0014 study showed that in patients with early DLBCL with aaIPI=0 and without a large mass, 3 courses of R-CHOP+IFRT resulted in a 4-year OS of 92%, which was comparable to the MInT study, and therefore, the National Comprehensive Cancer Network (NCCN) 2009 guidelines recommended that for patients with early stage DLBCL without a large mass 3 courses of R-CHOP + IFRT or 6 to 8 courses of R-CHOP are given.
It can be seen that radiotherapy can benefit some patients with early DLBCL. So, which patients can benefit from it? The study by Sehn et al. suggests that PET results may be a predictor of radiotherapy in patients with early DLBCL, and that patients with negative PET after 3 courses of R-CHOP do not need radiotherapy.
Mediastinal large B-cell lymphoma
Mediastinal large B-cell lymphoma (PMBCL) is a specific subtype of DLBCL and accounts for approximately 6% to 10% of DLBCL. Retrospective studies have shown that enhanced-dose chemotherapy regimens (e.g., MACOP-B, VACOP-B) are superior to CHOP or CHOP-like regimens for the first-line treatment of PMBCL. Can the introduction of rituximab improve the efficacy of PMBCL cells due to their expression of CD20? There is no definitive conclusion on this, but several of the above-mentioned clinical trials of rituximab in DLBCL included patients with PMBCL, for example the MInT study included 11% of the total number of patients with PMBCL, so it is assumed that rituximab in combination with chemotherapy may further improve the efficacy in PMBCL. Dunleavy et al. compared the efficacy of DA-EPOCH with R-DA-EPOCH in patients with primary PMBCL, with a median follow-up of 8.6 and 3.4 years in the two groups, respectively, with 100% OS and 94% EFS in the R-DA-EPOCH group, higher than 94% (P=0.1) and 64% (P=0.036) in the DA- EPOCH group , the investigators concluded that rituximab may improve the efficacy of PMBCL.
Since most patients with PMBCL have a large mediastinal mass that may not be completely eliminated by chemotherapy alone, IFRT has been commonly used in patients with PMBCL. The Italian retrospective study suggested that IFRT may further benefit those who are effective on chemotherapy, but the results of the study from Colombia, UK, showed that consolidation radiotherapy did not improve survival, and Dunleavy et al. also concluded that radiotherapy could be dispensed with in the context of R-DA- EPOCH chemotherapy. Therefore, the need for radiotherapy in patients with PMBCL and which group of patients requires radiotherapy remains to be further clarified.