The role of rituximab
Rituximab is a key component to the treatment of diffuse large B-cell lymphoma (DLBCL), with numerous trials showing a clear improvement in survival when rituximab is added to standard chemotherapy.
Trial Name |
Study Group Characteristics |
Treatment |
Outcome |
LNH 98.5 r |
- DLBCL
- 60-80 years of age
- n = 399
|
or
|
10 year-event-free survival (EFS) 35.1% vs 19.8%, P<0.0001, median overall survival (OS) 8.4 years vs 3.5 years, P<0.0001. |
RICOVER-60 r |
- DLBCL
- 61-80 years of age
- n = 1222
|
or
|
Six cycles of CHOP14 had the worst outcome. Progression-free survival (PFS) improved after 6 cycles of R-CHOP14 (relative risk (RR) 0.50, P<0.0001), and 8 cycles of R-CHOP14 (RR 0.59, P=0.0001). OS improved only with 6 cycles of R-CHOP14 (RR 0.63, P=0.0031). Of the four regimens assessed in this study, 6 cycles of R-CHOP14 was the preferred treatment for elderly patients. |
ECOG 4494/CALGB 9793 r |
- DLBCL
- > 60 years of age
- n = 632
|
- CHOP21 (x 6 or 8) +/- Maintenance rituximab (MR)
or
- R-CHOP21 (x 6 or 8) +/- MR
|
Two-year failure-free survival (FFS) rates from the second random assignment were 77%, 79%, 74%, and 45% for R-CHOP, R-CHOP+MR, CHOP+MR, and CHOP, respectively. Rituximab administered as induction or maintenance with CHOP significantly prolonged FFS; however, after R-CHOP, no benefit was provided by maintenance rituximab. |
MInT r |
- DLBCL
- 18-60 years of age
- n = 842
|
or
|
Compared with chemotherapy alone, rituximab plus chemotherapy improved the complete response (CR) rate (68% vs 86%, respectively; P<0.0001), increased the 3-year EFS rate (59% vs 79%, respectively; P<0.0001), and improved the 3-year OS rate (84% vs 93%, respectively; P=0.0001). |
The number of cycles
No randomised trial has specifically addressed the issue of the number of R-CHOP21 cycles, but a prospective, randomised trial has directly addressed this question with CHOP14. The RICOVER-60 trial compared six and eight cycles of CHOP14, each with and without rituximab. It included 1222 patients between the ages of 61 to 80 years with aggressive non-Hodgkin lymphoma (80% DLBCL).r There was no difference in the 3 year OS in the six versus eight cycles of R-CHOP14 (78 vs 73% respectively). A randomised trial of 1080 patients with DLBCL treated with 8 cycles of R-CHOP21 or 6 cycles of R-CHOP14 + 2 further doses of rituximab showed that at 46 months of follow up there was no significant difference in OS or PFS.r Another randomised trial of 600 older adults with DLBCL compared 8 cycles of R-CHOP14 with 8 cycles of R-CHOP21 showed similar response rate (RR), EFS and OS in both groups.r
Favourable prognosis DLBCL
The FLYER Trial demonstrated equivalent (non-inferiority) outcomes in patients ≤60 with favourable prognosis DLBCL (aaIPI =0 without bulky (≥7.5 cm)) disease treated with 4 cycles of R-CHOP21+ 2 cycles of rituximab compared to 6 cycles of R-CHOP21.r
© Lancet 2020
Number of rituximab doses
The PETAL study demonstrated that two additional rituximab doses failed to improve outcomes in CD 20 positive lymphoma’s who achieved a negative interim PET scan (cycle 2).r
© Journal of Clinical Oncology 2018
R-CHOP21 versus R-CHOP14
Three large phase III studies have demonstrated that R-CHOP14 is not more effective than R-CHOP21 in both DLBCL and indolent B-cell lymphoma.rrr R-CHOP14 (mandatory G-CSF prophylaxis) appears to have a lower frequency of neutropenia and infection compared with R-CHOP21 (discretionary G-CSF prophylaxis).rr
No role for maintenance rituximab in DLBCL
While there is a benefit with maintenance rituximab after R-CHOP in follicular lymphoma (FL), this has not been proven in DLBCL. The role of maintenance rituximab (MR) was assessed in randomised trial of 632 older adults. The trial compared R-CHOP to CHOP. The 415 patients who achieved a CR were randomised to either maintenance rituximab or observation. MR did not improve failure-free survival rates.r
Older adults
In elderly patients, unfit for standard treatment with R-CHOP consideration should be given to dose reduced R-mini-CHOP.
Follicular or Indolent lymphoma
The role of rituximab
Rituximab is a key component to the treatment of FL with numerous trials showing a clear improvement in survival when rituximab is added to standard chemotherapy. These trials have shown improved RR, time to progression, PFS and OS.rrrrr A meta-analysis of seven randomised trials including 1943 patients with previously untreated or previously treated indolent non-Hodgkin lymphoma showed that the addition of rituximab to chemotherapy resulted in a higher overall response rate (ORR) (RR of obtaining a tumour response 1.21; 95% CI 1.16-1.27), improved disease control (HR of developing a disease-associated event 0.62; 95% CI 0.55-0.71) and better OS (hazard ratio (HR) for mortality 0.65; 95% CI 0.54-0.78).rr
R-CHOP21 versus R-CHOP14
The phase III JCOG 0203 trialr randomised 300 patients aged 20-69 years old, with untreated stages III to IV indolent B-cell lymphoma, to receive 6 cycles of R-CHOP21 or R-CHOP14. G-CSF was given to all patients with R-CHOP14 and R-CHOP21. Maintenance rituximab was not allowed. The primary endpoint was PFS, with secondary endpoints of OS and toxicity. At 6 years, there was no significant difference in PFS or OS between arms (R-CHOP21 vs R-CHOP14 PFS: 41% vs 43% respectively, P=0.30; OS: 87% v 88% respectively, P=0.65). Although grade 4 neutropenia and grade 3 infections were more frequent in the R-CHOP21 group, R-CHOP was feasible in both arms.
The role of maintenance rituximab
The role of maintenance rituximab in FL has been clearly demonstrated in a number of trials. Refer to Non-Hodgkin Lymphoma Rituximab Maintenance.
Efficacy
R-CHOP versus CHOP
Diffuse Large B-Cell Lymphoma:
Overall survival (OS) was investigated in elderly DLBCL patients (60-80 years old) treated with CHOP and R-CHOP in the LNH 98.5 trial.r Median OS was 3.5 years (95% CI: 2.2-5.5) in the CHOP arm and 8.4 years (95% CI: 5.4-not reached) in the R-CHOP arm (P<0.0001).
© Blood 2010
In the MInT trialr of young DLBCL patients (18-60 years old), compared with CHOP-like chemotherapy alone, rituximab plus CHOP-like therapy increased the 3-year EFS rate (59% vs 79%, respectively; P<0.0001) and improved the 3-year OS rate (84% vs 93%, respectively; P=0.0001).
© Lancet 2006
Follicular Lymphoma:
The GLSG study of R-CHOP21 versus CHOP21 in untreated, advanced-stage FLr demonstrated superior OS with R-CHOP at 3 years follow up (6 vs 17 deaths, respectively, P=0.016).
© Blood 2005
R-CHOP14 versus R-CHOP21
Diffuse Large B-Cell Lymphoma:
The UK Clinical Research Network trial of R-CHOP14 versus R-CHOP21 in untreated bulky stage IA to stage IV DLBCLr found no significant difference between groups in 2-year OS (82·7% vs 80·8; HR 0·90; P=0·3763) or PFS (75·4% vs 74·8%; HR 0·94; P=0·5907).
© Lancet 2013
Follicular Lymphoma:
The JCOG 0203 Trialr of R-CHOP21 versus R-CHOP14 in untreated stages III to IV indolent B-cell lymphoma demonstrated no significant difference in PFS (41% vs 43% respectively, P=0.30) or OS (87% vs 88% respectively, P=0.65) at 6 years.
© Journal of Clinical Oncology 2011
Toxicity
R-CHOP versus CHOP
In the RICOVER-60 trial,r there was a greater number of patients who experienced more toxicities in the 8-cycle treatment arms when compared to the 6-cycle treatment arms. There were 92 treatment-related deaths - 50 in the 8-cycle treatment arms and 42 in the 6-cycle regimens. 62 second malignancies were reported after a median follow up of 34.5 months. Toxicities are summarised in the table below.
© Lancet Oncology 2008
R-CHOP14 versus R-CHOP21
In the UK Clinical Research Network trial of R-CHOP14 versus R-CHOP21 in DLBCL, rates of grade 3 or 4 neutropenia and febrile neutropenia were higher in the R-CHOP21 group (with no mandatory G-CSF), whereas grade 3 or 4 thrombocytopenia was higher with R-CHOP14.r
© Lancet Oncology 2013