Follicular B cell lymphoma
In 2006 the EORTC 20981 intergroup studyr randomised 474 patients with relapsed or resistant follicular B cell lymphoma (grade 1 to 3A), maximum of two prior non-anthracycline or immunotherapy containing regimens, to R-CHOP or CHOP for six cycles following randomisation to maintenance (375 mg/m2 every 3 months for two years) or observation.
R-CHOP significantly increased overall response rate compared to CHOP (85.1% versus 72.3%, p < 0.01). Rituximab maintenance was associated with a median PFS of 51.5 months versus 14.9 months (P< 0.01). In addition, overall survival was superior with rituximab maintenance over observation only (OS at 3 years of 85% versus 77%, P=0.011, HR 0.52). In 2010, these results were updated,r and remained highly significant. Comparing maintenance with no maintenance, PFS was 3.7 versus 1.3 years.
The PRIMA (Primary RItuximab and MAintenance) study randomised 1,217 patients with previously untreated follicular lymphoma, following immunochemotherapy (R-CHOP, R-CVP or R-FCM) to observation or maintenance rituximab (375 mg/m2) every 8 weeks for two years.r
At 36 months median follow up, the progression free survival (PFS) in the maintenance arm was 74.9% versus 57.6% in the observation only arm (P<0.0001). Overall survival was not significantly different and there was an increase in grade 3 or 4 adverse events (24% versus 17%, P=0.0026) in the maintenance arm and grade 2-4 infective episodes (39% versus 24%, P < 0.0001). The ECOG1496r study (included de novo small lymphocytic as well as follicular grade 1 and 2) showed a significant PFS advantage to rituximab maintenance (given as weekly X 4 repeated every six months for two years) of 68% versus 33% at 3 years.
There was no significant difference in OS. Modelling of the PRIMA data yielded an increased mean PFS of 1.5 years, OS by 1.21 years, and QALYs gained by 1.11 years.r
In a study of 280 patients with relapsed rituximab-naive follicular NHL, which also involved rituximab "purging" pre autograft, patients randomised to post transplant rituximab demonstrated improved PFS (10 years 54% v 37%) but not OS. Maintenance was administered 4 times at 2 monthly interval.r
The SAKK 35/03 trial randomised 165 patients with untreated, relapsed, stable or chemotherapy-resistant follicular lymphoma to receive short-term (n=82) or long-term (n=83) rituximab maintenance therapy. Rituximab 375 mg/m2 was administered intravenously every 2 months as four doses for short-term therapy and for a maximum of 5 years or until relapse, progression or unacceptable toxicity occurred for long term therapy. The primary end point was EFS and secondary end points PFS, OS and toxicity.r
At a median follow-up period of 6.4 years, in the short-term arm the median EFS was 3.4 years (95% CI, 2.1 to 5.3) and in the longer-term arm it was 5.3 years (95% CI, 3.5 to not available) (P = .14). More adverse effects were experienced in patients who received long term rituximab treatment compared to those who received four doses, with 76% v 50% of patients with at least one adverse event (P , .001), five versus one patient with grade 3 and 4 infections, and three versus zero patients discontinuing treatment because of unacceptable toxicity, respectively. There was no difference in OS between the two groups.r
A retrospective analysis found maintenance rituximab to improve PFS in patients who were treated with bendamustine and rituximab induction therapy on the BRIGHT study. Randomised controlled studies may be required to further test maintenance rituximab after BR therapy.r
A meta-analysis of seven trials including 2315 patients treated with rituximab maintenance (n=1145) for follicular lymphoma had improved overall survival compared with observation (n=1170). Median overall survival in the rituximab maintenance group was 12 years (95% CI 11.5 to not yet reached) compared to 11.5 years in the observation group. PFS was improved by rituximab maintenance compared to observation for patients with follicular lymphoma (HR 0.57, 95% CI 0.51-0.64).r
Rituximab was associated with a higher risk of adverse events, with infection being the major toxicity. Infection occurred in 33.6% (7.1% grade 3-4) of patients on maintenance rituximab and 23.6% (4.9% grade 3-4) of the observation group.r
Mantle cell lymphoma
Rituximab has been used as maintenance therapy following initial chemotherapy for mantle cell lymphoma and may be a reasonable alternative in transplant ineligible patients.r
It has also been used in transplant eligible patients in a phase 3 trial involving 299 patients was conducted by Le Gouill et al. between September 2008 through August 2012. The role of rituximab maintenance therapy given after autologous stem-cell transplantation (AuSCT) in patients with untreated mantle cell lymphoma (MCL) was investigated.r
Four courses of induction R-DHAP (rituximab, dexamethasone, cytarabine, and a platinum derivative) immunochemotherapy given every 21 days, was followed by the R-BEAM (rituximab, carmustine, etoposide, cytarabine, and melphalan) conditioning regimen prior to AuSCT. Patients who had a partial response received a rescue induction therapy with four courses of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) every 14 days. Only patients who had a response (confirmed or unconfirmed complete remission (CR) or a partial response (PR)) were eligible to undergo transplantation. The overall response rate was 89%, and the complete response rate 77% and transplantation was performed in 257 patients. After AuSCT, 240 patients were randomised to receive maintenance therapy (n=120) with intravenous rituximab 375 mg/m2 every 2 months for 3 years, or to undergo observation (n=120). The primary end point was event-free survival (EFS).r
The rate of EFS at 4 years from start of randomisation was 79% (95% confidence interval [CI], 70 to 86) in the rituximab group versus 61% (95% CI, 51 to 70) in the observation group (P=0.001).
PFS at 4 years was 83% (95% CI, 73 to 88) in the rituximab group versus 64% (95% CI, 55 to 73) in the observation group (P<0.001). OS rate was 89% (95% CI, 81 to 94) in the rituximab group versus 80% (95% CI, 72 to 88) in the observation group (P=0.04). The rate of overall survival at 4 years was higher in the rituximab group than in the observation group (hazard ratio for death, 0.50; 95% CI, 0.26 to 0.99; P=0.04) according to a Cox regression unadjusted analysis.r
Maintenance rituximab significantly improves OS and PFS in patients re-treated with chemotherapy for relapsed or resistant follicular B cell lymphoma (375 mg/m2 every 12 weeks for 2 years in the EORTC study).r
In patients with untreated follicular B cell lymphoma, maintenance therapy every eight weeks significantly improves PFS although the benefits in overall survival are less certain.r
In patients with mantle-cell lymphoma who were younger than 66 years of age at diagnosis, rituximab maintenance therapy after transplantation prolonged event-free survival, progression-free survival, and overall survival.r
Eight weekly versus 12 weekly delivery schedules have not been cross compared in the two patient populations. The duration of maintenance in the EORTC and PRIMA studies was 2 years. Ongoing studies are examining the optimal duration of maintenance.r
The role of maintenance rituximab in other indolent lymphomas is less clear.