Follicular B cell lymphoma
In 2006 the EORTC 20981 intergroup study randomised 474 patients with relapsed or resistant follicular B cell lymphoma (grade 1 to 3A) to R-CHOP or CHOP for 6 cycles following randomisation to rituximab maintenance (R-M) (375 mg/m2 every 3 months for 2 years) or observation.r R-CHOP significantly increased overall response rate compared to CHOP (85.1% vs 72.3%, p < 0.01). R-M was associated with a median progression-free survival (PFS) of 51.5 months versus 14.9 months (P< 0.01). In addition, overall survival (OS) was superior with R-M over observation only (OS at 3 years of 85% vs 77%, P=0.011, HR 0.52). In 2010, these results were updated and remained highly significant. PFS for R-M was 3.7 years vs 1.3 years with no maintenance.r
The PRIMA 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 2 years. At 36 months median follow up, PFS in the maintenance arm was 74.9% vs 57.6% in the observation only arm (P<0.0001) and OS was not significantly different.r
The ECOG1496 study (included de novo small lymphocytic as well as follicular grade 1 and 2) showed a significant PFS advantage to rituximab maintenance (given as four weekly doses repeated every six months for two years) of 68% vs 33% at 3 years.r 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% vs 37%) but not OS. Maintenance was administered at 2 monthly intervals for 4 doses.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 for 4 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 endpoint was event-free survival (EFS) and secondary endpoints were PFS, OS and toxicity. 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 = 0.14). 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 OS compared with observation (n=1170). Median OS in the R-M 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 R-M compared to observation for patients with follicular lymphoma (HR 0.57, 95% CI 0.51-0.64).r
Mantle cell lymphoma
Rituximab has been used as maintenance therapy following initial chemotherapy for mantle cell lymphoma (MCL) 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 which investigated the role of rituximab maintenance therapy given after autologous stem-cell transplantation (AuSCT) in patients < 66 years old with untreated MCL (n=299). Treatment consisted of 4 cycles of R-DHAP induction every 21 days, followed by R-BEAM conditioning regimen prior to AuSCT. Patients who had a partial response received rescue induction therapy with 4 cycles of R-CHOP every 14 days. Only patients who had a response (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 257 patients underwent transplantation. After AuSCT, 240 patients were randomised to receive maintenance therapy (n=120) with rituximab 375 mg/m2 administered intravenously every 2 months for 3 years, or to undergo observation (n=120), with EFS being the primary endpoint.r
The rate of EFS at 4 years from start of randomisation was 79% (95% CI, 70 to 86) in the rituximab group vs 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 vs 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 vs 80% (95% CI, 72 to 88) in the observation group (P=0.04). The rate of OS at 4 years was higher in the rituximab group than in the observation group (HR for death, 0.50; 95% CI, 0.26 to 0.99; P=0.04) according to a Cox regression unadjusted analysis.r
Eight weekly versus 12 weekly delivery schedules have not been cross compared in the different patient populations. Ongoing studies are examining the optimal duration of maintenance.r The duration of maintenance in the EORTC, PRIMA and ECOG1496 studies was 2 years.
The evidence supporting the administration of rituximab via the subcutaneous (SC) route is based on multiple pharmacokinetics studies and phase III clinical trials providing head-to-head comparison of efficacy.
The pharmacokinetic non-inferiority data from three keys studies (SparkThera, SABRINA stage 1 and SAWYER stage 1) has been summarised in a review article by Davies A et al.r
Summary of Ctrough and AUC data from pharmacokinetic analyses in the SparkThera, SABRINA and SAWYER studiesr
© Adv Ther 2017
Direct head-to-head comparisons of the efficacy of rituximab administered via IV versus SC routes, in conjunction with chemotherapy, were conducted in the following clinical studies:
1. SABRINA part II:r 410 patients with previously untreated follicular lymphoma were randomly assigned, 205 to IV rituximab and 205 to SC rituximab. Investigator-assessed overall response at the end of induction was 84·9% (95% CI 79.2–89.5) in the IV group and 84·4% (95% CI 78.7–89.1) in the SC group. At a median follow-up of 37 months, PFS (HR 0.84, 95% CI 0.57–1.23), EFS (0.91, 0.64–1.31), and OS (0.81, 0.42–1.57) did not differ significantly between the two groups.
2. MabEase:r 576 patients with diffuse large B lymphoma were randomised 2:1 to receive either SC rituximab or IV rituximab, in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy in either 14 or 21 day cycles. Efficacy endpoints showed no difference between the two arms at the end of induction therapy. At 24 months of follow up, PFS was 75.0% (95% CI 69.9–79.4) in the SC group and 81.5% (95% CI 74.7 – 86.6) in the IV group (P=0.175), and EFS was 68.6% (95% CI 63.3–73.4) and 73.4% (95% CI 66.0–79.4), respectively (P=0.456).
© Haematologica 2017