Updated Results of the PRIMA Study Confirms the Benefit of 2-Years Rituximab Maintenance In Follicular Lymphoma Patients Responding to Immunochemotherapy.

Abstract 1788

The GELA-sponsored intergroup PRIMA Phase III study was designed to investigate the potential benefit of 2-years of rituximab maintenance in high tumour burden follicular lymphoma patients responding to one of three non-randomised first line immunochemotherapy treatments. The results of the pre-planned interim analysis with 24 months median follow-up were positive and demonstrated a significant reduction in the risk of progression for patients randomized to rituximab maintenance (Salles et al., ASCO 2010). We present here the updated efficacy and safety results after an additional year of follow-up, when all randomized patients had completed the observation/maintenance period.

From December 2004 until April 2007, 1217 patients were enrolled from 223 centres. Complete data are available for 1193 patients who had the following pre-induction treatment characteristics: median age 56 years [range 22–87]; 52% male; 90% Ann Arbor stage III-IV; 33% B symptoms; 55% bone marrow involvement; 4% ECOG performance status >1; 34% elevated LDH; 32% β₂-microglobulin≥3mg/L; FLIPI score 0–1 (21%), FLIPI 2 (36%), FLIPI 3–5 (43%). Most patients (74%) received R-CHOP induction (22% R-CVP, 4% R-FCM).

Patients responding to induction therapy were stratified based on their immunochemotherapy regimen and response [CR/CRu versus PR], and randomized to observation or rituximab maintenance, 1 infusion (375 mg/m²) every 8 weeks for 2 years. A total of 1018 randomised patients were analyzed according to the ITT principle (513 observation/505 rituximab maintenance). All initial pre-treatment characteristics were well balanced between arms and the response status at time of randomization was CR=39%; CRu=31% and PR=29% (others 1%).

After a median follow-up of 36 months, 3-year progression free survival was 60.3% (95% confidence interval [CI] 55.8 – 64.5%) in the observation arm and 78.6% (95% CI 74.7 – 82%) in the rituximab maintenance arm, respectively (stratified Log-Rank, P<.0001; hazard ratio [HR]=0.55, 95% CI 0.44 – 0.68). In pre-planned analyses of patient subgroups categorized by age, sex, FLIPI score, induction chemotherapy and response to induction, the effect of rituximab maintenance was found to be consistent with the overall study results. In a Cox regression multivariate analysis, older age (P=.0013), male sex (P=.013), higher FLIPI group (P<.0001), R-CVP induction treatment (P=.003) and rituximab maintenance (P<.0001) were all significant variables associated with inferior progression free survival. A significant reduction in the number of patients starting a new anti-lymphoma treatment (HR=0.60, 95% CI 0.47 – 0.76) or starting a new chemotherapy (HR=0.62, 95% CI 0.47 – 0.81) was also observed for rituximab maintenance. Regarding response to treatment, 52% of the patients that were in PR at the time of randomization converted to CR or CRu at the end of 2-year maintenance in the rituximab maintenance arm compared to 30% of patients in the observation arm (P=.0001). As a result, 361 out of 482 patients evaluated (75%) in the rituximab maintenance arm were in CR or CRu as compared to 268 out of 491 patients evaluated (55%) in the observation arm (P< .0001). At the time of the data cut-off, 30 patients (6%) had died in the observation arm compared to 26 patients (5%) in the rituximab maintenance arm (HR=0.87, 95% CI 0.51 – 1.47).

The most common adverse events reported were infections, which occurred in 24% and 39% of the patients in the observation and rituximab maintenance arms respectively. Grade 3–4 adverse events were reported in 17% of patients in the observation arm and 24% in the rituximab maintenance arm (neutropenia 1% vs 4%; infections 1% vs 4%, respectively) but these lead to treatment discontinuation in only 8 and 19 patients, respectively.

In conclusion, after an additional year of follow-up, these data demonstrate a sustained benefit of 2 years of rituximab maintenance therapy after immunochemotherapy, resulting in improved progression free survival and complete response rates. No additional or unexpected toxicities were observed. All randomized patients have an excellent survival to date and longer follow-up will explore factors affecting overall survival in these patients. The PRIMA results indicate that rituximab maintenance should be considered in all follicular lymphoma patients who have responded to first line immunochemotherapy.