Rituximab maintenance in follicular lymphoma (FL): nine-year follow up of the PRIMA study 

The PRIMA study (NCT00140582) was an open-label, multicenter, international, randomised phase III study, which recruited patients between 2004 and 2007 and evaluated rituximab maintenance in patients with high–tumour burden follicular lymphoma (FL) responding to first-line rituximab-containing immunochemotherapy.  

After a median follow-up of three years, the original publication reported a significant improvement in progression-free survival (PFS) with rituximab maintenance (74.9%) versus observation (57.6%), but no significant difference in overall survival (OS).¹

In the recent publication, Emmanuel Bachy, Université Claude Bernard Lyon 1,  Institut National de la Santé et de la Recherche Médicale (INSERM), FR, and colleagues present nine years of follow-up data and a final safety overview (previously presented at the 59^th Annual Meeting & Exposition of the American Society of Hematology), the Lymphoma Hub summary is here).²

Study design

• Aim: To assess the use of rituximab as a maintenance treatment after immunochemotherapy
• Patients were >18 years old, had previously untreated high-tumor burden FL
• Induction treatment was rituximab (375 mg/m² on Day one of each chemotherapy course) in combination with either: cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP; six cycles), cyclophosphamide, vincristine, and prednisone (CVP; eight cycles), or fludarabine, cyclophosphamide, and mitoxantrone (FCM; six cycles)
• Patients who achieved complete response (CR), unconfirmed complete response (CRu) or a partial response (PR) to first-line immunochemotherapy went on to be randomised 1:1 to either rituximab maintenance (375 mg/m², once every eight weeks) starting eight weeks after last induction treatment or observation (no additional treatment)
• In total, 1018 patients completed induction and were randomised to rituximab maintenance (n=505) or observation (n=513)
  • A total of 607 patients from the original cohort consented to the extended follow up (n=309 rituximab; n=298 observation)
• The primary endpoint was Investigator-assessed progression-free survival (PFS)
• Secondary endpoints were time to next anti-lymphoma treatment (TTNLT), time to next chemotherapy treatment (TTNCT), OS, transformation rate at relapse and safety

Results

• Median follow-up was 9 years (range 0–11.5 years)
• Patients who were not included in the extended follow-up had more adverse prognostic factors than those included due to automatic exclusion of patients who died before analysis

Progression-free survival

• At the final data collection point, the median PFS was 10.5 years in the rituximab maintenance arm versus1 years in the observation arm (hazard ratio [HR] 0.61; 95% CI 0.52– 0.73; p <0.001)
• Ten-year PFS estimates were 51.1% and 35% in the rituximab maintenance arm versus the observation arm respectively
• Subgroup analysis of PFS, categorized by age, sex, FLIPI score, induction chemotherapy, and response to induction, showed a consistent benefit of rituximab maintenance over observation

Time to next anti-lymphoma treatment

• Median TTNLT was not reached in rituximab arm and was 6.1 years in observation arm (HR 0.66; 95% CI 0.55–0.78; p <0.001)
• At the final data cut-off, 212 patients (42%) in the rituximab maintenance arm and 284 patients (55.4%) in the observation arm had either started a new anti-lymphoma treatment or had died before receiving it
• TTNLT estimates at 10 years were 53.4% vs2% (rituximab vs observation)

Time to next chemotherapy treatment

• TTNCT was not reached in rituximab arm and was 9.3 years in observation arm (HR 0.71; 95% CI 0.59– 0.86; p <0.001;)
• A final data cut-off, 188 patients (37.2%) in the rituximab maintenance arm and 244 patients (47.6%) the observation arm had either started a new chemotherapy treatment or had died before receiving it

Overall survival

• Despite this apparent benefit with rituximab maintenance therapy, there was no OS difference between the groups
• Median OS was not reached in either arm (HR 1.04; 95% CI, 0.77– 1.4; p = 0.7948)
• Estimated 10-year OS rates were approximately 80% in both arms (80.1% rituximab maintenance; 79.9% observation)

Safety

• Since randomisation, 56.9% of patients in the rituximab arm and 38.2% of patients in the observation arm experienced at least one adverse event (AE)
• There was a higher rate of serious AEs (21.2% vs4%) and grade III–IV AEs (24.4% vs 16.9%) in the rituximab arm compared to the observation arm
  • The higher rate of grade III–IV AEs was largely due to higher rates of cytopenias (5.2% vs6%) and infections (4.4% vs 1%) in the rituximab arm
• The most common grade III–IV AEs were neoplasms benign, malignant, and unspecified, with a similar incidence between study arms (approximately 4% in both arms)
• A total of 88 patients (17.4%) have died in the rituximab maintenance arm since randomisation versus 84 patients (16.4%) in the observation arm
• The most frequent causes of death were progressive disease (51.1% rituximab maintenance; 47.6% observation) and solid tumors (5.7 % rituximab maintenance; 20.2% observation)
• Death as a result of a second neoplasm was four times more frequent in observation arm compared to the rituximab arm

Conclusions

• The 9-year follow-up of the PRIMA study demonstrated that rituximab maintenance after induction immunochemotherapy provided a significant long-term PFS benefit over observation, but this did not translate into an OS benefit
• Bachy and colleagues noted that despite the lack of OS benefit, more than half of the patients in the rituximab maintenance arm did not experience disease progression and did not require new anti-lymphoma treatment beyond 10 years
• Safety results were consistent with previous analyses and rituximab maintenance was generally well tolerated, with no unexpected safety signals observed after an additional four years of follow-up