Clinical trialPhase 3Blood cancers (leukaemia, lymphoma and myeloma)Lymphoma

Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled trial

The Lancet · 20111217 patients entered induction; 1019 patients with complete or partial response were randomised (505 patients in the rituximab maintenance group and 513 patients in the observation group)

Salles G, Seymour JF, Offner F, López-Guillermo A, Belada D, Xerri L, et al. The Lancet. 2011. 377:42-51

A newer report of this study has been published: Sustained Progression-Free Survival Benefit of Rituximab Maintenance in Patients With Follicular Lymphoma: Long-Term Results of the PRIMA Study. (2019)

Study type: Clinical trial
Study name: PRIMA
Phase: Phase 3
Design: Randomised, open-label, controlled, multicentre trial (223 centres in 25 countries)
Sample size: 1217 patients entered induction; 1019 patients with complete or partial response were randomised (505 patients in the rituximab maintenance group and 513 patients in the observation group)
Source: The Lancet · 2011
Trial registration: NCT00140582

In plain words

In this study, patients with follicular lymphoma who had responded to their first treatment (rituximab with chemotherapy) were divided into two groups: one group had another 2 years of rituximab, and the other group was only watched. In the group that had maintenance rituximab, the chance of the disease not getting worse after 3 years was higher (about 75% vs 58%). On the other hand, infections and serious side effects were more common in this group, and no significant difference in overall survival was seen during the follow-up of this study. The decision about maintenance treatment should be made with your treating doctor.

Key results

74.9% vs 57.6%

Progression-free survival (PFS) (median follow-up 36 months)

Rituximab maintenance vs observation; HR 0.55 (95% CI 0.44–0.68); P<0.0001

130 patients vs 218 patients

Number of patients with disease progression

Rituximab maintenance vs observation

361 patients (71.5%) vs 268 patients (52.2%)

Complete response or unconfirmed complete response 2 years after randomisation

P=0.0001

HR 0.87 (95% CI 0.51–1.47)

Overall survival

Not significant

Drugs in this study:Rituximab (Rituxan/MabThera)

Dose and schedule cards

Rituximab maintenance (PRIMA trial) and single-agent rituximab

Maintenance: follicular lymphoma with a high tumour burden that has achieved a complete or partial response to induction immunochemotherapy; single agent: asymptomatic follicular lymphoma with a low tumour burdenOn the page “Lymphoma” · Treatment regimens and dosing: follicular lymphoma

Drug	Dose	Route	Schedule
Maintenance
Rituximab	375 mg/m²	IV	Every 8 weeks, starting 8 weeks after the last induction cycle
Single agent
Rituximab	375 mg/m²	IV	Weekly for 4 weeks

Cycle length: Maintenance: every 8 weeks
Duration: Maintenance: 2 years (12 doses); single agent: 4 weekly doses, with or without 12 maintenance infusions every 2 months for 2 years

Maintenance from PRIMA and the FDA label. Single-agent rituximab in asymptomatic low-volume lymphoma from the British trial; this treatment only delayed the time until new treatment was needed. Active surveillance is also a standard approach for these patients.

On the page “Lymphoma” · Treatment regimens and dosing: follicular lymphoma

Niraparib maintenance (PRIMA)

Advanced disease with complete or partial response to first-line platinum; current FDA label: HRD-positive only; ESMO: can also be considered in HRD-negative disease [I, B]Cycle length: ContinuousOn the page “Ovarian cancer” · First line: maintenance therapy (based on BRCA and HRD)

Advanced disease with complete or partial response to first-line platinum; current FDA label: HRD-positive only; ESMO: can also be considered in HRD-negative disease [I, B]

Drug	Dose	Route	Schedule
Niraparib	Weight less than 77 kg or platelets less than 150,000: 200 mg; weight 77 kg or more and platelets 150,000 or more: 300 mg	Oral, once daily (taking it at bedtime helps reduce nausea)	Continuously

Cycle length: Continuous
Duration: Start no later than 12 weeks after the last platinum dose; label: until progression or toxicity; ESMO: 3 years

Monitoring: complete blood count weekly for the first month, monthly for the next 11 months and periodically thereafter; blood pressure and heart rate at least weekly for the first 2 months, then monthly for the first year. Platelets below 100,000: withhold for up to 28 days with weekly blood counts. Dose reduction: 200 → 100 mg; 300 → 200 → 100 mg; moderate hepatic impairment: 200 mg. In PRIMA, overall survival did not differ (HR 1.01).

On the page “Ovarian cancer” · First line: maintenance therapy (based on BRCA and HRD)

Previously untreated follicular lymphoma: with chemotherapy, then maintenance

Previously untreated CD20-positive follicular lymphomaOn the page “Rituximab (Rituxan/MabThera)” · Combination regimens and the subcutaneous form (FDA label)

Previously untreated CD20-positive follicular lymphoma

Drug	Dose	Route	Schedule
Induction
Rituximab	375 mg/m²	IV infusion (rate as in the prescribing notes)	Day 1 of each chemotherapy cycle
Maintenance (in complete or partial response)
Rituximab	375 mg/m²	IV infusion (rate as in the prescribing notes)	Every 8 weeks

Cycle length: As per the chemotherapy regimen; then every 8 weeks
Duration: Induction up to 8 doses; maintenance 12 doses starting 8 weeks after the end of induction

On the page “Rituximab (Rituxan/MabThera)” · Combination regimens and the subcutaneous form (FDA label)

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Rituximab maintenance

Rituximab 375 mg/m² every 8 weeks for 2 years.

2Observation

Observation without maintenance therapy.

Source of the regimen details: Abstract of the paper

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Patients with previously untreated follicular lymphoma needing systemic therapy. These patients received one of three non-randomised induction immunochemotherapy regimens used in routine practice. Only patients with a complete or partial response to induction were randomised.

Endpoints

Primary endpoint: progression-free survival (PFS). Analysis was by intention to treat. Secondary endpoints reported in the abstract included complete response or unconfirmed complete response 2 years after randomisation, overall survival and adverse events.

Safety and side effects

Grade 3 and 4 adverse events were recorded in 121 patients (24%) in the rituximab maintenance group and 84 patients (17%) in the observation group (risk ratio 1.46; 95% CI 1.14–1.87; P=0.0026). Infections (grade 2 to 4) were the most common adverse events, occurring in 197 patients (39%) and 123 patients (24%), respectively (risk ratio 1.62; 95% CI 1.35–1.96; P<0.0001).

Clinical significance and place in guidelines

This study showed that 2 years of rituximab maintenance after first-line immunochemotherapy in follicular lymphoma significantly improves progression-free survival. Given the increase in infections and grade 3 and 4 adverse events and the lack of a significant overall survival difference in this report, treatment choice should be individualised. The exact status of this approach in clinical guidelines and drug approvals should be checked in up-to-date sources.

Limitations

The study was open-label without blinding. Induction regimens were not randomised (three immunochemotherapy regimens used in routine practice). Median follow-up was 36 months, and overall survival showed no significant difference. The risk of infections and grade 3 and 4 adverse events was higher in the maintenance group.

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.