Clinical trialPhase 3Lymphoma

Rituximab versus a watch-and-wait approach in patients with advanced-stage, asymptomatic, non-bulky follicular lymphoma: an open-label randomised phase 3 trial

The Lancet Oncology · 2014379 patients from 118 centres in the United Kingdom, Australia, New Zealand, Turkey and Poland (of whom 84 had been enrolled in the rituximab induction group before it was closed early)

Ardeshna KM, Qian W, Smith P, Braganca N, Lowry L, Patrick P, et al. The Lancet Oncology. 2014. 15:424-435

Study type: Clinical trial
Phase: Phase 3
Design: Open-label, three-arm randomised trial (1:1:1 allocation) with central randomisation by minimisation, stratified by treatment centre, grade, stage and age
Sample size: 379 patients from 118 centres in the United Kingdom, Australia, New Zealand, Turkey and Poland (of whom 84 had been enrolled in the rituximab induction group before it was closed early)
Source: The Lancet Oncology · 2014
Trial registration: NCT00112931

In plain words

In advanced follicular lymphoma that causes no symptoms and where the amount of tumour is small, treatment is usually delayed until the disease gets worse, with only monitoring in the meantime. In this study, giving rituximab meant patients went longer without needing chemotherapy or radiotherapy: after 3 years, 88% of patients in the maintenance rituximab group, compared with 46% in the watch-and-wait group, had not needed a new treatment. Severe side effects were few and all of them cleared up.

Key results

46% (95% CI 39–53) vs 88% (83–92)

Patients not needing treatment at 3 years: watch and wait vs maintenance rituximab

HR 0.21; 95% CI 0.14–0.31; P<0.0001

78% (95% CI 69–87)

Patients not needing treatment at 3 years in the rituximab induction group

Compared with watch and wait: HR 0.35; 95% CI 0.22–0.56; P<0.0001

HR 0.75 (95% CI 0.41–1.34)

Rituximab induction vs maintenance rituximab (time to new treatment)

P=0.33; no significant difference

Significant improvement on the Mental Adjustment to Cancer scale and the Illness Coping Style score

Quality of life: maintenance rituximab vs watch and wait (from baseline to month 7)

P=0.0004 and P=0.0012

No improvement compared with watch and wait

Quality of life in the rituximab induction group

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

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

1Watch and wait (watchful waiting)

Monitoring without treatment until disease progression. Further details in the full text of the paper.

2Rituximab induction

Rituximab at a dose of 375 mg/m² weekly for 4 weeks. Enrolment into this group was closed on 30 September 2007 and the study was changed to two groups.

3Maintenance rituximab

Rituximab induction (375 mg/m² weekly for 4 weeks) followed by a maintenance schedule of 12 further infusions given every 2 months for 2 years.

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

Asymptomatic patients (age ≥18 years) with advanced-stage, low-tumour-burden follicular lymphoma (grades 1, 2 and 3a). Patients were enrolled from 15 October 2004 to 25 March 2009.

Endpoints

Primary endpoints: time to initiation of new treatment and quality of life (QoL) at month 7 (i.e. 6 months after the end of rituximab induction). The time to initiation of new treatment was analysed for all randomised patients by intention to treat.

Safety and side effects

18 serious adverse events were reported in the rituximab groups (4 in the induction group and 14 in the maintenance group). 12 of these were grade 3 or 4 (5 infections, 3 allergic reactions and 4 cases of neutropenia), all of which resolved completely.

Clinical significance and place in guidelines

According to the abstract, the authors conclude that rituximab monotherapy should be considered as a treatment option for patients with asymptomatic, advanced-stage, low-tumour-burden follicular lymphoma. The abstract gives no information on overall survival or the status of this strategy in clinical guidelines; its place in current guidelines should be checked separately.

Limitations

The study design was open-label. Enrolment into the rituximab induction group was closed early, so this group (84 patients) was smaller and the study was changed to two groups. The primary endpoints were time to initiation of new treatment and quality of life, not overall survival. The main study has been completed and is in long-term follow-up.

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.