In a comparison of patients with asymptomatic stage II, III, or IV follicular lymphoma, results of a randomized trial demonstrated that rituximab (Rituxan) maintenance therapy can delay the time to treatment for patients with nonbulky disease. The results of an Intergroup randomized trial of rituximab vs a watch-and-wait strategy were presented at a plenary session during the 52nd Annual Meeting of the American Society of Hematology (ASH).¹

"Rituximab maintenance therapy significantly delays time to treatment in asymptomatic patients. Delaying chemotherapy may become a popular option for patients with asymptomatic follicular lymphoma and could become the standard of care in the future," stated lead author Kirit M. Ardeshna, MD, University College London Hospitals.

The average lifespan of patients diagnosed with follicular lymphoma was 8 to 10 years, before the introduction of rituximab, Dr. Ardeshna told listeners. "Previous studies showed no improved survival for early treatment with chemotherapy vs watchful waiting in asymptomatic patients. Most physicians employ watchful waiting, which can defer the need for chemotherapy for about 2.5 years," he continued.

Study Design

The investigators sought to determine whether a strategy of B-cell depletion with rituximab could further delay the time to treatment with chemotherapy. The study enrolled 463 patients with asymptomatic stage II, III, or IV follicular lymphoma. Median age was 60 years (range, 27-67 years); 54% were female; 89% had grade 1 or 2 disease; 21% had stage II, 40% had stage III, and 39% had stage IV; 42% had bone involvement.

Patients were randomly assigned in a 1:1:1 ratio to one of three arms: watchful waiting (arm A, n = 186); rituximab at 375 mg/m² once a week for 4 weeks (arm B, induction therapy, n = 84); or the same induction therapy with rituximab followed by rituximab maintenance every 2 months for 2 years (arm C, n = 192).

The study was originally designed to enroll about 600 patients, but 3 years into the trial the second arm of the study was discontinued based on the efficacy of the maintenance therapy arm. At a median follow-up of 32 months, far fewer patients required chemotherapy or radiotherapy (the primary endpoint) in the rituximab maintenance arm vs watchful waiting. At 3 years after randomization, no new therapy was required by 49% of patients in the watchful waiting arm, 80% of patients in the induction therapy arm, and 91% of those treated with rituximab maintenance therapy. At the time of the ASH Annual Meeting, 95% of patients were alive and no differences in overall survival were evident among the three arms.

Significant Results

Time to initiation of new therapy was significantly longer in the rituximab arm (P < .001 for each of the rituximab arms vs watchful waiting; see Fig. 1). Overall median time to initiation of new therapy in the watchful waiting arm was 34 months, similar to a previous trial of watchful waiting by the same group of investigators.²

Median time to initiation of new therapy had not yet been reached in the two rituximab arms at the time of the ASH meeting. The rate of progression-free survival was significantly greater in both rituximab-containing arms (P < .001 for each of the arms vs watchful waiting).

Rituximab was well tolerated. The investigators reported seven infections (all grade 3), five allergic reactions, and four cases of neutropenia.

Looking Ahead

Dr. Ardeshna said the investigators plan to follow the patients for about 7 more years to evaluate their response to chemotherapy or radiotherapy when further treatment is initiated. "A variety of regimens will be used, and most of them will probably include rituximab. Whether treating patients upfront with rituximab will ultimately impact on their survival is unknown," he commented. He emphasized that the investigators want to assess whether previous exposure to rituximab will affect response to chemotherapy (with or without rituximab).

"Watchful waiting is not dead. Ten years after diagnosis, 20% of asymptomatic patients with follicular lymphoma will not require therapy, but we need to identify who those patients are," he noted.

Results of a quality-of-life analysis of this trial will be forthcoming.

The study was funded by Cancer Research UK and sponsored by University College London. Roche provided free rituximab for the study. ■

References

1. Ardeshna KM, Qian W, Smith P, et al: An intergroup randomized trial of rituximab versus a watch and wait strategy in patients with stage II, III, and IV, asymptomatic, non-bulky follicular lymphoma (grades 1, 2, and 3a): A preliminary analysis. 52nd ASH Annual Meeting. Abstract 6. Presented December 5, 2010.

2. Ardeshna KM, Smith P, Norton A, et al: Long-term effect of a watch and wait policy versus immediate systemic treatment for asymptomatic advanced-stage non-Hodgkin lymphoma: A randomised controlled trial. Lancet 362:516-522, 2003.