Treatment options for patients with advanced-stage (stage III/IV) FL are similar to those for stage II FL. For asymptomatic patients with non-bulky disease, the watch-and-wait approach with treatment upon disease progression may be appropriate.16 Results from a study by Ardeshna et al conducted in asymptomatic patients with advanced-stage low-tumor-burden FL showed that 88% of patients on maintenance treatment with rituximab did not require treatment at 3 years compared with 46% in the watch-and-wait group (P<0.0001).15 The rituximab induction arm was affected by early closure because of poor accrual. Moreover, there were 18 serious adverse events, possibly as a consequence of treatment with rituximab. However, this study highlights that rituximab monotherapy is a possible option for patients with asymptomatic, low-tumor-burden FL, particularly for those who may not tolerate chemotherapy or for those with slowly progressive disease.8

Patients with advanced-stage FL that is progressive, symptomatic, and/or has associated cytopenias are candidates for chemoimmunotherapy. The choice of chemotherapy agents depends on the drug availability and physician choice. Common treatment regimens include BR, R-CHOP, and R-CVP. Recent evidence suggests that BR is effective as a first-line regimen in patients with advanced disease. In a randomized Phase III study, treatment with BR resulted in non-inferior clinical response compared with standard rituximab chemotherapy (R-CHOP or R-CVP), with an acceptable toxicity profile.17 In a prospective, randomized, open-label study in patients with previously untreated indolent lymphoma, first-line therapy with BR resulted in greater progression-free survival and fewer toxic effects compared with R-CHOP.18

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Patients who respond to induction treatment with R-CVP or R-CHOP are potential candidates for maintenance therapy with rituximab. Primary RItuximab and MAintenance (PRIMA) was a randomized open-label study to investigate the effect of 2 years of rituximab maintenance therapy (375 mg/m² every 8 weeks) after first-line treatment with rituximab plus chemotherapy.19 At a median follow-up of 3 years, progression-free survival was significantly improved in the rituximab maintenance group (75%) compared with the observation group (58%) (P<0.0001). Furthermore, a significantly greater proportion of patients achieved a complete response with rituximab maintenance therapy than those in the observation group (72% vs 52%, respectively; P=0.0001). However, there was no difference in the overall survival between the 2 groups in this study.19 Further investigation is needed to understand the long-term toxicities of rituximab maintenance therapy and to identify the patients most likely to benefit from this treatment regimen.

A recent study by Kahl et al20 failed to demonstrate a significant clinical benefit from continuing rituximab maintenance treatment in patients with advanced-stage, low-tumor-burden FL after induction with the single-agent rituximab. Although rituximab maintenance therapy should be considered after rituximab plus chemotherapy, it is not recommended after rituximab monotherapy (Table 1; Figure 1). Furthermore, rituximab maintenance therapy after induction with rituximab monotherapy is of less clinical benefit in patients with low-tumor-burden FL, compared with rituximab re-treatment.20

Rituximab is also effective in the re-treatment setting and is used in combination with chemotherapy regimens for the treatment of relapsed/refractory FL. Common chemotherapy regimens include first-line (BR, R-CHOP, and R-CVP) and second-line (fludarabine, cyclophosphamide plus mitoxantrone or fludarabine monotherapy) regimens (Table 1). In patients with early relapse (1–2 years), a non-cross-resistant regimen is preferable (eg, bendamustine before or after CHOP). If patients subsequently experience remission for 6 months, the addition of rituximab should be considered (Table 1).8