The identification of prognostic factors and scoring systems, both clinical and tissue/host based, has helped to refine prognostication for patients with FL and may help guide therapeutic decisions. The Groupe D’Etude des Lymphomes Folliculaires (GELF) and The Follicular Lymphoma International Prognostic Index (FLIPI) scores have emerged as important prognostic models in FL [6, 7]. While the GELF criteria seek to stratify patients by tumor burden and determine when to start cytotoxic therapy, the FLIPI serves as a prognostic model for survival determination. Entry criteria for most clinical trials of untreated FL separate patient groups based on the GELF and/or FLIPI criteria.

The GELF criteria were established in the late 1990s to separate patients into low and high tumor burden based on prognostic factors as noted in Table 1 [7, 8]. In the original 1997 study, patients designated with high tumor burden had a shorter median survival of 71 months compared with the low-risk group whose survival endpoint had not been reached. These criteria have been used to define patient populations who warranted initiation of cytotoxic chemotherapy based on symptoms attributable to their disease/lymphoma or high-risk features (e.g., compression of vital organs) versus asymptomatic patients with low-risk features who were included in “watch-and-wait” (W&W) randomized trials. Over the past two decades, lymphoma groups around the world have used similar, but slightly modified criteria (Table 1) [7–18].

The FLIPI was originally published in 2004, as a prognostic score for newly diagnosed advanced-stage FL [19], then for early-stage disease [20], and also FL in first relapse [21]. An updated report by Federico et al. [6] included the prognostic significance of FLIPI among FL patients treated with rituximab-based treatment (i.e., FLIPI-2). This analysis yielded 3 distinct risk groups with significantly different outcomes (Table 2). The German Low-Grade Lymphoma Study Group (GLSG) also validated the FLIPI risk groups for newly diagnosed high tumor burden FL patients treated with rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP) [11]. An important distinction of the FLIPI is that it is a prognostic scoring system for survival; however, unlike GELF criteria, it is not necessarily a tool to dictate when treatment should or should not be initiated for FL. There is no published data showing that treatment initiation based on FLIPI is associated with enhanced outcomes, especially toward potential improvement in the natural history of the disease. Nonetheless, an adverse FLIPI score (i.e., 3–5) has been integrated into several ongoing clinical trials as selection criteria for initiation of therapy in patients with untreated FL.

Traditional treatment options for FL include expectant observation for asymptomatic and low tumor burden disease and multiagent cytotoxic chemotherapy for patients who are symptomatic and/or have high tumor burden. Biologic therapy has become an integral part of therapy with agents that target B lymphocytes, such as monoclonal anti-CD20 antibodies and radiolabeled anti-CD20 antibodies. Treatment response to cytotoxic and biologic therapies is high initially; however, with subsequent treatments, response rate and remission duration typically decline and cumulative toxicities increase. The identification of novel targeted agents and new combinations of therapeutics provide the opportunity to continue to improve outcomes for patients with FL.

The anti-CD20 radioimmunoconjugates ¹³¹I-tositumomab (Bexxar, GlaxoSmithKline) and ⁹⁰Y-ibritumomab tiuxetan (Zevalin, Spectrum Pharmaceuticals) deliver ionizing radiation to target tumor cells and their neighbors. They are relatively easy to administer, safe, and effective in relapsed/refractory FL [33, 34], including rituximab-refractory disease [35]. Contraindications to their use include thrombocytopenia (i.e., <100 × 10⁹/L) and/or >20–25 % bone marrow involvement with lymphoma. Radioimmunotherapy (RIT) has also been incorporated into the frontline management of patients with untreated indolent lymphoma as a single agent [38] and also through the paradigm of sequential therapy giving one dose of RIT after multiagent induction chemotherapy. Morschhauser et al. reported results of phase III FIT (first-line indolent trial) examining consolidative RIT versus no consolidation in patients who achieved CR or partial remission (PR) following chemotherapy induction [30]. Patients were randomized to one dose of ⁹⁰Y-ibritumomab tiuxetan or no consolidation. RIT significantly improved median PFS in all patients (36.5 months vs. 13.3 months with no RIT; P < 0.0001). This gain was observed regardless of the depth of initial response to induction chemotherapy, although the benefit appeared to be greater for patients in PR versus CR. A limitation of the FIT trial was that the majority of patients did not receive rituximab-based induction chemotherapy. The extent of benefit of consolidation RIT after combined rituximab/chemotherapy therapy is not clear.

¹³¹I-tositumomab also has been incorporated sequentially following chemotherapy [16, 37]. Further information regarding the role of up-front, sequential RIT in indolent NHL should be available soon from the large US intergroup study led by the Southwest Oncology Group (S0016). In that phase III trial, untreated FL patients were randomly assigned to 6 cycles of R-CHOP versus 6 cycles of CHOP followed by ¹³¹I-tositumomab.

Most patients with FL will develop progressive disease including after an initial durable response to immunochemotherapy. Patients with asymptomatic recurrent FL do not require immediate treatment, but need close monitoring for the development of symptomatic disease. There are a number of treatment options for patients with relapsed or refractory FL (Table 5). A number of factors will impact the treatment choice for relapsed disease. These include duration of previous remission(s), type and amount prior therapy used, current tumor burden (at progression), and patient age and comorbidities. Treatment options include immunotherapy alone, immunotherapy combined with chemotherapy, chemotherapy alone, and radioimmunotherapy. Additionally, there should be consideration for consolidation with stem cell transplantation (autologous vs. allogeneic) in select patients.