Follicular lymphoma (FL) is the second most common type of non-Hodgkin lymphoma (NHL) in Western Countries, accounting for 20% of all NHL and for 70% of all indolent forms, with a median age at diagnosis of about 60 years [1–3]. Before the advent of chemotherapy, the majority of patients with FL died within 5 years. With the current therapies, the expected median survival is approximately 8–10 years . About 85% of FL cases have a specific translocation t(14;18) that leads to the overexpression of the BCL2 protein, a member of a family of anti-apoptotic proteins, although other genetic alterations may be detected in this subtype of lymphoma. As defined by the WHO, FLs are characterized by a follicular growth pattern including centrocytes (small- to medium-sized cells) and centroblasts (large cells), and are graded from I to III according to the amount of centroblasts present. The clinical aggressiveness of the tumor increases with an increasing numbers of centroblasts. Grade I is defined by ≥5 centroblasts/high power field (hpf) (follicular small cleaved), Grade II by 6 to 15 centroblasts/hpf (follicular mixed), Grade III by more than 15 centroblasts/hpf (follicular large cell). Grade III has been subdivided into Grade IIIa, in which centrocytes are present and Grade IIIb, in which there are sheets of centroblasts. Grade from I to IIIa are considered as indolent NHL subtypes, while grade IIIb behaves as an aggressive lymphoma and is treated similarly to a diffuse large B-cell lymphoma . Bone marrow involvement is very common (about 70% of all cases) with paratrabecular lymphoid aggregates, although other organ involvement is uncommon. FL cells express monoclonal immunoglobulin (Ig) light chains; they are CD19+, CD20+, CD10+, CD22+ and BCL2+, while they are negative for CD5 and CD23. Clonal Ig gene rearrangements are also present and most cases have extensive somatic mutations.
In recent decades, the introduction of several treatment options (single alkylating agents, combination chemotherapy with or without doxorubicin or fludarabine, total lymphoid irradiation) has improved the overall survival (OS) for patients with FL, with complete remission rates ranging from 65 to 85% . Fisher et al. demonstrated that the introduction of the anti-CD20 monoclonal antibody Rituximab significantly improved OS . The prognosis of FL at diagnosis is currently evaluated on the basis of specific indexes: the Follicular Lymphoma International Prognostic Index (FLIPI) considers five prognostic factors, including patient age, stage, number of involved nodal areas, serum lactate dehydrogenase and hemoglobin level . It was developed through an international retrospective study of survival data on 4167 patients with FL diagnosed between 1985 and 1992. Currently, FLIPI is a widely accepted tool for risk assessment of FL. However, the FLIPI has been designed prior to the era of anti-CD20 monoclonal antibodies and the initial cohort does not represent the present course of the disease. More recently, a modified version of this scoring system, the FLIPI-2, was proposed by Federico et al.  on the basis of the F2 study, in which 1093 patients between January 2003 and May 2005 with a newly diagnosed FL were registered and 942 individuals receiving treatment were selected as the study population. This new prognostic score has, as a target end point, progression-free survival (PFS), considered more realistic than OS for a type of lymphoma with a median survival likelihood of 10 years.
Treatment options are stage-related: while disseminated FL is considered an incurable disease, with a trend to relapse, localized stage FL potentially has a different clinical outcome. In fact, it has been demonstrated that in 50% of cases it is possible to obtain a definitive eradication of the disease. According to the current guidelines [10, 11], stage I–II disease should not be managed with a frontline strategy of watchful waiting, radiation therapy representing the gold standard for this group of patients: a radiation dose of 30 to 36 Gy delivered in 15 to 20 fractions over 2–4 weeks is associated with local control rates of more than 95%. Despite the limited stage, BCL2/IgH+ positive cells could be found at diagnosis in the peripheral blood and/or bone marrow of 16 of 24 patients (66.6%) by quantitative PCR and radiotherapy was capable of clearing blood and marrow Bcl2+ cells, a response which persisted after a median follow-up of 43.5 months . No data are currently available concerning the efficacy on PFS of rituximab in localized FL, although rituximab is capable of reducing the proportion of residual Bcl2+ cells detectable in the peripheral blood and/or bone marrow of a proportion of patients following radiotherapy.
In stage III–IV disease, treatment can be safely deferred without a survival disadvantage if none of the following features occurs: systemic symptoms, high tumor burden, extranodal disease, cytopenia due to marrow involvement, spleen involvement, leukemic phase, serous effusions, erythrocyte sedimentation rate > 20 mm/h, high lactate dehydrogenase levels. A policy of watchful waiting is particularly advisable in elderly patients (> 70 years). The presumed advantage of a watchful waiting approach is that patients are spared the toxic side effects of chemotherapy. As already specified, patients with advanced and symptomatic FL are treated with the expectation that the disease will witness a relapsing and remitting course, and may require several lines of treatment during the course of the disease.
For many years, the standard first-line treatment was alkylator-based, frequently in combinations including vinca alkaloids, anthracyclines or fludarabine-based schedules, with similar OS and PFS [13, 14]. More recently, several phase III trials have confirmed the efficacy of rituximab in combination with an alkylator-containing regimen, both with and without the inclusion of anthracyclines [16, 17]. There is a suggestion that the duration of response in patients treated with rituximab and anthracycline-based therapies might be superior to that obtained with less intensive regimens utilizing alkylators; a specific randomized trial, FOLL-05, has been recently conducted in Italy with the aim of demonstrating the most effective first-line therapy in terms of OS and PFS for FL between the R-CVP, R-CHOP and R-FM schedules. Although chemotherapy in combination with rituximab has improved outcomes in the newly diagnosed setting, patients with FL almost always relapse and require a succession of therapies over many years. Patients who relapse after a first-line therapy not containing either anthracyclines or fludarabine should receive anthracycline- or fludarabine-based polychemotherapy together with rituximab; patients under the age of 65 with extended relapses after a first-line therapy containing either anthracyclines or fludarabine should be treated with high-dose therapy and autologous stem cell transplant. The same consideration should be made for first-line resistant patients .
With regard to new treatment options, Bendamustine is a DNA alkylating agent with novel properties, which has been studied in relapsed or rituximab-refractory FL patients . The efficacy of bendamustine is probably related to its incomplete cross-reactivity with other chemotherapeutic agents. Phase II trials of bendamustine in combination with rituximab in relapsed FL have reported an ORRs of 92% and a median PFS of 23 months . Ongoing studies are examining bendamustine with bortezomib, lenalidomide, temsirolimus, ofatumumab, alemtuzumab and other novel agents [20, 21]. Different maintenance strategies have been utilized in an attempt to prolong PFS in FL. Interferon (IFN) alpha has been used for several years with this aim. A meta-analysis of data from the pre-rituximab era  suggests that the addition of IFN as maintenance therapy for FL improves PFS, while the benefit on OS is less evident; in a recent report, pooled data from different randomized studies of the German Low Grade Lymphoma Study Group suggest that IFN maintenance prolongs remission duration also after rituximab-containing induction treatments . With regard to rituximab as maintenance treatment, there has been a growing body of evidence demonstrating the clinical advantage of rituximab maintenance therapy following various induction regimens. The European Organization for Research and Treatment of Cancer (EORTC) conducted one of the pivotal Phase III trials in patients with relapsed or refractory FL (EORTC; 20891 trial). The study demonstrated the benefits of rituximab maintenance administered every three months for two years following chemotherapy or immunochemotherapy . An important study was conducted using rituximab as maintenance after first-line therapy: the results of the PRIMA study  indicate that rituximab maintenance conferred significant PFS benefits (Hazard ratio 0.50; 95% CI: 0.39–0.64), but no effect on OS was seen. A recent meta-analysis by Vidal et al.  focused on the impact on OS of rituximab maintenance in both first line and previously treated patients has reported similar results: in fact, refractory or relapsed FL patients treated with rituximab maintenance had an improved OS, whereas previously untreated patients had no survival benefit. Ongoing studies will define the optimal maintenance duration (two years versus five years or until relapse or progression).
Although a large proportion of FL patients respond to immunochemotherapy, there is a group of patients with resistant/refractory disease for whom there is a need for new agents in an attempt to overcome the poor prognosis. There are three main groups of novel therapeutic agents, as well as other monoclonal antibodies (novel anti-CD20 antibodies such as ofatumumab and GA101 or antibodies against targets other than CD20), agents that target signal transduction pathways (e.g., proteasome inhibitors, Bcl-2 and Bcl-6 inhibitors), microenvironment modulatory drugs (immunomodulatory drugs, e.g. lenalidomide) [26–30]. Recently, in a phase I trial, GA101 was tested in 21 resistant or refractory CD20+ indolent NHL patients : the overall response rate was 43% (5 complete responses and 4 partial responses). The majority of reported adverse events were of grade 1 or 2. A similar experience, conducted treating 27 relapsed or refractory FL patients with ofatumumab, showed an overall response rate of 22% with a median PFS of 5.8 months . Upcoming phase III studies will demonstrate if targeted therapies can further improve the management of patients with FL.
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