Initial treatment of stage 2 to 4 follicular lymphoma

INTRODUCTION — 

Follicular lymphoma (FL) is the second most common type of non-Hodgkin lymphoma (NHL). It is the most common of the clinically indolent NHLs defined as those lymphomas in which survival of the untreated patient is measured in years. (See "Classification of hematopoietic neoplasms".)

With modern therapies, the median survival of these patients is in excess of 20 years, and some patients will experience a "functional cure" with long-term remission and death due to other causes.

Treatment of FL depends on the stage of disease at presentation (table 1). Patients with stage 1 FL are candidates for radiation therapy, which achieves prolonged progression-free survival in a significant percentage of patients.

The treatment of patients with more advanced disease (stage 2 to 4) depends on the presence of symptoms, the burden and aggressiveness of disease, and patient characteristics. Treatment of this group is more akin to the long-term management of chronic disease with a focus on symptom control, avoidance of potential long-term treatment-related toxicities, and early identification of histologic transformation. Many patients will receive several different treatment regimens, often separated by several years without active therapy.

The initial treatment of stage 2 to 4 FL is discussed here. The initial treatment of stage 1 FL and the management of relapsed or refractory FL are presented separately, as are the epidemiology, clinical presentation, pathologic features, and diagnosis of FL.

●(See "Initial treatment of stage 1 follicular lymphoma".)

●(See "Treatment of relapsed or refractory follicular lymphoma".)

●(See "Histologic transformation of follicular lymphoma".)

●(See "Clinical manifestations, pathologic features, diagnosis, and prognosis of follicular lymphoma".)

PRETREATMENT EVALUATION — 

The pretreatment evaluation both determines the extent and aggressiveness of disease and provides information about the individual's performance status and comorbidities that are likely to have an impact on treatment options.

The pretreatment evaluation for patients with more advanced-stage FL is similar to that of patients with stage 1 FL. This is discussed in more detail separately. (See "Initial treatment of stage 1 follicular lymphoma", section on 'Pretreatment evaluation'.)

GOALS OF THERAPY — 

Treatment of FL aims to alleviate symptoms, reverse cytopenias, improve quality of life, and minimize long-term treatment-related toxicities. Modern therapy that incorporates anti-CD20 antibodies prolongs survival, and a sizeable minority may be "functionally cured" with response to initial therapy lasting over 12 to 15 years [1-3].

While modern treatment regimens are often given with the goal of achieving a complete response, a sizeable minority of patients will attain only a partial response. Some of these patients will achieve a complete response if additional therapy (eg, maintenance) is administered. Some interventions, such as the use of maintenance therapy and the substitution of obinutuzumab for rituximab, have been shown to delay progression but have not demonstrated an improvement in overall survival. (See 'Choice of antibody: Obinutuzumab versus rituximab' below.)

A decision regarding these treatment options must take into account the individual patient's goals of therapy, values, and preferences. Individuals differ in the value they place on the avoidance of toxicity and the delay of further antilymphoma treatment. Different patients who are equally informed of these risks and benefits are likely to make different treatment decisions. (See 'Use of maintenance' below.)

ASYMPTOMATIC DISEASE

Indications for treatment — Patients with asymptomatic, stable stage 2 to 4 FL do not require immediate treatment. Historically, these patients have been managed with a "watch and wait" strategy, as early treatment has not demonstrated an overall survival (OS) benefit. However, there has been a shift towards early administration of single-agent rituximab in this population based on evidence that it postpones the use of cytotoxic chemotherapy, albeit with an increased risk of infection and impaired immune response. We consider either approach reasonable, and the choice between these depends on patient values and preferences (algorithm 1). (See 'Single-agent rituximab' below.)

The disease course without treatment is variable, with some patients demonstrating stable disease for years and others progressing more rapidly. Rarely, patients may have spontaneous remissions lasting longer than one year [4].

Clinicians differ in the criteria that they use to define "symptomatic disease" that prompts the initiation of more substantial treatment. The two most commonly used systems are those proposed by the Groupe d'Etude des Lymphomes Folliculaires (GELF) [5] and the British National Lymphoma Investigation (BNLI) [6]. Our approach, described below, incorporates factors of each.

The following findings are clear indications for treatment:

●Local symptoms due to progressive or bulky nodal disease

●Compromise of normal organ function due to progressive or bulky disease

●Presence of systemic B symptoms (ie, fevers, weight loss, night sweats)

●Presence of symptomatic extranodal disease, such as effusions

●Cytopenias due to extensive bone marrow infiltration, autoimmune hemolytic anemia or thrombocytopenia, or hypersplenism

●An increase in disease tempo

These criteria are used as general indications for therapy because treatment of these factors is thought to improve quality of life. These are similar to the indications for therapy used in the trials comparing observation versus initial therapy described in the following section and most of the trials of chemoimmunotherapy. Importantly, while they are indications for treatment, it is uncommon for autoimmune hemolytic anemia and autoimmune thrombocytopenia to be due to FL. An evaluation for other causes of autoimmune cytopenia should be performed prior to initiating therapy for this indication alone.

Single-agent rituximab — For asymptomatic, stable patients with stage 2 to 4 FL, single-agent rituximab and initial observation ("watch and wait") are equally acceptable alternatives, and the choice between these depends on patient values and preferences (algorithm 1). Chemoimmunotherapy is reserved for symptomatic disease. Patients with hepatitis C virus (HCV) infection who are asymptomatic from their lymphoma might benefit from an initial trial of treatment directed at the HCV. (See 'Patients with hepatitis C' below.)

When compared with watchful waiting, single-agent rituximab can delay FL progression and postpone chemoimmunotherapy, although it has not demonstrated an OS benefit. There is an increased risk of infections and impaired vaccine response related to immunosuppression. In addition, rituximab imposes a risk of hepatitis B virus reactivation among patients positive for hepatitis B surface antigen (HBsAg) or antibodies against hepatitis B core antigen (anti-HBc). (See 'Antibody safety and route of administration' below.)

We typically administer rituximab weekly for four weeks, then every two months for four additional doses [7,8]. An alternative is rituximab weekly for a total of four doses (days 1, 8, 15, and 22) [4].

Standard-formulation rituximab is administered intravenously using body surface area (BSA)-adjusted dosing (375 mg/m² per dose). Patients who have tolerated at least one full dose of intravenous rituximab are candidates for a subcutaneous formulation (rituximab-hyaluronidase) that uses a fixed dose (1400 mg) and a shorter administration time [9]. An extended-duration subcutaneous regimen may result in higher rituximab exposure and superior efficacy [7]. (See 'Antibody safety and route of administration' below.)

Support for rituximab in this setting comes from an international phase 3 trial, which randomly assigned 379 patients with stage 2 to 4, asymptomatic, nonbulky FL to initial management with one of three strategies [3,4]:

●Watchful waiting

●Rituximab induction (rituximab 375 mg/m² weekly for four doses)

●Rituximab induction followed by maintenance rituximab (administered every two months for two years)

Poor accrual resulted in the early closure of the rituximab induction arm. Key findings were:

●Rituximab treatment delayed the use of cytotoxic chemotherapy. Median time to next therapy (TTNT) was 5.6 years with watchful waiting, 14.8 years with rituximab induction, and not reached after a median of 14.7 years with rituximab induction and maintenance. A sizeable percentage of patients in all three arms had not started a new therapy at 15 years: watchful waiting (34 percent), rituximab induction (48 percent), and rituximab maintenance (65 percent). Early use of rituximab therapy did not appear to impair the effect of subsequent treatment, as illustrated by similar time to initiation of second new treatment in the three arms.

●Some in the watchful waiting group experienced a confirmed spontaneous remission (19 percent), most of whom subsequently relapsed or required therapy. Most patients in the watchful waiting group received chemoimmunotherapy upon progression; very few were treated with single-agent rituximab.

●Rituximab therapy was associated with improved ratings on quality-of-life (QOL) measures, reflecting a decrease in anxiety. By contrast, there was no significant improvement in measures of physical, social, and functional well-being [10]. With longer follow-up, the perceived impact of FL on QOL decreased over time in both groups.

●Among the 272 patients treated with rituximab, there were 18 serious adverse events potentially related to rituximab therapy, including infections (9 events), allergies (5 events), and neutropenia (4 events).

●There was similar OS in the three arms (15-year OS 68, 66, and 73 percent, respectively) and rates of histologic transformation.

Support for subcutaneous rituximab-hyaluronidase in this setting comes from a randomized trial (FLIRT) which compared the following in 202 patients with low tumor burden FL [7]:

●Induction rituximab (intravenous rituximab 375 mg/m² weekly for four doses), or

●Extended rituximab (intravenous rituximab once, followed by three weekly doses of rituximab-hyaluronidase 1400 mg per dose, followed by rituximab-hyaluronidase administered every two months for four additional doses)

Extended rituximab resulted in higher complete remission (CR) rates (59 versus 36 percent) and improved progression-free survival (PFS; four-year PFS 58 versus 41 percent; hazard ratio [HR] 0.59, 95% CI 0.39-0.52). TTNT and OS were similar in the two arms.

Importantly, those assigned to the extended rituximab arm received fixed-dose subcutaneous rituximab rather than BSA-adjusted standard rituximab for all but the first dose. This resulted in these patients having a higher average rituximab exposure in the first three months. Post-hoc analysis found high rituximab exposure in the first three months to be independently associated with higher CR rates, superior PFS, and TTNT, and the high exposure in the extended rituximab arm likely accounts for the superior outcomes.

"Watch and wait" strategy — For asymptomatic, stable patients with stage 2 to 4 FL, single-agent rituximab and initial observation ("watch and wait") are equally acceptable alternatives, and the choice between these depends on patient values and preferences (algorithm 1). As described in detail separately, single-agent rituximab delays progression and postpones cytotoxic chemotherapy. However, prospective trials have demonstrated similar OS with deferred therapy, and this approach avoids the cost and toxicity of treatment. (See 'Single-agent rituximab' above.)

When applying a "watch and wait" strategy, we follow patients in clinic every three months for the first year and then every three to six months thereafter until progressive disease is noted. At these appointments, we perform a history and physical examination, and laboratory studies, including a complete blood count with differential, chemistries with liver and kidney function and electrolytes, and lactate dehydrogenase (LDH). Imaging studies are repeated only if clinically indicated. Progressive disease is identified by an enlarging liver, spleen, or lymph node mass or by the development of new lesions, signs, or symptoms (table 2) [11,12].

Histologic transformation (HT) of FL to a more aggressive lymphoma variant, such as diffuse large B cell lymphoma (DLBCL), occurs regardless of whether FL is treated aggressively or conservatively, at a rate of ≤1 percent per year [13-16]. HT should be suspected if there is a rapid progression of lymphadenopathy, infiltration of extranodal sites, the development of systemic symptoms, or an elevated serum LDH. Biopsy to evaluate for HT is indicated in such circumstances. In addition, all patients should have a biopsy at the time of progression to confirm relapse and evaluate for HT. (See "Histologic transformation of follicular lymphoma".)

Several randomized trials comparing chemotherapy regimens of different intensities versus a "watch and wait" strategy followed by chemotherapy at the time of progression support the use of an initial period of observation for asymptomatic patients with low-volume disease [5,6,17-21]. This approach does not jeopardize survival, and a prolonged treatment-free period may decrease the potential for drug resistance by avoiding exposure of the tumor to chemotherapy. Prospective studies have reported that a sizeable percentage is able to avoid treatment for a prolonged period. In the National LymphoCare Study, 40 percent of patients managed with a "watch and wait" strategy had not required treatment after a median follow-up of eight years [22]. In a randomized trial of "watch and wait" versus single-agent rituximab, 46 percent of patients did not need treatment after three years, and 34 percent had not required treatment after 15 years [3,4,23].

SYMPTOMATIC DISEASE

High tumor burden: Chemoimmunotherapy — For patients with high tumor burden, symptomatic FL, we suggest chemoimmunotherapy (eg, anti-CD20 antibody plus chemotherapy or lenalidomide) rather than single-agent rituximab (algorithm 1). Single-agent rituximab may be considered for patients with comorbid conditions that make them poor candidates for chemotherapy and/or disease that progresses slowly over years. (See 'Low tumor burden: Rituximab alone' below.)

This approach is generally consistent with that of major guidelines, including those from the National Comprehensive Cancer Network (NCCN), the European Society of Medical Oncology (ESMO), and the British Society for Haematology [24-26].

Chemoimmunotherapy is an effective treatment for FL. Meta-analyses of randomized trials have demonstrated that the addition of rituximab to chemotherapy improves overall survival (OS), overall response, and disease control [27-33]. While direct comparisons to single-agent rituximab are limited, indirect comparisons and at least one randomized trial suggest that chemoimmunotherapy results in a more rapid and deeper response and delays progression [34]. (See 'Lenalidomide plus rituximab' below.)

A choice among chemoimmunotherapy regimens for the initial treatment of FL depends on patient and tumor characteristics (algorithm 1). Several regimens have demonstrated efficacy in prospective trials, and there is no clear OS advantage for one regimen over another. However, toxicities differ, and the choice of initial therapy will impact the options for treatment at the time of relapse or histologic transformation (HT).

Clinically indolent FL

Choice of therapy — For most patients with high tumor burden, symptomatic FL without concern for HT, we prefer either bendamustine plus rituximab (BR) or lenalidomide plus rituximab (R²) given trials that suggest similar efficacy when compared with R-CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab), and the avoidance of alopecia and cardiac toxicity (algorithm 1). They also preserve the opportunity to use an anthracycline-based regimen if HT occurs in the future. (See 'Bendamustine plus rituximab' below.)

BR and R² appear to have similar efficacy but differ in their toxicities, administration burdens, and implications for subsequent therapy. R² is a newer option with limited long-term data; when compared with BR, induction with R² is administered over a longer duration (18 versus 6 months) and has a different toxicity profile (more rash and diarrhea; less cytopenias, nausea, and neuropathy). Bendamustine can result in long-lasting T cell lymphopenia, and, while uncertain, bendamustine exposure may alter the efficacy of T cell-based immunotherapies at relapse [35,36]. By contrast, the use of R² as induction limits its use at relapse. (See 'Lenalidomide plus rituximab' below.)

Studies have reported increased deaths in patients >70 years treated with standard-dose BR. If BR is used in older adults, we modify the treatment plan by lowering the dose of bendamustine or limiting the number of cycles.

Single-agent rituximab remains an acceptable initial treatment for patients with comorbid conditions that make them poor candidates for chemoimmunotherapy and for those with a low tumor burden and/or disease progressing slowly over years. (See 'Low tumor burden: Rituximab alone' below.)

Bendamustine plus rituximab — Bendamustine plus rituximab (BR) (table 3) is one of our preferred treatment options for patients with high tumor burden, symptomatic FL without concern for HT (algorithm 1). A preference for BR over R-CHOP is based on trials that demonstrated better tolerability (including avoidance of alopecia and cardiac toxicity) and similar efficacy. It also preserves the opportunity to use an anthracycline-based regimen if HT occurs in the future. (See 'Choice of therapy' above.)

Increased deaths have been reported in patients >70 years treated with BR; we modify the treatment plan for these patients by lowering the dose of bendamustine (to 70 mg/m²), limiting the number of cycles, or offering an alternative chemotherapy backbone (eg, O-CVP [cyclophosphamide, vincristine, and prednisone plus obinutuzumab]).

BR is associated with a more marked and prolonged T cell depletion than R-CVP (cyclophosphamide, vincristine, and prednisone plus rituximab) or R-CHOP. While uncertain, prior exposure to bendamustine might alter the efficacy of T cell-mediated immunotherapies, such as bispecific antibodies or chimeric antigen receptor T cell, for the treatment of relapsed disease [35,36].

Six cycles of BR was compared with six cycles of standard R-CHOP in a randomized, phase 3 trial (StiL trial) of 514 patients with stage 2 to 4 follicular, indolent, and mantle cell lymphoma, and showed superior median progression-free survival (PFS; 69.5 versus 31.2 months; hazard ratio [HR] 0.58, 95% CI 0.44-0.74) with less toxicity, including lower rates of grade 3 and 4 neutropenia (29 versus 69 percent) and leukocytopenia (37 versus 72 percent), fewer infectious episodes (37 versus 50 percent), less paresthesia (7 versus 29 percent), less stomatitis (6 versus 19 percent), and no alopecia [37]. OS was similar in the two arms (70 versus 66 percent at 10 years) [38]. The number of second malignancies was similar between the two treatment arms (39 versus 47 cases).

In the international phase 3 BRIGHT trial, 447 previously untreated patients with follicular, indolent, or mantle cell lymphoma were randomly assigned to six cycles of BR versus R-CHOP or R-CVP (as determined by the investigator prior to randomization) [39-41]. BR resulted in similar complete (31 versus 25 percent) and overall (97 versus 91 percent) response rates. BR was associated with higher rates of vomiting, drug hypersensitivity, and secondary malignancies, and lower rates of peripheral neuropathy/paresthesia and alopecia. The use of prophylactic antiemetics was not specified in the protocol and was more common among patients assigned to R-CHOP. BR improved PFS (66 versus 56 percent at five years; HR 0.61, 95% CI 0.45-0.85) for the group as a whole. While the study was overall positive and favored BR, limitations included the use of both R-CVP and R-CHOP in the control arm and that the PFS difference was no longer statistically significant when patients with mantle cell lymphoma were removed from the analysis (HR 0.70, 95% CI 0.49-1.01). Maintenance rituximab was used in 197 patients and, on subgroup analysis, a PFS benefit was seen whether or not maintenance was used. OS was similar in the two treatment arms (HR 1.15; 95% CI 0.72-1.84).

Bendamustine was a chemotherapy backbone option in the phase 3 GALLIUM study, which compared an obinutuzumab-based induction and maintenance strategy versus a rituximab-based induction and maintenance strategy in 1202 patients with previously untreated stage 2 to 4 FL [42,43]. Post-hoc analyses have suggested higher rates of fatal adverse events among older adults receiving bendamustine-based therapy. This is described in more detail below. (See 'Choice of antibody: Obinutuzumab versus rituximab' below.)

Data regarding the use of BR in patients with the more aggressive histologic grade 3a disease are limited. Retrospective series have reported efficacy that appears to be superior to R-CVP and similar to R-CHOP [44,45].

Lenalidomide plus rituximab — Lenalidomide plus rituximab (R²) is one of our preferred treatment options for patients with high tumor burden, symptomatic FL without concern for HT (algorithm 1). Some contributors use R² frequently in the first-line setting while others typically reserve it for patients with relapsed or refractory FL. Initial trials suggest that R² results in similar PFS to that seen with chemoimmunotherapy but with a different toxicity profile. When compared with single-agent rituximab, R² improves PFS and increases toxicity. It also preserves the opportunity to use an anthracycline-based regimen if HT occurs in the future.

R² was compared with chemoimmunotherapy in an international, open-label, randomized phase 3 trial (RELEVANCE) of 1030 patients with treatment-naïve FL (median age 59; range 23 to 89) [46-48]. In each arm, treatment was given for a total of 30 months. R² was administered for 18 months and followed by one year of rituximab maintenance. Chemoimmunotherapy with R-CHOP (72 percent), BR (23 percent), or R-CVP (5 percent) was administered for approximately six months and followed by two years of maintenance therapy. At a median follow-up of 72 months, when compared with chemoimmunotherapy, those assigned to R² had the following outcomes:

●Similar rates of complete remission (CR; 48 versus 53 percent), with higher rates of complete molecular response (90 versus 77 percent in an analysis of 222 evaluable patients).

●Similar PFS (60 versus 59 percent at six years; HR 1.03, 95% CI 0.84-1.27). Those with progression within 24 months of initial treatment had inferior survival regardless of initial treatment.

●Similar OS (89 versus 89 percent at six years; HR 1.00), with more deaths from lymphoma (29 versus 17 patients) and fewer deaths from other causes (6 versus 13 patients).

●Similar percentage of grade 3 or 4 adverse events (65 versus 68 percent). Higher rates of dose reduction (36 versus 14 percent), dose interruption (59 versus 35 percent), or early treatment discontinuation (11 versus 3 percent). Grade 5 treatment-emergent adverse events occurred in nine patients receiving R² and six patients receiving chemoimmunotherapy.

●More rash (43 versus 24 percent), diarrhea (37 versus 19 percent), and tumor flare (6 versus <1 percent).

●Fewer episodes of severe neutropenia (32 versus 50 percent) and febrile neutropenia (2 versus 7 percent), less growth factor use (23 versus 68 percent), and less nausea, vomiting, and neuropathy.

●Similar cumulative incidence of HT at six years (4.4 versus 3.3 percent), and similar percent with second primary malignancies (11 versus 13 percent).

The rates of treatment discontinuation suggest that R² is associated with moderate toxicity in this population, but dose modifications were frequent. The toxicities seen in the chemoimmunotherapy arm are greater than those expected with BR and likely reflect the high percentage of patients treated with R-CHOP. Further data on efficacy come from two small phase 2 trials of R² in treatment-naïve FL with median follow-ups of five and eight years, where over 70 percent of patients achieved a complete response, and estimated five-year PFS rates were approximately 70 percent [49-51]. By contrast, the use of lenalidomide plus obinutuzumab is investigational. In a phase 2 study of lenalidomide plus obinutuzumab (O-R, also called GALEN) in treatment-naïve FL with median follow-up of 3.7 years, approximately 80 percent of patients achieved a complete response, and the estimated three-year PFS was 82 percent (95% CI 73-88 percent) [52].

R² was compared with single-agent rituximab in a multicenter, open-label phase 2 trial (SAKK 35/10) of 154 patients (median age 62, range 29 to 85) with treatment-naïve stage 2 to 4 FL [34]. In both treatment arms, rituximab was administered weekly for weeks 1 through 4 and 12 through 15. Those assigned to R² also received lenalidomide daily for 18 weeks. At a median follow-up of four years, R² resulted in the following:

●Higher rates of confirmed or unconfirmed CR by computed tomography (61 versus 36 percent).

●Superior PFS (median 5.0 versus 2.3 years; HR 0.60, 95% CI 0.38-0.97).

●Similar OS (≥90 percent at four years).

●Lower rates of treatment discontinuation due to insufficient response at week 10 (4 versus 21 percent).

●More treatment discontinuation due to toxicity (13 patients versus 1 patient).

●More grade 3 or higher toxicity (56 versus 22 percent), including neutropenia (23 versus 7 percent). In addition, there were higher rates of low-grade fatigue, diarrhea, and rash.

While R² prolongs PFS over that seen with single-agent rituximab, it also increases toxicity and has not demonstrated an improvement in OS. Single-agent rituximab remains an acceptable initial treatment for patients with comorbid conditions that make them poor candidates for chemoimmunotherapy and for those with a low tumor burden and/or disease progressing slowly over years. (See 'Low tumor burden: Rituximab alone' below.)

Clinically aggressive FL

Evaluate for histologic transformation — HT of FL to a more aggressive lymphoma variant, such as diffuse large B cell lymphoma (DLBCL), occurs regardless of whether FL is treated aggressively or conservatively, at a rate of ≤1 percent per year [13-16]. HT should be suspected if there is a rapid progression of lymphadenopathy, infiltration of extranodal sites, the development of systemic symptoms, or an elevated serum lactate dehydrogenase (LDH). A biopsy to evaluate for HT is indicated in such circumstances. In addition, all patients should have a biopsy at the time of progression to confirm relapse and evaluate for HT. The evaluation and management of HT is discussed in detail separately. (See "Histologic transformation of follicular lymphoma".)

R-CHOP, O-CHOP, or O-CVP — For younger, fit patients with an aggressive clinical presentation, we prefer anthracycline-containing chemotherapy regimens used for clinically aggressive lymphomas, including HT (algorithm 1) (eg, R-CHOP (table 4) or O-CHOP [cyclophosphamide, doxorubicin, vincristine, and prednisone plus obinutuzumab]). This includes patients with a clinical picture suggesting HT (eg, B symptoms, increased LDH, rapid growth) even if transformation is not confirmed on biopsy [13,16,53]. These patients have an increased risk of undetected or subsequent transformation, which is the leading cause of death for patients with FL [54]. Using an anthracycline-containing chemotherapy regimen will allow for the treatment of undetected transformation.

For older, frail patients or those with cardiac disease who have an aggressive clinical presentation, we prefer O-CVP to avoid the cardiotoxicity of R-CHOP. In a randomized trial, when compared with R-CHOP, R-CVP resulted in shorter PFS at 3 years (46 versus 68 percent) and 8 years (42 versus 49 percent) but similar OS (83 percent at 8 years in both arms) [55,56]. In the GALLIUM study, the substitution of obinutuzumab for rituximab improved PFS regardless of chemotherapy backbone, albeit with a moderate increase in toxicity [42,43,57,58]. (See 'Choice of antibody: Obinutuzumab versus rituximab' below.)

Data regarding the use of BR or R² in this population are limited, and we await further data before using these regimens in this setting. Retrospective series have reported the efficacy of BR, which appears to be superior to R-CVP and similar to R-CHOP [44,45]. Data regarding the risk of HT after bendamustine or CHOP remain debated, although the incidence appears slightly higher in patients treated with bendamustine [16,59].

Numerous trials have evaluated the use of R-CHOP in FL [1,31,55,56,60,61]. Overall response rates are >90 percent, and approximately one-half of patients will be alive without progression after 7 to 10 years. Common side effects include severe neutropenia (69 percent) and mild to moderate alopecia, nausea, vomiting, and infusion-related reactions. There is a 1 to 2 percent treatment-related mortality rate. In addition, R-CHOP carries a small but important risk of anthracycline cardiotoxicity, the risk of which increases with increasing cumulative lifetime dose. Cardiac function should be monitored to detect asymptomatic disease [62]. (See "Risk and prevention of anthracycline cardiotoxicity" and "Clinical manifestations, diagnosis, and treatment of anthracycline-induced cardiotoxicity".)

In the randomized trial of R-CHOP versus BR (StiL trial), the overall response rate was 91 percent, with a median time to progression of 6.8 years and a four-year OS rate of 83 percent [37,38]. (See 'Bendamustine plus rituximab' above.)

Choice of antibody: Obinutuzumab versus rituximab — Rituximab was the first anti-CD20 monoclonal antibody to be used successfully in FL and remains our preferred agent in patients with previously untreated disease. There are less data regarding the use of obinutuzumab in previously untreated FL, although one randomized trial (GALLIUM) suggests that obinutuzumab-based induction and maintenance prolongs PFS over that seen with rituximab-based therapy.

The GALLIUM study was an international, open-label, randomized trial comparing an obinutuzumab-based induction and maintenance strategy versus a rituximab-based induction and maintenance strategy in 1202 patients with previously untreated stage 2 to 4 FL [42,43,57,58]. Participating treatment centers selected one of the following chemotherapy regimens to use with the antibody for induction: bendamustine (57 percent), CHOP (33 percent), or CVP (10 percent), and clinical characteristics of patients were different in these three groups. Patients responding to induction received up to two years of maintenance with the same antibody they received during induction. The two arms had similar estimated rates of overall response (84 versus 79 percent) and complete response (78 versus 73 percent). At a median follow-up of 7.9 years, the obinutuzumab-based strategy resulted in the following:

●Superior PFS (63 versus 56 percent at 7 years) and time to next lymphoma therapy (74 versus 65 percent at 7 years). Post-hoc analysis showed consistent improvement of PFS with all three backbone regimens: For BR, HR 0.79 (95% CI 0.61-1.03); for CHOP, HR 0.81 (95% CI 0.60-1.10); and for CVP, HR 0.62 (95% CI 0.37-1.05).

●Similar OS (89 versus 87 percent at 7 years; HR 0.86, 95% CI 0.63-1.18) and similar rates of HT.

●Higher rates of grade 3 to 5 adverse events (75 versus 68 percent), infusion-related events (59 versus 49 percent), febrile neutropenia (6.9 versus 4.9 percent), and grade 3/4 infections (20 versus 15.6 percent).

Fatal adverse events were seen in 4 and 3.4 percent of patients receiving obinutuzumab and rituximab, respectively. Fatal adverse events were numerically more common in patients receiving bendamustine (4 percent) than CHOP (2 percent) or CVP (2 percent). However, these data are complicated to interpret since the backbone chemotherapy was not randomly assigned and the analysis was not adjusted for baseline patient characteristics, which varied among the groups. The difference in fatal adverse event rates by chemotherapy backbone was most prominent among patients over age 70 years, in whom rates were numerically higher with bendamustine than with CHOP (16 of 119, 13 percent versus 1 of 55, 2 percent). Most deaths in those receiving a bendamustine backbone occurred during maintenance immunotherapy. Causes are difficult to ascertain as the number of deaths was small, although bendamustine plus obinutuzumab had more deaths due to second malignancies and infection, whereas BR had more deaths due to nervous system disorders. Among patients younger than 70 years of age, fatal adverse events did not differ numerically by chemotherapy backbone.

These results suggest improved PFS with the use of an obinutuzumab-based induction followed by obinutuzumab maintenance as compared with rituximab-based induction followed by rituximab maintenance. It is not known whether this will translate into a survival benefit in the future, and we feel the use of either antibody is reasonable at this time. When considering the choice of anti-CD20 antibody, the potential toxicities and the value of PFS as a clinical endpoint must be interpreted within the context of the disease course.

Use of maintenance — Some experts offer maintenance with an anti-CD20 monoclonal antibody (rituximab or obinutuzumab) after induction to achieve deeper responses and delay progression. Maintenance prolongs PFS; there is no OS benefit and no change in transformation rate. Even though maintenance is designed to have a low toxicity profile, some studies suggest that nonrelapse mortality may be higher among patients receiving maintenance after bendamustine-based combinations. As such, a decision regarding its use in an individual patient must take into consideration both the potential benefit from attaining a deeper response and the likelihood that this patient will tolerate the prolonged therapy.

Some of our contributors routinely offer maintenance, while others do not. Clinicians who choose to administer maintenance should use one of the established regimens, such as that used in the PRIMA study (rituximab every two months for a total of two years) or the GALLIUM study (rituximab or obinutuzumab every two months for a total of two years) [42,63,64]. Trials that used longer courses of maintenance (eg, four years) have noted increased toxicity towards the end of maintenance [65,66]. As such, maintenance should not exceed two years.

The largest trial to address maintenance was the Primary Rituximab and Maintenance (PRIMA) phase 3 intergroup trial, in which 1018 patients with previously untreated FL who had demonstrated an initial response to chemoimmunotherapy were randomly assigned maintenance with rituximab (375 mg/m² administered intravenously every 8 weeks for 24 months) or placebo [2,63,64]. The induction regimen used was determined by the investigator and included R-CHOP (75 percent), R-CVP (22 percent), and R-FCM (3 percent; fludarabine, cyclophosphamide, mitoxantrone, and rituximab). Rituximab maintenance resulted in:

●Improved PFS (75 versus 58 percent at 36 months; median 10.5 versus 4 years).

●Higher percentage of patients in complete response or unconfirmed complete response at 24 months (72 versus 52 percent).

●Higher overall rate of severe (grade 3/4) adverse events (24 versus 17 percent).

●Higher rate of infections (39 versus 24 percent), the majority of which could be treated in the ambulatory setting.

●Similar survival and quality of life ratings; 10-year OS 80 percent (HR 1.04; 95% CI 0.77-1.40).

Approximately 4 percent transformed to a more aggressive histology; most cases of HT occurred in the first year, with a median time to transformation of 9.7 months [13].

PRIMA was included in a meta-analysis of seven trials evaluating rituximab maintenance after chemotherapy or chemoimmunotherapy in 2315 patients with FL [67]. For the group as a whole, maintenance rituximab improved PFS (HR 0.57; 95% CI 0.51-0.64) and OS (HR 0.79; 95% CI 0.66-0.96), although the absolute improvement in median OS was small (12 versus 11.5 years). Maintenance rituximab was associated with a greater risk of adverse events, most commonly infections (34 versus 24 percent). On subset analysis, a survival benefit was not seen when maintenance rituximab was given after rituximab-containing induction.

It is not clear whether these results can be safely extrapolated to patients treated with other initial chemotherapy regimens, such as BR. In an earlier study using a multidrug fludarabine-containing combination regimen, rituximab maintenance was associated with severe (grade 3 or 4) toxicities and unclear benefit [68]. Similarly, while numbers were small, rituximab maintenance in PRIMA did not appear to benefit patients treated with a similar fludarabine-based combination [63,64].

Some studies suggest that nonrelapse mortality may be higher among patients receiving maintenance after bendamustine-based combinations [42,43,69], while others have not [39-41,70,71]. Overall, the quality of the evidence addressing this issue is low. As an example, a subset analysis of the GALLIUM study raised concerns of increased fatal adverse events among patients over age 70 years receiving maintenance after bendamustine-based induction [42,43]. However, in this trial, the backbone chemotherapy was not randomly assigned, and the analysis was not adjusted for baseline patient characteristics, which varied among the groups. A similarly high rate of fatal adverse events (5 percent) was seen in a small phase 2 trial of BR followed by rituximab maintenance in patients >60 years with low tumor burden FL [69]. By contrast, a retrospective study of 640 patients (median age 60) treated with BR as initial therapy for FL reported a lower fatal adverse event rate with BR (2.5 percent overall), which was similar among patients who did or did not receive maintenance therapy [70]. In this study, the PFS benefit from maintenance was limited to those patients who had a partial remission; a PFS benefit was not seen in those who attained a CR following at least four cycles of BR.

Although no statistical difference in the risk of HT was observed in the prospective PRIMA study [2,63,64], a retrospective study including >10,000 patients suggested that rituximab maintenance was associated with a lower risk of HT (cumulative risk of 3.6 versus 5.9 percent at 10 years) [14].

As such, some contributors do not routinely administer rituximab maintenance. A subset of patients may elect to proceed with maintenance after discussion of the potential harms and benefits.

Low tumor burden: Rituximab alone — Single-agent rituximab is an acceptable initial treatment for patients with comorbid conditions that make them poor candidates for chemoimmunotherapy and for those with a low tumor burden and/or disease progressing slowly over years (algorithm 1). Rituximab has a low toxicity profile and good response rates and has been shown to delay disease progression in these populations. Long-term follow-up is limited, and it is not known if survival is improved. However, a large international randomized trial comparing watchful waiting versus initial treatment with rituximab suggested that initial treatment with rituximab delays FL progression and postpones cytotoxic chemotherapy [3,4]. (See 'Single-agent rituximab' above.)

We offer a finite schedule of rituximab rather than continuing rituximab until progression. The following administration schedules were used in randomized trials and are equally acceptable approaches:

●Rituximab weekly for a total of four doses (days 1, 8, 15, and 22) [72]

●Rituximab weekly for four weeks, followed by four additional doses administered every two months [8,73]

Standard-formulation rituximab is administered intravenously using body surface area (BSA)-adjusted dosing (375 mg/m² per dose). Patients who have tolerated at least one full dose of intravenous rituximab are candidates for a subcutaneous formulation (rituximab-hyaluronidase) that uses a fixed dose and a shorter administration time [9]. An extended-duration subcutaneous regimen may result in higher rituximab exposure and superior efficacy [7]. (See 'Antibody safety and route of administration' below.)

There is an increased risk of infections and impaired vaccine response related to immunosuppression. Rituximab also imposes a risk of hepatitis B virus reactivation among patients positive for hepatitis B surface antigen (HBsAg) or antibodies against hepatitis B core antigen. (See 'Antibody safety and route of administration' below.)

The data described below suggest that single-agent rituximab is associated with low toxicity and high response rates in patients with low tumor burden FL [8,72-76]. By contrast, using prolonged courses of rituximab until progression increases the total rituximab used by three to four times, adds expense, inconvenience, and toxicity, and does not improve OS.

Several randomized trials have evaluated the schedule modifications for the administration of single-agent rituximab in FL, with the following lessons:

●In a trial of previously untreated or relapsed/refractory FL (SAKK 35/98), after administering four weekly doses of rituximab, adding rituximab every two months for four more doses improved median event-free survival (23 versus 12 months) with no apparent increase in toxicity [8,73]. Following this extended schedule, 45 percent of responders remained in remission eight years after completing therapy [8].

●In a trial of previously untreated or relapsed/refractory FL (SAKK 35/03), after administering four weekly doses of rituximab, adding rituximab every two months for four more doses was just as effective and less toxic than adding rituximab every two months for a maximum of five years [75,77]. After a median follow-up of 10 years, subgroup analysis of the 46 treatment-naïve patients assigned to eight total doses of rituximab reported good PFS (median 6.6 years, 42 percent at 10 years) and OS (median 11 years, 85 percent at 10 years).

●In a trial of low tumor burden, previously untreated FL (RESORT), after administering four weekly doses of rituximab, adding rituximab every three months until progression prolonged remission (71 versus 37 percent at 7 years) and increased the likelihood of avoiding cytotoxic chemotherapy or radiation (83 versus 63 percent at 7 years) [72,78]. However, there was no difference in OS (83 versus 84 percent at 10 years), and anxiety levels did not differ by assigned treatment (maintenance versus observation) [74].

Antibody safety and route of administration — The major toxicities of anti-CD20 antibodies include:

●Infusion reactions (ie, fevers, rigors, and hypotension). (See "Infusion-related reactions to monoclonal antibodies for cancer therapy".)

●Infections and impaired immune response (eg, vaccine response) related to immunosuppression. (See "Secondary immunodeficiency induced by biologic therapies", section on 'Monoclonal antibodies to B cells'.)

●Hepatitis B virus reactivation among patients positive for HBsAg or antibodies against hepatitis B core antigen. (See "Hepatitis B virus reactivation associated with immunosuppressive therapy".)

●Rarely, JC virus infection can result in potentially fatal progressive multifocal leukoencephalopathy. (See "Progressive multifocal leukoencephalopathy (PML): Epidemiology, clinical manifestations, and diagnosis".)

Most studies have utilized intravenous administration. A subcutaneous formulation (rituximab-hyaluronidase) that uses a fixed dose and a shorter administration time is an acceptable alternative for patients who have tolerated at least one full dose of intravenous rituximab [9,79]. Randomized trials have demonstrated comparable efficacy and safety of the two formulations in patients with FL, diffuse large B cell lymphoma, and chronic lymphocytic leukemia [80-83]. Many patients preferred the convenience of the subcutaneous formulation, while others preferred intravenous administration [82]. Some studies suggest that fixed subcutaneous dosing may result in higher rituximab exposure and superior efficacy [7].

If the circulating white blood cell (WBC) count is elevated or there is a high burden of disease, some chemoimmunotherapy protocols follow a different administration schedule for cycle 1 to avoid giving full-dose rituximab and chemotherapy on the same day. As an example, when administering bendamustine plus rituximab, two options are to:

●Administer rituximab as a single agent on the first one to two days of cycle 1 (ie, split dose over two days if WBC >25,000/microL), and administer bendamustine on the following two days.

●Administer 50 mg/m² of rituximab on the first day of cycle 1, followed by the remainder of the dose (325 mg/m²) on day 3, and give bendamustine on days 1 and 2.

These adjustments during cycle 1 improve safety and do not appear to have a negative impact on disease response. By cycle 2, the WBC count will have declined dramatically in most patients, and the remainder of the cycles are administered with full-dose rituximab and bendamustine on day 1, followed by bendamustine alone on day 2.

Is there a role for radiation? — The role of radiation therapy (RT) in stage 3 to 4 FL is limited to the use of local palliative radiation for the treatment of locally symptomatic disease. Consolidation RT given after chemotherapy does not appear to improve outcomes and may result in second malignancies. Some experts offer RT to selected patients with stage 2 FL. (See 'Stage 2 FL' below.)

Local low-dose radiation (eg, total dose of 4 grey [Gy]) can be used for the palliation of locally symptomatic disease. (See "Treatment of relapsed or refractory follicular lymphoma", section on 'Radiation therapy and radioimmunotherapy'.)

Studies have failed to demonstrate improvements in relapse-free survival or OS when RT is added to conventional chemotherapy. Although myelodysplasia (MDS) and acute leukemia are uncommonly seen in patients with indolent lymphomas treated with chemotherapy alone, a 15-year cumulative incidence of MDS and secondary acute leukemia of 17 percent has been reported for the combination of low-dose total lymphoid irradiation and cytotoxic chemotherapy [84]. This suggests that combined modality therapy increases the incidence of hematopoietic stem cell disorders.

SPECIAL SITUATIONS

Grade 3 FL (including follicular large B cell lymphoma) — Follicular large B cell lymphoma is a distinct clinicopathologic entity in the World Health Organization Classification, 5^th edition (WHO5) [85], and corresponds to follicular lymphoma grade 3b in the International Consensus Classification (ICC) [86]. Although these tumors demonstrate follicular architecture, they are comprised of solid sheets of centroblasts, and the clinical presentation, behavior, and outcome with treatment more closely approximate that of diffuse large B cell lymphoma (DLBCL) [44,87-91]. (See "Initial treatment of advanced-stage diffuse large B cell lymphoma".)

The impact of tumor grade on the management of other FL tumors (grade 1, 2, or 3a) is less clear, and reporting is not required by the WHO5. However, the ICC employs a grading schema that uses a scale from 1 to 3, with those with >15 centroblasts per high-power field categorized as grade 3. Grade 3 FL is subdivided into grade 3a, in which centrocytes are present, and grade 3b, in which there are solid sheets of centroblasts. Although controversial, differences in molecular genetics as well as clinical behavior suggest that FL grade 3a is an indolent disease more closely resembling those with grade 1 or 2 [44,87-91]. However, when compared with grade 1 or 2 tumors, grade 3a tumors have an increased risk of histologic transformation [13,92].

Stage 2 FL — Stage 2 FL is defined as FL in two or more nodal groups on the same side of the diaphragm with or without limited contiguous extranodal involvement (table 1). For patients with stage 2 FL, we prefer a management approach similar to that used for stage 3 or 4 FL. Other clinicians offer radiation therapy (RT) to a subset of these patients, in which the disease can be encompassed by a reasonable radiation field (eg, stage 2 disease with groin and ipsilateral iliac involvement). Details regarding the use of RT are discussed separately. (See "Initial treatment of stage 1 follicular lymphoma", section on 'Radiation therapy (RT)'.)

Patients with stage 2 FL have been included in most studies of RT in FL. Studies using contemporary radiation practices suggest that patients with stage 2 FL are unlikely to be cured with RT [93,94]. As an example, an international multicenter retrospective study evaluated the outcomes of 512 patients with stage 1 or 2 FL who underwent RT administered with curative intent [93]. The percentage of patients free from progression at five years was lower among those with stage 2 disease (49 versus 74 percent).

Subset analyses of trials of RT for stage 1 or 2 FL have also identified tumor bulk as a marker of worse outcome following RT alone. As an example, in a retrospective analysis of 237 patients with stage 1 or 2 FL treated with RT with curative intent, rates of progression-free survival at 10 years decreased with increasing tumor volume (77, 50, and 28 percent for patients with completely excised lesions, <5 cm lesions, and ≥5 cm lesions, respectively) [95]. However, rates of overall survival at 10 years did not differ with tumor volume (76, 62, and 78 percent, respectively). It is unknown whether increasing therapy intensity for patients with bulky disease would improve outcomes in this population.

Patients with hepatitis C — An initial trial of treatment directed at the hepatitis C virus (HCV) infection may be indicated for patients with HCV who are asymptomatic from their lymphoma and would otherwise not require the initiation of lymphoma-specific therapy. (See "Extrahepatic manifestations of hepatitis C virus infection", section on 'Lymphoma'.)

A number of reports, primarily from Europe, have indicated that treatment of a coexisting HCV infection has resulted in complete clinical remissions in some patients with indolent lymphoma, including FL [96-102].

One study evaluated the effect of treatment with pegylated interferon plus ribavirin in 13 patients with clinically indolent B cell non-Hodgkin lymphoma and coexisting HCV infection [99]. Hematologic and virologic responses were correlated. Complete hematologic responses were seen in seven patients. Two patients had a partial response and two had stable disease. Time to response ranged from 2 to 24 months.

RESPONSE EVALUATION AND SURVEILLANCE FOR RELAPSE — 

After the completion of initially planned treatment of FL, patients should be evaluated to determine the disease response to treatment and should be followed longitudinally for relapse (table 2). The response evaluation of patients with stage 2 to 4 FL is the same as that of patients with stage 1 FL. This is discussed in more detail separately. (See "Initial treatment of stage 1 follicular lymphoma", section on 'Evaluation of response to therapy'.)

While interim-response assessment using positron emission tomography combined with a computed tomography scan (PET/CT) is discouraged, the role of PET/CT at the end of first-line therapy should be underlined. Several studies have shown that patients with a positive PET/CT after a six-month immunochemotherapy regimen have a higher risk of disease progression and death. In one study polling three different trials, the hazard ratio for progression-free survival for patients with a positive PET scan versus those with a negative PET scan was 3.9 (95% CI 2.5-5.9), and for overall survival was 6.7 (95% CI 2.4-18.5) [103]. Similar results were reproduced in the prospective evaluation of PET/CT in the GALLIUM trial [104]. Since no therapeutic intervention has yet demonstrated a benefit in those with a positive post-treatment PET/CT, we monitor these patients closely and have a low threshold to biopsy for suspected histologic transformation.

Following the completion of therapy, restaging, and documentation of complete or partial remission, patients are seen at periodic intervals to monitor for treatment complications and assess for progression. This is discussed in more detail separately. (See "Initial treatment of stage 1 follicular lymphoma", section on 'Surveillance for relapse'.)

While studies are evaluating the role of minimal residual disease (MRD) testing and response-adapted therapy for FL, these approaches remain investigational. In one large multicenter study (FOLL12) that used imaging and MRD measurements to de-escalate or escalate therapy, those randomly assigned to standard therapy (including rituximab maintenance) had superior progression-free survival and similar overall survival to those assigned to response-adapted therapy (in whom maintenance was omitted) [105]. In another study (GALLIUM), detectable MRD midinduction or at the end of induction with chemoimmunotherapy was associated with worse progression-free survival and overall survival; however, MRD had a low sensitivity for predicting progression, as only 25 percent of patients with progression within two years of treatment had detectable MRD at the end of induction [106].

Early relapse (eg, within two years) is associated with poor outcomes and requires aggressive management. This is discussed in more detail separately. (See "Treatment of relapsed or refractory follicular lymphoma", section on 'Recognize early treatment failure'.)

CLINICAL TRIALS — 

The treatment of patients with stage 2 to 4 FL varies widely [107,108]. Whenever available, patients should be encouraged to participate in clinical trials.

Often there is no better strategy to offer a patient than enrollment onto a well-designed, scientifically valid, peer-reviewed clinical trial. Additional information and instructions for referring a patient to an appropriate research center can be obtained from the United States National Institutes of Health (www.clinicaltrials.gov).

PROGNOSIS — 

Patients with FL generally have an excellent prognosis. With modern treatment regimens, the median survival of these patients is in excess of 20 years [109], and some patients will experience a "functional cure" with long-term remission and death due to other causes [1,2,54,110-112].

However, FL is a heterogeneous disease, and some patients have a more rapid progression and shorter survival [113]. While prognostic tools, such as the Follicular Lymphoma International Prognostic Index (FLIPI) score (table 5), can be used to identify populations at higher risk of progression, better methods are needed to determine risk for the individual patient. (See "Clinical manifestations, pathologic features, diagnosis, and prognosis of follicular lymphoma", section on 'Prognosis'.)

This subject is discussed in detail separately. (See "Clinical manifestations, pathologic features, diagnosis, and prognosis of follicular lymphoma", section on 'Follicular lymphoma IPI (FLIPI)'.)

Patients with FL progressing within 24 months of initial immunochemotherapy (ie, early treatment failure) do poorly with standard treatment approaches and require more aggressive therapy. (See "Treatment of relapsed or refractory follicular lymphoma", section on 'Recognize early treatment failure'.)

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Management of follicular lymphoma".)

INFORMATION FOR PATIENTS — 

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient education" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Follicular lymphoma (The Basics)")

●Beyond the Basics topics (see "Patient education: Follicular lymphoma in adults (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Prognosis – Most patients with follicular lymphoma (FL) have an excellent prognosis (median overall survival [OS] >20 years). A subset has a more aggressive course (early progression, histologic transformation, high-risk features). (See 'Prognosis' above.)

●Pretreatment evaluation – A pretreatment evaluation determines disease stage and comorbidities likely to impact treatment (table 1 and algorithm 1). Enrollment in clinical trials is encouraged. (See 'Pretreatment evaluation' above.)

●Asymptomatic disease – For patients with asymptomatic, stable, stage 2 to 4 FL, single-agent rituximab and initial observation ("watch and wait") are equally acceptable alternatives, and the choice between these depends on patient values and preferences. With initial observation, approximately one-third of patients will be treatment-free at 15 years. A finite course of single-agent rituximab delays progression and postpones cytotoxic chemotherapy, albeit with an increased risk of infection, impaired immune response (eg, vaccine response), and no clear impact on OS. Chemoimmunotherapy is reserved for symptomatic disease. (See 'Asymptomatic disease' above.)

Antiviral therapy directed at hepatitis C virus (HCV) may be indicated for patients with HCV who do not otherwise have an indication for FL treatment. (See 'Patients with hepatitis C' above.)

●Chemoimmunotherapy for symptomatic, high tumor burden – For patients with symptomatic, high tumor burden FL, we suggest chemoimmunotherapy (eg, anti-CD20 antibody plus chemotherapy or lenalidomide) rather than single-agent rituximab (algorithm 1) (Grade 2B). While we generally suggest rituximab-based combinations (Grade 2C), obinutuzumab-based regimens are an acceptable alternative and may be preferred by patients who are willing to tolerate increased toxicity and place a high value on improved progression-free survival (PFS). (See 'High tumor burden: Chemoimmunotherapy' above and 'Choice of antibody: Obinutuzumab versus rituximab' above.)

•Clinically indolent disease – For most patients with high tumor burden, symptomatic FL without concern for histologic transformation, we suggest either bendamustine plus rituximab (BR) or lenalidomide plus rituximab (R²) rather than R-CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab) (Grade 2C), given similar efficacy and avoidance of alopecia and cardiac toxicity. BR and R² appear to have similar efficacy, but they differ in toxicity, administration burdens, and implications for subsequent therapy. If BR is used in patients >70 years, we lower the dose of bendamustine or limit the number of cycles. (See 'Choice of therapy' above.)

•Clinically aggressive disease – For patients with an aggressive clinical presentation, we suggest an anthracycline-containing chemotherapy regimen (eg, R-CHOP (table 4) or O-CHOP [cyclophosphamide, doxorubicin, vincristine, and prednisone plus obinutuzumab]) (Grade 2C). This includes patients with a clinical picture suggesting histologic transformation (eg, B symptoms, increased lactate dehydrogenase, rapid growth) even if not confirmed on biopsy. For older, frail patients or those with cardiac disease, we prefer O-CVP (cyclophosphamide, vincristine, and prednisone plus obinutuzumab) to avoid the cardiotoxicity of R-CHOP. (See 'Clinically aggressive FL' above.)

•Use of maintenance – Some contributors use maintenance therapy while others do not. Maintenance prolongs PFS; there is no clear OS benefit or change in transformation rate. Some studies suggest increased nonrelapse mortality when maintenance is given after bendamustine-based combinations. Patients and clinicians who place a high value on prolonged PFS may reasonably choose a strategy that incorporates maintenance with the understanding that toxicity will be increased. (See 'Use of maintenance' above.)

When administering maintenance, it is important to use one of the established regimens, such as that used in the GALLIUM study or PRIMA study (rituximab every two months for a total of two years).

●Rituximab alone for select patients – Single-agent rituximab is an acceptable alternative in patients with comorbid conditions that make them poor candidates for chemotherapy and for those with a low tumor burden and/or disease progressing slowly over years. (See 'Low tumor burden: Rituximab alone' above.)

For patients initially treated with rituximab therapy alone, we utilize a finite schedule of rituximab rather than continuing rituximab until progression (maintenance rituximab). Rituximab is administered as four weekly doses followed either by observation or by the same dose of rituximab every two months for four additional doses.

●Response evaluation – Patients are evaluated after treatment with laboratory studies and imaging (eg, whole-body fluorodeoxyglucose positron emission tomography/computed tomography [FDG PET/CT]), in addition to a history and physical examination, to determine response to therapy (table 2). Patients attaining a complete or partial remission are followed at periodic intervals for disease progression. Patients who do not achieve a partial remission are treated as refractory disease. (See "Initial treatment of stage 1 follicular lymphoma", section on 'Evaluation of response to therapy'.)

●Relapsed or refractory disease – The treatment of relapsed or refractory disease is presented separately. (See "Treatment of relapsed or refractory follicular lymphoma".)