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Initial treatment of stage II to IV follicular lymphoma

Initial treatment of stage II to IV follicular lymphoma
Literature review current through: Jan 2024.
This topic last updated: Jul 07, 2023.

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".)

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

Patients with stage III or IV disease (sometimes called "advanced stage") are not cured with conventional therapies. Treatment of this group is more akin to the long-term management of a chronic disease with a focus on symptom control. Most patients with stage III or IV FL will receive a number of different treatment modalities (eg, immunotherapy, chemoimmunotherapy, RT) in various combinations, often separated by several years without active therapy.

The management of patients with stage II FL is more variable. In the majority of patients, we typically offer treatment similar to that used for stage III or IV FL, while other clinicians offer treatment similar to that used for stage I FL. (See "Initial treatment of stage I follicular lymphoma", section on 'Stage II FL' and 'Stage II FL' below.)

Treatment also depends on the histologic grade of the tumor as determined by the number of centroblasts per high power field. The recommendations presented here pertain to patients with histologic grade 1, 2, or 3a FL; patients with grade 3b FL are treated with regimens used for other clinically aggressive lymphomas (eg, diffuse large B cell lymphoma). (See 'Grade 3 FL' below.)

The initial treatment of stage II, III, or IV FL is discussed here. The initial treatment of stage I FL and the management of relapsed or refractory FL are presented separately, as are the epidemiology, clinical presentation, pathologic features, diagnosis, and pathobiology of FL.

(See "Initial treatment of stage I follicular lymphoma".)

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

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

(See "Pathobiology 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 stage II, III, or IV FL is similar to that of patients with stage I FL. This is discussed in more detail separately. (See "Initial treatment of stage I follicular lymphoma", section on 'Pretreatment evaluation'.)

GOALS OF THERAPY — Patients with stage II, III, or IV FL are usually not cured with conventional treatment. While remissions can be attained, repeated relapses are common. Treatment focuses on the alleviation of symptoms, reversal of cytopenias, and improvement of quality of life. While not curative, modern therapy that incorporates anti-CD20 antibodies prolongs survival. (See 'Immunotherapy-based treatment' below.)

While modern chemoimmunotherapy regimens are often given with the goal of achieving a complete response, a sizeable minority of patients treated with these regimens will attain only a partial response. Some of these patients will achieve a complete response if additional therapy (eg, maintenance) is administered. In addition, for this group as a whole, some interventions, such as maintenance therapy and the use of obinutuzumab, prolong progression-free survival but have not demonstrated an improvement in overall survival.

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 anti-lymphoma treatment. Different patients who are equally informed of these risks and benefits are likely to make different treatment decisions. (See 'Use of maintenance' below.)

INITIAL MANAGEMENT — At the time of diagnosis, the vast majority of patients with FL will have stage II (11 to 16 percent), stage III (22 to 33 percent), or stage IV (26 to 40 percent) disease (table 1) [1,2]. With modern treatment regimens, the median survival of these patients is in excess of 20 years [3]. However, FL is a heterogeneous disease and some patients have a more rapid progression and shorter survival [4]. While prognostic tools such as the Follicular Lymphoma International Prognostic Index (FLIPI) score (table 2) 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'.)

Therapeutic strategy — Our approach to patients with stage III or IV FL depends on the histologic grade, presence of symptoms or organ dysfunction, and disease tempo (algorithm 1). 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 [5-8]. The management of stage II FL is more variable. (See 'Stage II FL' below.)

The treatment of patients with stage III or IV FL varies widely [2,9]. Whenever available, patients should be encouraged to participate in clinical trials. Asymptomatic patients can be observed initially. Once therapy is indicated, immunotherapy-based treatment (eg, anti-CD20 antibody plus chemotherapy or anti-CD20 mAb alone) is preferred because it results in superior response rates, progression-free survival (PFS), and overall survival (OS). Single-agent rituximab may be considered for patients with comorbid conditions that make them poor candidates for chemotherapy. Single-agent rituximab is also a reasonable alternative for those with a low tumor burden and/or disease that progresses slowly over years.

Local low dose radiation (eg, total dose of 4 Gy) is reserved for the palliation of locally symptomatic disease. (See "Treatment of relapsed or refractory follicular lymphoma", section on 'Radiation for palliation'.)

Indications for treatment — Patients with asymptomatic, stable stage III or IV FL do not require immediate treatment but should be followed closely. The disease course 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 [10]. While we typically also defer therapy in patients with asymptomatic stage II FL, other clinicians may offer radiation therapy to a subset of these patients in which the disease can be encompassed by a reasonable radiation field. (See 'Stage II FL' below.)

Clinicians differ in the criteria that they use to initiate treatment. The two most commonly used systems are those proposed by the Groupe d-Etude des Lymphomes Folliculaires (GELF) [11] and the British National Lymphoma Investigation (BNLI) [12]. 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 with initial therapy described in the following section and most of the trials of chemotherapy for stage III or IV disease. Importantly, while 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.

Asymptomatic patients

"Watch and wait" strategy preferred — For asymptomatic, stable patients with stage II, III, or IV FL, we suggest initial observation. This preference is largely based on the prospective trials that have demonstrated no difference in OS with deferred therapy and the avoidance of cost, complications, and potential drug resistance. Patients seeking immediate treatment may reasonably choose initial therapy with rituximab alone. Chemoimmunotherapy is reserved for disease progression. (See 'Immunotherapy alone' below.)

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.)

We follow asymptomatic 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, physical examination, and laboratory studies including a complete blood count with differential, chemistries with liver and renal 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 3) [13,14].

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 approximately 2 percent per year [15,16], depending on the magnitude of the large cell component. 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 of a suspicious area is indicated in such circumstances. In addition, we have a low threshold for obtaining a biopsy for all patients with FL at the time of progression. (See "Histologic transformation of follicular lymphoma".)

Several randomized trials comparing chemotherapy regimens of different intensities with 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 [11,12,17-21]. 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.

Single-agent rituximab — Single-agent rituximab is an alternative to a "watch and wait" strategy for patients with asymptomatic, stable, stage II, III, or IV FL who desire immediate treatment. When compared with watchful waiting, single-agent rituximab may decrease anxiety and postpone cytotoxic chemotherapy without impacting OS.

We follow one of the administration schedules used in randomized trials in this setting [10,22]:

Rituximab weekly for a total of four doses (days 1, 8, 15, and 22), or

Rituximab weekly for four weeks, then every two months for two years

Standard formulation rituximab is administered intravenously using weight-based dosing (375 mg/mm2 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 [23]. An extended duration subcutaneous regimen may result in higher rituximab exposure, and superior efficacy [22]. (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 II to IV, asymptomatic, non-bulky FL to initial management with one of three strategies [10]:

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 therapy was associated with improved ratings on quality of life measures, reflecting a decrease in anxiety. There were 18 serious adverse events potentially related to rituximab therapy.

There was no difference in OS or rate of histologic transformation. As expected, more patients assigned to watchful waiting received a subsequent intervention within three years (54 versus 12 and 22 percent).

With longer follow-up available in abstract form, median time to next therapy was 2.7 years, 9.9 years, and not reached after a median of 12.3 years, respectively [24]. The addition of rituximab maintenance improved PFS. However, a sizeable percentage of patients in all three arms had not started a new therapy at 10 years: watchful waiting (29 percent), rituximab induction (49 percent), and rituximab maintenance (65 percent).

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 chemotherapy upon progression (91 percent); very few were treated with single-agent rituximab.

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 [22]:

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 two years)

Extended rituximab resulted in higher CR rates (59 versus 36 percent) and improved PFS (4-year PFS 58 versus 41 percent; HR 0.59, 95% CI 0.39-0.52). Time to next therapy (TTNT) and OS were similar in the two arms.

Importantly, those assigned to the extended rituximab arm received fixed-dose subcutaneous rituximab rather than weight-based 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.

Immunotherapy-based treatment

Choosing a strategy — Immunotherapy with an anti-CD20 monoclonal antibody (eg, rituximab, obinutuzumab) is a key component of the treatment of patients with symptomatic FL; chemoimmunotherapy results in superior response rates, PFS, and OS when compared with chemotherapy alone (algorithm 1) [25-31].

Experts differ in their preferred strategy and may choose different approaches depending on patient preference. The three main options, listed in order of increasing intensity are:

Single-agent rituximab administered for a defined course. (See 'Immunotherapy alone' below.)

Rituximab plus chemotherapy administered for six to eight cycles. (See 'Choice of regimen' below.)

Immunotherapy (rituximab or obinutuzumab) plus chemotherapy administered for six to eight cycles, followed by two years of single-agent immunotherapy as maintenance. (See 'Use of maintenance' below.)

We typically administer rituximab plus chemotherapy rather than single-agent rituximab because indirect comparisons suggest that this approach results in a more rapid and deeper response. Single-agent rituximab is an acceptable alternative for 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.

For most patients, we prefer a bendamustine-based regimen (eg, bendamustine rituximab or bendamustine obinutuzumab) because of its decreased toxicity and similar efficacy when compared with other regimens. Some contributors routinely use maintenance therapy while others do not. Maintenance therapy prolongs PFS; there is no OS benefit and no change in transformation rate. 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.

Chemoimmunotherapy

Choice of regimen — Many chemotherapy regimens have been combined with rituximab or obinutuzumab in prospective trials. A choice among these regimens depends on patient and tumor characteristics and whether maintenance therapy is planned (algorithm 1). Importantly, the choice of initial therapy will impact the options for treatment at the time of relapse or histologic transformation.

In general, we prefer bendamustine plus rituximab (BR) given the fewer side effects associated with this regimen and trials that suggest similar efficacy when compared with R-CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab). Considering the increased deaths seen in patients >70 years treated with BR, we modify the treatment plan for these patients by lowering the dose of bendamustine, limiting the number of cycles, or offering an alternative chemotherapy backbone. (See 'Bendamustine plus rituximab' below.)

Data regarding the use of BR in patients with the more aggressive histologic grade 3a disease are limited; R-CHOP may be preferred in this setting for fit patients with clinically aggressive disease. (See 'R-CHOP' below.)

R-CVP (cyclophosphamide, vincristine, and prednisone plus rituximab) is an alternative used by some of our contributors for patients with cardiac disease but is expected to result in a lower response rate and a shorter PFS. (See 'Patients with cardiac disease' below.)

Obinutuzumab has been used in combination with bendamustine, CHOP, and CVP, followed by obinutuzumab maintenance. In one study, this strategy improved PFS, but was associated with increased toxicity and cost [32]. The efficacy and toxicity of this approach may depend on the chemotherapy backbone used. In particular, non-relapse mortality may be higher among patients receiving maintenance after bendamustine-based combinations. (See 'Obinutuzumab-based regimens' below.)

While the combination of lenalidomide plus rituximab (R2) is emerging as a treatment option for patients with FL, we typically reserve this regimen for patients with relapsed or refractory FL. (See 'Lenalidomide plus rituximab or obinutuzumab' below.)

Fludarabine-based regimens are no longer recommended and not used due to high toxicity in this population [33-35].

The following sections illustrate the studies describing the efficacy and toxicity of BR and R-CHOP when compared with each other and other regimens.

Bendamustine plus rituximab — In general, we prefer bendamustine plus rituximab (BR) (table 4) given the fewer side effects associated with this regimen and trials that suggest similar efficacy when compared with R-CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab). 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. Our contributors differ in their use of maintenance after BR. (See 'Use of maintenance' below.)

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 II to IV follicular, indolent, and mantle cell lymphoma, and showed superior median 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 [36]. There was no difference in OS (70 versus 66 percent at 10 years) [37]. 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 (MCL) were randomly assigned to six cycles of BR versus R-CHOP or R-CVP (as determined by the investigator prior to randomization) [38-40]. 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 this finding lost statistical significance when the patients with MCL were removed from the analysis (HR 0.70, 95% CI 0.49-1.01), the suggested benefit would be clinically meaningful if true. 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 obinutuzumab-based induction and maintenance strategy versus a rituximab-based induction and maintenance strategy in 1202 patients with previously untreated stage II to IV FL [32,41]. 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 'Obinutuzumab-based regimens' 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 [42,43].

R-CHOP — As described above, BR is our preferred regimen for most patients since it is associated with fewer side effects and similar efficacy when compared with R-CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab). However, data regarding the use of BR in patients with the more aggressive histologic grade 3a disease are limited, although retrospective series have reported similar efficacy to anthracycline-based regimens [42,43]; R-CHOP (table 5) may be preferred in this setting for fit patients with clinically aggressive disease. Some contributors administer maintenance rituximab following R-CHOP, while others would not. (See 'Use of maintenance' below.)

Numerous trials have evaluated the use of R-CHOP in FL [29,35,44-47]. Overall response rates are >90 percent and approximately 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.

Standard R-CHOP was compared with R-CVP and R-FM (rituximab, fludarabine, mitoxantrone) in a randomized trial of 534 patients with stage II to IV FL [35,47]. When compared with R-CVP, R-CHOP and R-FM resulted in superior rates of PFS at three years (68 and 63 versus 46 percent) and eight years (49 and 52 versus 42 percent). The estimated OS rate at eight years was 83 percent and did not differ with treatment. R-FM had higher rates of severe neutropenia and second malignancies and was associated with a higher risk of dying due to causes unrelated to lymphoma progression.

In the randomized trial of R-CHOP versus BR described above, the overall response rate was 91 percent with a median time to progression of 6.8 years and four-year OS rate of 83 percent [36]. (See 'Bendamustine plus rituximab' above.)

Another randomized trial compared CHOP plus either rituximab or the anti-CD20 radioimmunoconjugate 131I-tositumomab in patients with previously untreated stage II to IV FL [44,45]. Responses were seen in >95 percent of patients in each group with 10-year PFS rates of 42 and 56 percent, respectively. Estimated 10-year OS was 78 percent and did not differ significantly by treatment arm. While overall rates of second malignancies were similar with the two treatments, deaths from myelodysplastic syndrome and acute myeloid leukemia were more common following 131I-tositumomab.

Obinutuzumab-based regimens — 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 novel anti-CD20 monoclonal antibodies (eg, obinutuzumab, ofatumumab) 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; however, this impact on PFS may depend on the chemotherapy backbone used.

The GALLIUM study was an international, open-label, randomized phase 3 trial comparing an obinutuzumab-based induction and maintenance strategy versus a rituximab-based induction and maintenance strategy in 1202 patients with previously untreated stage II to IV FL [32,41,48]. 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). Patients responding to induction received up to two years of maintenance with the same antibody they received during induction. At a median follow-up of 41 months, the obinutuzumab-based strategy resulted the following:

Similar estimated rates of overall response (84 versus 79 percent) and complete response (78 versus 73 percent)

Superior PFS (83 versus 79 percent at three years; HR 0.68, 95% CI 0.54-0.87) in the group as a whole and, on post-hoc subset analysis, among those receiving a backbone of bendamustine or CHOP

Similar OS (94 versus 92 percent at three years; HR 0.82, 95% CI 0.54-1.22) and similar rates of histologic transformation

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). The majority of 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 and 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. Patients with stage II to IV FL are not cured with conventional therapies. Most of these patients are managed over decades with a focus on symptom control. Active treatment may be separated by several years without active therapy and asymptomatic progression does not require immediate therapy.

Lenalidomide plus rituximab or obinutuzumab — While the combinations of lenalidomide plus rituximab (R2) and lenalidomide plus obinutuzumab (O-R, also called GALEN) are emerging as treatment options for patients with FL, we typically reserve them 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. O-R has not been directly compared to other regimens. Longer follow-up is needed to better evaluate long-term efficacy and toxicity of these regimens.

In two small phase 2 trials of R2 in treatment-naïve FL with median follow-ups of five and eight years, over 70 percent of patients achieved a complete response and estimated five-year PFS rates were approximately 70 percent [49-51]. In a phase 2 study of O-R in treatment-naïve FL with median follow-up of 3.7 years, approximately 80 percent of patients achieved a complete response and estimated three-year PFS was 82 percent (95% CI 73-88 percent) [52].

In an international, open-label phase 3 trial (RELEVANCE), 1030 patients with treatment-naïve FL were randomly assigned to R2 or chemoimmunotherapy [53-55]. 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 death from lymphoma (29 versus 17 patients) and less death from other causes (6 versus 13 patients) when compared to R-chemo.

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 9 patients receiving R2 and 6 patients receiving R-chemo.

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 histologic transformation 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. 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. We prefer BR as initial therapy for most patients rather than R2. This preference reflects our greater confidence in its long-term efficacy (trial follow-up >10 years versus 6 years), the shorter treatment time (6 versus 18 months when given without maintenance), and lower cost.

In a multicenter, open-label phase 2 trial (SAKK 35/10), 154 patients with treatment-naïve stage II to IV FL were randomly assigned to a short course of R2 or single-agent rituximab [56]. 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 (36 versus 25 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 'Immunotherapy alone' below.)

Use of maintenance — Maintenance therapy refers to the prolonged administration of agents with low toxicity profiles in an attempt to prevent progression of disease. While induction aims to achieve a complete remission, many patients only obtain a partial remission (PR). There has been an increasing interest in using anti-CD20 monoclonal antibodies (rituximab or obinutuzumab) as maintenance therapy after induction in order to achieve deeper responses. Maintenance improves PFS, but has not improved OS. Even though maintenance is designed to have a low toxicity profile, some studies suggest that non-relapse 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 offer maintenance therapy, 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) described below or the GALLIUM study described above [32,57,58]. Trials that have used longer courses of maintenance (eg, four years) have noted increased toxicity towards the end of maintenance [59,60]; as such, maintenance should not exceed two years. Anti-CD20 monoclonal antibodies also impose 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.)

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 eight weeks for 24 months) or placebo [57,58,61]. The induction regimen used was determined by the investigator and included R-CHOP (75 percent), R-CVP (22 percent), and R-FCM (3 percent). Rituximab maintenance resulted in:

Higher rates of PFS at 36 months (75 versus 58 percent); longer median PFS (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 histologic transformation occurred in the first year with a median time to transformation of 9.7 months [62].

PRIMA was included in a meta-analysis of seven trials evaluating rituximab maintenance after chemotherapy or chemoimmunotherapy in 2315 patients with FL [63]. 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 bendamustine plus rituximab (BR). The universal applicability of rituximab maintenance was questioned by the results of a randomized phase 3 trial that evaluated the use of rituximab or observation after initial therapy with R-FND in 234 older adults (age 60 to 75 years) with previously untreated FL [64]. Rituximab maintenance was associated with a trend toward improved PFS at two years (81 versus 69 percent), which did not reach statistical significance, and a higher rate of severe (grade 3/4) neutropenia (14 versus 1 percent). Variation in the benefit from rituximab maintenance by induction regimen was also suggested on a subset analysis of the PRIMA trial, in which there didn't appear to be a benefit following rituximab, fludarabine, cyclophosphamide, and mitoxantrone (R-FCM) [57,58].

Some studies suggest that non-relapse mortality may be higher among patients receiving maintenance after bendamustine-based combinations [32,41,65], while others have not [38-40,66,67]. 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 [32,41]. 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 [65]. In 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 [66]. 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 complete remission following at least four cycles of BR.

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

Immunotherapy 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 may improve quality of life (ie, decrease anxiety) and postpone cytotoxic chemotherapy [10]. (See 'Asymptomatic patients' 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) [68]

Rituximab weekly for four weeks, followed by four additional doses administered every two months [69,70]

Standard formulation rituximab is administered intravenously using weight-based dosing (375 mg/mm2 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 [23]. An extended duration subcutaneous regimen may result in higher rituximab exposure and superior efficacy [22]. (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 [68-73]. In 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.

The following describes the largest trials evaluating single-agent rituximab as initial therapy in patients with symptomatic FL:

An international trial (SAKK 35/98) of 202 patients with previously untreated or relapsed/refractory FL administered four weekly doses of single-agent rituximab [69,70]. The 151 patients with responding or stable disease at week 12 were randomized to no further treatment or an extended course of rituximab every two months for four doses. At a median follow-up of 35 months, extending the course of rituximab improved the median event-free survival (23 versus 12 months) with no apparent increase in toxicity. With longer follow-up, 45 percent of responders were still in remission at eight years following extended course rituximab [70].

In the SAKK 35/03 trial, 270 patients with untreated, relapsed, stable, or chemotherapy-resistant FL were treated with four weekly doses of rituximab [72,74]. The 165 patients achieving at least a partial response were randomly assigned to receive rituximab every two months for four additional doses or to rituximab every two months for a maximum of five years. Those assigned to five years of rituximab were more likely to experience toxicities (at least one adverse event 76 versus 50 percent) without significantly improved PFS, event-free survival, or OS. After a median follow-up of 10 years, subgroup analysis of the 46 treatment naïve patients assigned to eight total doses of rituximab reported estimated 10-year rates of PFS and OS of 42 and 85 percent and median PFS and OS of 6.6 and 11 years, respectively

In another multicenter trial (RESORT), 408 patients with low tumor burden previously untreated FL received four weekly doses of rituximab [68]. The 299 patients (73 percent) who achieved a complete or partial response were randomly assigned to rituximab maintenance every three months until progression or to observation and retreatment with rituximab at the time of progression. Patients receiving maintenance were less likely to require cytotoxic chemotherapy by three years (5 versus 16 percent). Estimated OS at five years was similar in both groups (94 percent), and there was no difference in the rate of histologic transformation. Anxiety levels did not differ by assigned treatment (maintenance versus observation) [71].

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 therapeutic monoclonal antibodies used for cancer therapy".)

Infections 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 hepatitis B surface antigen (HBsAg) or antibodies against hepatitis B core antigen (anti-HBc). (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 [23,75]. 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 [76-79]. Many patients preferred the convenience of the subcutaneous formulation, while others prefer intravenous administration [78]. Some studies suggest that fixed subcutaneous dosing may result in higher rituximab exposure and superior efficacy [22].

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 to 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 to 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 III to IV 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 II FL. (See 'Stage II FL' below.)

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 [80]. This suggests that combined modality therapy increases the incidence of hematopoietic stem cell disorders. As such, we do not use combined modality therapy in this patient population.

Is there a role for transplant? — For patients with previously untreated FL who require therapy, we recommend treatment with an immunotherapy-based regimen alone rather than an immunotherapy-based regimen followed by autologous hematopoietic cell transplantation (HCT). Outside of a clinical trial, HCT is reserved for patients with relapsed or refractory FL or for those with histologic transformation to a more aggressive histology. (See "Autologous hematopoietic cell transplantation in follicular lymphoma".)

Several prospective randomized trials have examined the use of high dose chemotherapy followed by autologous HCT in the treatment of newly diagnosed FL [81-90]. While some have demonstrated improvements in PFS, none has shown an OS benefit. A 2012 Cochrane systematic review and meta-analysis of these trials found that high dose chemotherapy followed by autologous HCT resulted in improved PFS (HR 0.42; 95% CI 0.33-0.54) but similar OS (HR 0.97; 95% CI 0.76-1.24) when compared with combination chemotherapy or immunochemotherapy [87]. There was also no difference in the rates of treatment-related mortality and rates of secondary hematologic and solid cancers.

Allogeneic HCT may cure a percentage of patients with FL but is associated with significant treatment-related mortality. As such, allogeneic HCT is reserved for younger, highly motivated patients with relapsed or resistant FL. This is discussed in more detail separately. (See "Allogeneic hematopoietic cell transplantation in follicular lymphoma".)

SPECIAL SITUATIONS

Grade 3 FL — Our approach to the treatment of patients with histologic grade 3 FL differs between cases with grade 3a and grade 3b:

Patients with grade 3a FL are managed similarly to patients with grade 1 or 2 FL. (See 'Initial management' above.)

Patients with grade 3b FL are treated with regimens used for clinically aggressive lymphomas (eg, diffuse large B cell lymphoma [DLBCL]). (See "Initial treatment of limited stage diffuse large B cell lymphoma".)

FL tumors are graded on a scale from 1 to 3 according to the number of centroblasts per high powered field. Those with >15 centroblasts per high-power field are 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 [91]. Although controversial, differences in molecular genetics as well as clinical behavior suggest that FL grade 3a is an indolent disease and 3b a more aggressive one [42,91-95].

FL grade 3b is often referred to as follicular large cell lymphoma. In contrast to lower grade FLs, this histologic variant has a lesser tendency to involve the bone marrow or peripheral blood and often presents with larger lymphoid masses. Although the follicular architecture is preserved, the clinical presentation, behavior, and outcome with treatment more closely approximates that of DLBCL.

Patients with grade 3b FL commonly present with a more clinically aggressive course, which may resemble histologic transformation. If histologic transformation is suspected, repeat biopsy is indicated. (See "Histologic transformation of follicular lymphoma".)

Stage II FL — Stage II 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 II FL, we prefer a management approach similar to that used for stage III or IV 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 II disease with groin and ipsilateral iliac involvement). Details regarding the use of RT are discussed separately. (See "Initial treatment of stage I follicular lymphoma", section on 'Radiation therapy (RT)'.)

Patients with stage II FL have been included in most studies of RT in FL. Studies using contemporary radiation practices suggest that patients with stage II FL are unlikely to be cured with RT [96,97]. As an example, an international multicenter retrospective study evaluated the outcomes of 512 patients with stage I or II FL who underwent RT administered with curative intent [96]. The percentage of patients free from progression at five years was lower among those with stage II disease (49 versus 74 percent).

Subset analyses of trials of RT for stage I or II 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 I or II 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, <5 cm lesions, and ≥5 cm lesions, respectively) [98]. 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 chemotherapy directed at their lymphoma. (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 with interferon and ribavirin has resulted in complete clinical remissions in some patients with indolent lymphoma, including FL [99-105].

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 [102]. 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.

Patients with cardiac disease — Patients with underlying cardiac disease may not be able to tolerate the use of an anthracycline (eg, doxorubicin) since these agents are toxic to cardiac cells. The use of anthracyclines in patients with a reduced ejection fraction is discussed separately. (See "Clinical manifestations, diagnosis, and treatment of anthracycline-induced cardiotoxicity" and "Risk and prevention of anthracycline cardiotoxicity".)

Patients with cardiac disease may be treated with bendamustine plus rituximab (BR) or single-agent rituximab, depending on the aggressiveness of disease and other patient characteristics. R-CVP (cyclophosphamide, vincristine, and prednisone plus rituximab) is an alternative used by some of our contributors in this setting for patients who cannot tolerate bendamustine. BR and single-agent rituximab are discussed above. (See 'Bendamustine plus rituximab' above and 'Immunotherapy alone' above.)

R-CVP is a non-anthracycline-containing chemoimmunotherapy regimen that has been used for patients with FL. When compared with BR and R-CHOP, R-CVP is expected to result in a lower response rate and a shorter progression-free survival [25,26,35]. Side effects are generally mild with gastrointestinal toxicities and peripheral neuropathy being most common. Severe (grade 3/4) neutropenia occurs in approximately 24 percent. Treatment-related deaths are uncommon. The overall response rate is 81 to 88 percent. Median time to progression is approximately 2.8 years with a three-year overall survival rate of 89 percent.

Histologic transformation — An integral part of the natural history of FL is progression to a higher grade histologic subtype, such as DLBCL. As is detailed separately, a subgroup of patients with FL who transform to a more aggressive histology may attain complete remission following treatment with anthracycline-based chemotherapy and some may be cured by high dose chemotherapy followed by autologous hematopoietic cell transplantation. (See "Histologic transformation of follicular lymphoma" and "Autologous hematopoietic cell transplantation in follicular lymphoma", section on 'Following histologic transformation'.)

RESPONSE EVALUATION AND SURVEILLANCE FOR RELAPSE — After 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. The response evaluation of patients with stage II to IV FL is the same as that of patients with stage I FL. This is discussed in more detail separately. (See "Initial treatment of stage I follicular lymphoma", section on 'Evaluation of response to therapy'.)

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 I follicular lymphoma", section on 'Surveillance for relapse'.)

While studies are evaluating response-adapted therapy for FL, these approaches remain investigational. In one large multicenter study (FOLL12) that used imaging and minimal residual disease (MRD) measurements to deescalate or escalate therapy, those randomly assigned to standard therapy had superior progression-free survival and similar overall survival than those assigned to response-adapted therapy [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 — 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; however, there are groups of patients who have more as well as less favorable survival. The Follicular Lymphoma International Prognostic Index (FLIPI) (table 2) was developed specifically for patients with FL, since the International Prognostic Index, which was developed in patients with clinically aggressive non-Hodgkin lymphoma, resulted in conflicting results, due in large part to a low number of patients with clinically indolent lymphoma (approximately 10 percent) belonging to the higher risk groups.

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 5th to 6th 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 10th to 12th 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.)

Indications for treatment – Stage III and IV FL are not curable, and most patients with asymptomatic disease may defer therapy. Patients seeking immediate treatment may reasonably choose rituximab alone; single-agent rituximab may decrease anxiety and postpone cytotoxic chemotherapy without impacting overall survival. (See 'Asymptomatic patients' above.)

While we typically also defer therapy in patients with asymptomatic stage II FL, other clinicians may offer radiation therapy (RT) to a subset of these patients with disease that can be encompassed by a reasonable radiation field. (See 'Indications for treatment' 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.)

Selection of initial therapy – For patients with previously untreated stage II to IV FL who require therapy, we recommend treatment that incorporates an anti-CD20 monoclonal antibody (rituximab or obinutuzumab) rather than chemotherapy alone or hematopoietic cell transplantation (Grade 1A). A choice among regimens depends on patient characteristics and physician comfort (algorithm 1). While we generally prefer rituximab-based combinations, 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 'Chemoimmunotherapy' above and 'Obinutuzumab-based regimens' above.)

For most patients, we suggest bendamustine-based regimens (eg, bendamustine rituximab [BR] or bendamustine obinutuzumab) rather than others (Grade 2B). This preference is based on the similar efficacy and less toxicity when compared with R-CHOP. Considering the increased deaths seen in patients >70 years treated with BR, we modify the treatment plan for these patients by lowering the dose of bendamustine, limiting the number of cycles, or offering an alternative chemotherapy backbone. (See 'Bendamustine plus rituximab' above.)

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 that non-relapse mortality may be higher among patients receiving maintenance 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).

There is a paucity of data regarding the use of BR in patients with the more aggressive histologic grade 3a disease; R-CHOP may be preferred in this setting for fit patients with clinically aggressive disease. (See 'R-CHOP' above.)

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 'Immunotherapy alone' above.)

For patients initially treated with rituximab therapy alone, we recommend a finite schedule of rituximab rather than continuing rituximab until progression (maintenance rituximab) (Grade 1B). 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.

Stage II FL – The management of stage II FL is more variable. For most patients with stage II FL, we suggest a management approach similar to that used for stage III or IV FL rather than initial RT as used for stage I FL (algorithm 1) (Grade 2C). This preference is based on observational studies that suggest cure with RT is less likely in this population. Other clinicians offer RT to a subset of these patients. (See 'Stage II FL' above.)

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 3). Patients attaining a complete or partial remission are followed at periodic intervals for disease progression. Patients who fail to achieve a partial remission are treated as refractory disease. (See "Initial treatment of stage I 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".)

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Topic 83847 Version 65.0

References

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