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Treatment of relapsed or refractory follicular lymphoma

Treatment of relapsed or refractory follicular lymphoma
Authors:
Arnold S Freedman, MD
Jonathan W Friedberg, MD
Section Editor:
Andrew Lister, MD, FRCP, FRCPath, FRCR
Deputy Editor:
Rebecca F Connor, MD
Literature review current through: Aug 2022. | This topic last updated: Aug 11, 2022.

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 the hematopoietic neoplasms".)

The vast majority of patients treated for FL will have an initial response to therapy with 40 to 80 percent demonstrating a complete response, depending on the initial regimen used. However, conventional therapy for FL is not curative and most of these patients will ultimately develop progressive disease. In addition, less than 10 percent of patients treated with initial chemoimmunotherapy will not respond to treatment (ie, refractory disease).

The treatment of relapsed or refractory FL is discussed here. The treatment of previously untreated FL (including treatment after watchful waiting) is presented separately as are the epidemiology, clinical presentation, pathologic features, diagnosis, and pathobiology of FL.

(See "Initial treatment of stage II to IV follicular lymphoma".)

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

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

(See "Pathobiology of follicular lymphoma".)

EVALUATION OF SUSPECTED RELAPSE OR RESISTANCE — After initial therapy, patients are followed at routine intervals to monitor for treatment-related complications and relapse. At these visits, they are evaluated with a history, physical examination, and blood work. Imaging studies are reserved for the evaluation of suspected relapse. (See "Initial treatment of stage I follicular lymphoma", section on 'Surveillance for relapse'.)

Rule out histologic transformation — We have a low threshold to biopsy prior to retreatment in order to confirm relapse and evaluate for histologic transformation. Imaging with a combined positron emission tomography/computed tomography (PET/CT) scan provides a new baseline of disease activity with information about the anatomic areas of involvement and their metabolic activity. Biopsy should aim to sample a lymph node with the highest activity on PET. Bone marrow biopsy is reserved for patients with unexplained cytopenias.

An integral part of the natural history of FL is progression to a higher grade histologic subtype, such as diffuse large B cell lymphoma. Biopsy is critical to identify those patients with histologic transformation since the treatment and prognosis differs from those with relapsed FL. Signs or symptoms that suggest histologic transformation include the rapid progression of lymphadenopathy, infiltration of uncommon extranodal sites (excluding the bone marrow), development of systemic symptoms (eg, fever, weight loss, night sweats), elevated serum lactate dehydrogenase (LDH), and/or hypercalcemia. The evaluation and management of histologic transformation is discussed separately. (See "Histologic transformation of follicular lymphoma".)

Recognize early treatment failure — Early treatment failure is defined as patients with FL progressing within 24 months (POD24) of initial immunochemotherapy with BR (bendamustine plus rituximab), R-CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab), or R-CVP (cyclophosphamide, vincristine, and prednisone plus rituximab), or within 12 months of single-agent rituximab. We offer these patients more aggressive therapy because they do poorly with standard treatment approaches (algorithm 1).

FL is a heterogeneous disease with a variable clinical course. Most patients will have a clinically indolent course requiring intermittent treatment over decades and overall survival (OS) rates that mirror the general population. In contrast, approximately 20 percent of patients have an aggressive disease course with short remission durations, frequent relapses, and shortened OS. Prognostic tools such as the Follicular Lymphoma International Prognostic Index (FLIPI) are unable to accurately discern indolent from aggressive tumors at the time of diagnosis. The best predictor of tumor aggressiveness is the duration of remission following initial treatment [1-7].

The prognostic importance of remission duration was initially shown in several prospective cohort studies (eg, National LymphoCare study), which reported inferior survival among patients progressing within 24 months of immunochemotherapy and within 12 months of rituximab [1,2,8-10]. The prognostic value of POD24 was validated in a pooled analysis of 13 international clinical trials that included >5000 patients treated initially with chemotherapy (49 percent), chemoimmunotherapy (46 percent), or rituximab alone (5 percent) [11]. A 24-month landmark analysis was used to report subsequent OS according to disease status at 24 months after initial treatment. Patients without POD24 were more likely to have favorable prognostic markers including a good performance status, low risk FLIPI score, female sex, and normal beta-2-microglobulin. After adjustment for gender and stratified by performance status and FLIPI, POD24 was associated with worse subsequent OS (estimated five-year OS 71 versus 94 percent; HR 3.03, 95% CI 2.65-3.47). This prognostic impact was seen in all treatment groups, including those treated with chemoimmunotherapy (estimated five-year OS 74 versus 95 percent; HR 3.58, 95% CI 2.85-4.49) and single-agent rituximab (estimated five-year OS 91 versus 98 percent; HR 3.96, 95% CI 1.24-12.64). However, the OS of those with POD24 after chemoimmunotherapy was clearly worse than that of those with POD24 after single-agent rituximab (estimated five-year OS 74 versus 91 percent).    

Biopsy to confirm relapse and exclude histologic transformation is especially important in patients with early treatment failure. In a retrospective analysis of data from the PRIMA study of maintenance rituximab, 37 percent of all biopsies performed within the first year demonstrated histologic transformation [3]. In another retrospective study, clinical or biopsy proven histologic transformation was seen in 76 percent of patients progressing within 24 months of initial treatment with BR [12]. Clinical histologic transformation was defined as a sudden rise in LDH to twice the upper limit of normal, rapid discordant localized nodal growth, new involvement of unusual extranodal sites, new B symptoms, or the development of hypercalcemia. (See 'Rule out histologic transformation' above.)

Indications for treatment — Patients with asymptomatic recurrent FL do not necessarily require immediate treatment, but should be followed closely for the development of symptomatic disease (algorithm 1). In general, the same indications for treatment used for first-line therapy are used at the time of relapse or progressive disease. These are presented separately. (See "Initial treatment of stage II to IV follicular lymphoma", section on 'Indications for treatment'.)

Relapse after RT alone — Patients with stage I FL may be initially treated with radiation therapy (RT) alone delivered with curative intent. Patients who relapse following treatment with RT alone are treated with single-agent rituximab or chemoimmunotherapy regimens used for the initial treatment of stage II to IV FL. Such regimens are discussed in more detail separately. (See "Initial treatment of stage II to IV follicular lymphoma".)

LATE RELAPSE

Goals of care and selection of therapy — Most patients relapsing more than 24 months after initial chemoimmunotherapy or more than 12 months after single-agent rituximab will have a clinically indolent course requiring intermittent treatment over decades and survival rates that mirror the general population [1,2]. While not curative, conventional modern therapy results in serial complete or partial remissions. Treatment focuses on the alleviation of symptoms, reversal of cytopenias, and improvement of quality of life (algorithm 1).

Patients with asymptomatic recurrent FL do not necessarily require immediate treatment, but should be followed closely for the development of symptomatic disease. Watchful waiting is unlikely to impact overall survival (OS) in this setting. The main treatment options for patients with symptomatic late relapse include:

Immunotherapy with single-agent rituximab

Chemoimmunotherapy with an anti-CD20 antibody (eg, obinutuzumab or rituximab) plus chemotherapy

Novel agents (eg, lenalidomide, copanlisib, tazemetostat)

Since patients with FL experience serial relapses, many will be treated with several of these options at some point during their disease course. A preferred order for their use has not been established. At each relapse, a choice among these options must consider the response to prior therapies, comorbidities that may impact eligibility for current and future therapies, how current treatment decisions may affect future therapies, and patient preference.

EZH2 mutations are seen in approximately 20 percent of FL and generally predict for more favorable disease, which responds better to all treatments. Testing for EZH2 mutations can help guide use of the EZH2 inhibitor tazemetostat. We offer tazemetostat to patients with EZH2 mutation in first relapse and to patients without EZH2 mutation in subsequent relapse.  

For most patients with late relapse, we suggest treatment with an anti-CD20 monoclonal antibody, either alone or in combination with chemotherapy or lenalidomide. Patients with a poor performance status may prefer single-agent rituximab for its relatively low toxicity profile, especially if prior treatment with single-agent rituximab resulted in prolonged remission (eg, >24 months). In contrast, patients with a good performance status may prefer chemoimmunotherapy or lenalidomide plus obinutuzumab for their superior response rates despite greater toxicity and no proven improvement in survival rates. Novel agents (eg, copanlisib, tazemetostat) are often reserved for multiply relapsed FL; however, lenalidomide-based combinations are an attractive option even in first relapse given initial results from studies that suggest similar efficacy and a different toxicity profile when compared with chemoimmunotherapy. (See 'Lenalidomide plus rituximab or obinutuzumab' below.)

The response assessment after the treatment of relapsed FL mirrors that used after initial therapy (table 1).

Immunotherapy-based treatment — Monoclonal antibodies directed against CD20 (ie, immunotherapy) are a key component to the treatment of patients with FL; as discussed separately, their incorporation into initial therapy results in superior response rates, progression-free survival (PFS), and OS when compared with chemotherapy alone. (See "Initial treatment of stage II to IV follicular lymphoma", section on 'Immunotherapy-based treatment'.)

Anti-CD20 monoclonal antibodies are also used, either alone or in combination with chemotherapy, in the treatment of patients with relapsed or refractory FL.

Single-agent rituximab versus obinutuzumab or ofatumumab — When an anti-CD20 monoclonal antibody is offered as a single agent, we suggest rituximab rather than obinutuzumab or ofatumumab. Rituximab appears to be at least as effective and likely better tolerated when compared with obinutuzumab or ofatumumab in this setting.

Single-agent rituximab is an acceptable treatment for patients with relapsed FL who have 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 OS is improved.

The ideal dosing schedule of rituximab is not known. We offer a finite schedule of rituximab rather than continuing rituximab until progression. The following administration schedules were used in the randomized trials and are equally acceptable approaches:

Intravenous rituximab 375 mg/m2 per week for a total of four doses [13].

Intravenous rituximab 375 mg/m2 per week for four weeks followed by four additional doses administered every two months [14,15].

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 [16].

Rituximab was compared with ofatumumab in a randomized phase III trial (HOMER) of 438 patients with rituximab-sensitive indolent non-Hodgkin lymphoma (NHL, 98 percent FL) relapsed greater than six months after completing the last prior treatment with single-agent rituximab or a rituximab-containing regimen [17]. When compared with ofatumumab, rituximab was at least as effective in terms of overall response rate (ORR, 66 versus 50 percent) and PFS (median 21 versus 16 months) and resulted in a similar percentage of patients with grade 3 or greater adverse events (28 versus 37 percent). Similarly, a phase II randomized trial failed to demonstrate a PFS or OS benefit with obinutuzumab when compared with rituximab in 175 patients with relapsed indolent B cell lymphoma (85 percent FL) [18].

A phase II trial studied the safety and efficacy of retreatment with rituximab in 57 patients with relapsed, advanced, indolent non-Hodgkin lymphoma (NHL) (92 percent FL), all of whom had previously responded to rituximab [19]. The ORR was 40 percent, with 11 percent complete remissions (CR); estimated median time to progression after treatment was 18 months. Side effects were mild to moderate (grades 1 or 2) and self-limited, and resembled those seen in previously untreated patients. In another trial of 143 patients initially treated with four weekly doses of rituximab, responses to retreatment with rituximab were seen in 34 of 56 patients (61 percent) at first progression, 8 of 12 patients at second progression, and 0 of 4 patients at third progression [13]. (See 'Antibody safety and route of administration' below.)

Extending the schedule of rituximab and increasing the number of doses from four to eight prolongs the duration of response, but does not appear to improve OS. A study of 202 adults with newly diagnosed or relapsed/refractory FL who did not progress after four weekly doses of once weekly rituximab were randomly assigned to observation or rituximab infusions at 3, 5, 7, and 9 months [14]. After a median observation time of 35 months, patients who received extended rituximab dosing had superior median event-free survival (EFS; 23 versus 12 months). OS rates did not differ.

Chemoimmunotherapy — Anti-CD20 monoclonal antibodies are used in combination with many different chemotherapy regimens for the treatment of relapsed or refractory FL. This approach is supported by numerous studies including a large meta-analysis that demonstrated superior response rates and OS when rituximab was added to conventional chemotherapy in patients with previously treated or previously untreated FL [20].

Choice of anti-CD20 antibody — Multiple anti-CD20 monoclonal antibodies have been studied in relapsed or refractory FL. Of these, either rituximab or obinutuzumab are reasonable agents to use in combination with chemotherapy in this setting.

For most patients with relapsed or refractory FL being treated with chemotherapy, we suggest obinutuzumab rather than rituximab. This preference is largely based on a randomized trial (GADOLIN) that demonstrated an OS benefit for bendamustine plus obinutuzumab when compared with single-agent bendamustine in the relapsed setting and extrapolation of the GALLIUM study that showed improved PFS with obinutuzumab-based regimens versus rituximab-based regimens in previously untreated advanced stage FL [21-23]. Details of the GALLIUM study are presented separately. (See "Initial treatment of stage II to IV follicular lymphoma", section on 'Obinutuzumab-based regimens'.)

In contrast, ofatumumab is not indicated for the treatment of FL. In a randomized trial (COMPLEMENT A+B), the addition of ofatumumab to bendamustine did not improve PFS or OS in rituximab-refractory indolent non-Hodgkin lymphoma [24].

Choice of regimen — The optimal chemotherapy regimen for relapsed FL is unknown and practice varies. While numerous regimens have demonstrated activity in this setting, there is a paucity of randomized trials offering direct comparisons. Accurate comparisons of response rates cannot be made across trials due to changes over time in the response assessment and response definitions. As such, a choice among chemotherapy regimens is primarily made based on the patient's exposure to prior chemotherapy, the regimens' expected toxicities, and the clinician's experience with the regimen.

At first late relapse following chemoimmunotherapy, we typically offer treatment with an anti-CD20 monoclonal antibody plus CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), bendamustine, or lenalidomide, depending on the patient's history of prior therapy (algorithm 1). As examples, a backbone of CHOP may be preferred for a patient who has previously received bendamustine, while a bendamustine backbone may be preferred for a patient who has previously received CHOP. Retreatment with bendamustine plus rituximab is also reasonable for those who had a long initial remission duration (eg, five years). Initial results suggest that lenalidomide-based combinations are an attractive option even in first relapse with similar efficacy and a different toxicity profile when compared with chemoimmunotherapy. (See 'Lenalidomide plus rituximab or obinutuzumab' below.)

The data supporting the use of bendamustine-based and CHOP-based regimens are described below along with data regarding the efficacy of other regimens in the relapsed or refractory setting:

Bendamustine-based — The combination of bendamustine plus obinutuzumab (BO) or bendamustine plus rituximab (BR) (table 2) may be preferred for a patient who has previously received therapy that included CVP or CHOP. Some experts consider retreatment with a bendamustine-based regimen to be reasonable for those who had a long initial remission duration with BR (eg, five years). Increased deaths have been reported in patients >70 years of age treated with bendamustine in the GALLIUM study [25]; when offering BR to older patients, we lower the dose of bendamustine (to 70 mg/m2) and/or limit the number of cycles. We do not routinely offer maintenance after bendamustine as it has not demonstrated a survival benefit and has associated toxicities.

Fatal and/or serious toxicities can be seen with bendamustine, including infusion reactions, skin reactions, extravasation injury, hepatotoxicity, infections [26], myelosuppression, and embryo-fetal toxicity.

The following trials have demonstrated high response rates with bendamustine-based therapy in the relapsed setting and a survival benefit for BO over that seen with bendamustine alone:

Two phase 2 trials of BR in a total of 130 patients with relapsed or refractory NHL (49 percent FL) reported response rates of 90 to 92 percent (55 to 60 percent complete) [27,28]. Median PFS was approximately two years. The most common severe (grade 3/4) toxicity was myelosuppression with leukopenia (16 to 36 percent) and thrombocytopenia (3 to 9 percent). A phase 3 noninferiority study comparing BR versus fludarabine plus rituximab in relapsed or refractory indolent lymphoma reported higher response rates, PFS, and OS with BR [29].

In one trial (GADOLIN), 396 patients with rituximab-refractory indolent NHL (81 percent FL) were randomly assigned to six cycles of bendamustine alone versus six cycles of bendamustine plus obinutuzumab (BO), followed by obinutuzumab maintenance for two years [22,23]. The addition of obinutuzumab improved PFS (median 26 versus 14 months) and OS (HR 0.67; 95% CI 0.47-0.96). (See 'Use of maintenance' below.)

Bendamustine was included as a chemotherapy backbone in the GALLIUM study that showed improved PFS with obinutuzumab-based regimens versus rituximab-based regimens in previously untreated advanced stage FL [21]. (See "Initial treatment of stage II to IV follicular lymphoma", section on 'Obinutuzumab-based regimens'.)

CHOP-based — CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) plus obinutuzumab (O-CHOP) or rituximab (R-CHOP) (table 3) may be preferred for a patient with late relapse who has previously received bendamustine.

There is limited data evaluating the use of R-CHOP in patients who received initial treatment with rituximab-based therapy. The most common severe (grade 3/4) side effect with R-CHOP in the relapsed setting is granulocytopenia (63 percent) [30,31]. Other common side effects are generally mild to moderate alopecia, nausea, vomiting, and infusion-related reactions. There is a 1 percent treatment-related mortality rate.

Trials of O-CHOP have reported response rates as high as 96 percent in relapsed/refractory FL [32]. CHOP was included as a chemotherapy backbone in the GALLIUM study that showed improved PFS with obinutuzumab-based regimens versus rituximab-based regimens in previously untreated advanced stage FL [21]. (See "Initial treatment of stage II to IV follicular lymphoma", section on 'Obinutuzumab-based regimens'.)

Use of maintenance — Some of our contributors offer maintenance therapy with an anti-CD20 monoclonal antibody (rituximab or obinutuzumab), while others do not. Maintenance improves PFS, but its impact on OS is not clear. Even though maintenance is designed to have a low toxicity profile, 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.

Clinicians who choose to administer maintenance should use one of the established regimens, such as that used in the GALLIUM study (obinutuzumab or rituximab every two months for a total of two years) [21]. Trials that have used longer courses of maintenance (eg, four years) have noted increased toxicity toward the end of maintenance [33,34]; 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 decision to use maintenance at relapse should take into consideration whether the patient was exposed to an anti-CD20 antibody at the time of relapse. It is reasonable to offer maintenance if the relapse did not occur while the patient was receiving maintenance with that antibody. This is largely based on extrapolation of data demonstrating prolonged PFS with maintenance following initial therapy. Patients progressing while on maintenance therapy are not expected to benefit from further maintenance with that same antibody at relapse. Patients progressing on rituximab maintenance are eligible for obinutuzumab maintenance at relapse. The use of maintenance following initial therapy is presented separately. (See "Initial treatment of stage II to IV follicular lymphoma", section on 'Use of maintenance'.)

A meta-analysis of nine trials including 2586 adult patients with FL reported that patients who received maintenance rituximab demonstrated the following when compared with patients who were observed or treated with rituximab at the time of relapse [35]:

Higher rates of severe (grade 3 or 4) toxicities, especially infection-related adverse events (RR 1.67, 95% CI 1.40-2.00).

Superior rates of OS for patients with relapsed disease (HR 0.72, 95% CI 0.57-0.91), but not for those with previously untreated FL (HR 0.86, 95% CI 0.60-1.25) or if the patients were eligible for rituximab retreatment at disease progression (HR 0.86, 95% CI 0.49-1.49).

Data on obinutuzumab maintenance in the relapsed setting are more limited. In one randomized study, bendamustine plus obinutuzumab followed by obinutuzumab maintenance improved PFS, but not OS, when compared with bendamustine alone [22,23]. However, because of the trial design, it is impossible to know whether the incorporation of maintenance contributed to this benefit. We do not routinely offer maintenance after bendamustine given the unclear impact on survival and concerns raised in some reports of increased fatal adverse events among patients receiving maintenance after bendamustine-based induction, especially among patients over age 70 [21,25].

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

Infusion reactions (ie, fevers, rigors, and hypotension). Less common infusion reactions include mucocutaneous reactions (Stevens-Johnson syndrome, vesiculobullous dermatitis, and toxic epidermal necrolysis). (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".)

Rare cases of severe, sometimes fatal disseminated intravascular coagulation (DIC) have been reported in patients treated with obinutuzumab [36].

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 [16]. 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 [37-40].

Novel agents — Novel agents (eg, PI3K inhibitors) are often reserved for multiply relapsed FL; however, novel agents are appropriate for a subset of patients in first relapse:

We offer the EZH2 inhibitor tazemetostat in first relapse to the approximately 20 percent of patients with FL demonstrating an EZH2 mutation. (See 'Tazemetostat' below.)  

Lenalidomide-based combinations are an attractive option even in first relapse for the broader population with FL given initial results from studies that suggest similar efficacy and a different toxicity profile when compared with chemoimmunotherapy. (See 'Lenalidomide plus rituximab or obinutuzumab' below.)

EARLY TREATMENT FAILURE — Patients with FL progressing within 24 months of initial immunochemotherapy or within 12 months of single-agent rituximab (ie, early treatment failure) do poorly with standard treatment approaches. Low quality evidence suggests improved outcomes with more aggressive therapy. A similar approach is used for patients with FL that is refractory to initial therapy.

Goals of care — With conventional chemotherapy regimens, the approximately 20 percent of patients with early treatment failure experience frequent relapses and substantially shortened survival [1,2]. The prognostic impact of early treatment failure is discussed in more detail separately. (See 'Recognize early treatment failure' above.)

Treatment with more aggressive therapy aims to improve survival, although data supporting this approach are limited. These aggressive treatments are associated with more severe toxicity and an increased risk of early mortality. The goals of care for an individual must take into consideration his or her values and preferences with the understanding that the prognosis is poor with standard approaches.

Therapeutic strategy — There is no standard therapy for patients progressing within 24 months of initial immunochemotherapy or within 12 months of single-agent rituximab (ie, early treatment failure) and practice varies widely [41]; as such, we encourage patients to participate in clinical trials whenever possible. Outside of a clinical trial, our approach depends on whether there is histologic transformation and whether the patient is a candidate for high dose chemotherapy and autologous hematopoietic cell transplantation (HCT) (algorithm 1):

Biopsy to confirm relapse and exclude histologic transformation is especially important in patients with early treatment failure [3,12]. The treatment of histologic transformation is discussed in more detail separately. (See "Histologic transformation of follicular lymphoma".)

For patents who are eligible for HCT, we suggest chemoimmunotherapy with O-CHOP or bendamustine plus obinutuzumab with the goal of attaining a complete remission (CR). Those who attain a CR are candidates for high dose chemotherapy with autologous HCT rescue offered in an attempt to attain long-term remission. Patients with early treatment failure after single-agent rituximab who achieve CR with chemoimmunotherapy may reasonably defer high dose chemotherapy until subsequent relapse. For those who are unable to achieve CR, options include serial novel agents (eg, lenalidomide, PI3K inhibitors, tazemetostat) with a plan for autologous HCT in CR or chimeric antigen receptor T cells (CAR-T therapy). (See 'Chimeric antigen receptor T cells' below.)

For patients who are ineligible for autologous HCT or CAR-T, or do not wish to undergo these procedures, we suggest treatment with serial novel agents rather than chemoimmunotherapy. This preference is based on short-term follow-up of trials that suggest these novel agents are effective in this setting and an understanding that responses to chemoimmunotherapy are likely to be short-lived.

Patients with early relapse are likely to require treatment with many different therapies at some point during their disease course. A preferred order for their use has not been established. At each relapse, a choice among these options must take into account the response to prior therapies, comorbidities that may impact eligibility for current and future therapies, and how current treatment decisions may affect future therapies.

As examples:

High dose chemotherapy with autologous HCT rescue can prolong the progression-free survival (PFS) and overall survival (OS) rates of patients in CR or with minimal disease at the time of HCT. However, autologous HCT may affect bone marrow reserve. (See 'Autologous transplant for eligible patients' below and "Autologous hematopoietic cell transplantation in follicular lymphoma".)

Studies with limited follow-up suggest that CAR-T is very effective in a highly selected cohort of patients, but has substantial short-term toxicity, is technically complex, and is expensive. Otherwise fit patients with early treatment failure who demonstrate chemotherapy-sensitive disease may be ideal candidates for this approach in second or greater remission. CAR-T has largely supplanted allogeneic HCT in this setting. (See 'Chimeric antigen receptor T cells' below.)

The response assessment after the treatment of relapsed FL mirrors that used after initial therapy (table 1).

Autologous transplant for eligible patients — Retrospective analyses suggest that autologous HCT prolongs remissions in patients with early treatment failure (algorithm 1). Eligibility for HCT is primarily determined based on the patient's age, their performance status, and/or the presence of comorbid conditions. This is discussed in more detail separately. (See "Determining eligibility for autologous hematopoietic cell transplantation".)

Several retrospective analyses have suggested that autologous HCT improves survival when compared with chemoimmunotherapy alone [42-46]. As examples:

An analysis of data from an HCT registry identified 440 patients with early treatment failure and reported the following [42]:

Autologous HCT (240 patients) – estimated five-year OS 70 percent (95% CI 64-76 percent); 5 percent nonrelapse mortality

Matched sibling donor allogeneic HCT (105 patients) – estimated five-year OS 73 percent (95% CI 64-81 percent); 17 percent nonrelapse mortality

Matched unrelated donor allogeneic HCT (95 patients) – estimated five-year OS 49 percent (95% CI 39-60 percent); 33 percent nonrelapse mortality

Estimated five-year survival rates were similar for autologous HCT and matched sibling donor allogeneic HCT, but worse for matched unrelated donor allogeneic HCT. On multivariate analysis, when compared with autologous HCT, matched sibling donor allogeneic HCT had a lower relative risk of mortality more than 24 months after HCT (RR 0.29; 95% CI 0.12-0.67). These five-year survival rates compare favorably to outcomes with chemoimmunotherapy alone; however, their eligibility for HCT necessitates that this group is younger and fitter, have few comorbidities, and usually have chemotherapy-responsive disease.

Another retrospective registry analysis evaluated the outcomes of 349 patients with early treatment failure [43]. When the population was analyzed as a whole, OS was similar whether or not HCT was performed. However, in a planned subset analysis, when compared with those who didn't undergo HCT, the 123 patients receiving autologous HCT within one year of treatment failure had superior OS at five years (73 versus 60 percent). A mortality benefit for early autologous HCT was maintained when the analysis was matched for age and other known prognostic variables. These results suggest that early autologous HCT may benefit those with early treatment failure. However, this analysis did not provide information on what therapies were offered at the time of relapse or how the disease responded to second-line therapy. The benefit found with HCT could be due to a more favorable response to second-line therapies.

High dose chemotherapy with autologous HCT and allogeneic HCT are discussed in more detail separately. (See "Autologous hematopoietic cell transplantation in follicular lymphoma", section on 'Relapsed disease' and "Allogeneic hematopoietic cell transplantation in follicular lymphoma", section on 'Nonmyeloablative and reduced intensity HCT'.)

MULTIPLY RELAPSED DISEASE

Sequencing of therapies — Most patients with FL experience serial relapse and will be treated with many available agents at some point during their disease course. A preferred order for their use has not been established.

Novel agents (eg, lenalidomide, copanlisib, tazemetostat) may be used for multiply relapsed FL. A choice is primarily made based on the patient's prior treatment, the regimens' expected toxicities, route of administration, and the clinician's experience with the regimens. As an example, lenalidomide may be preferred by some patients because of its oral route of administration, while others may prefer an intravenous regimen that incorporates treatment-free days. While testing for EZH2 mutations can identify patients who are more likely to respond to the EZH2 inhibitor tazemetostat, responses have also been seen in patients without EZH2 mutations.

While relapsed FL is typically sensitive to additional therapy, the depth and duration of remission generally becomes shorter with each subsequent therapy [47,48]. Treatment focuses on the alleviation of symptoms and improvement of quality of life. The response assessment after the treatment of relapsed FL mirrors that used after initial therapy (table 1).

Chimeric antigen receptor T (CAR-T) cell therapy is an option for patients with multiply relapsed FL. The use of CAR-T therapy is individualized weighing disease tempo, availability of other treatments, and expected toxicity. Since most patients with relapsed FL have favorable outcomes with other, less toxic treatment options, we generally reserve CAR-T therapy for patients with multiply relapsed FL with short prior remission durations (eg, <24 months). (See 'Chimeric antigen receptor T cells' below.)

Where available (eg, Europe), mosunetuzumab is an option for patients with multiply relapsed FL, and may be appropriate for use after or instead of CAR-T therapy. (See 'Mosunetuzumab' below.)

Novel agents

Lenalidomide plus rituximab or obinutuzumab — Lenalidomide plus rituximab (R2) and lenalidomide plus obinutuzumab (O-R) are acceptable alternatives for the treatment of late or early relapse. While follow-up is limited, these regimens appear to have similar efficacy to chemoimmunotherapy, but different toxicity. Lenalidomide carries boxed warnings regarding embryo-fetal toxicity, hematologic toxicity, and venous and arterial thromboembolism. The rate of venous thromboembolism in patients with FL receiving lenalidomide is similar to that seen in multiple myeloma [49]. As such, we use aspirin (81 mg daily) for thromboembolic prophylaxis in patients receiving lenalidomide.

Support for the use of R2 comes from the following randomized trials, which have demonstrated superior progression-free survival (PFS) when compared with either agent by itself and from studies in treatment-naïve patients that show similar PFS compared with chemoimmunotherapy (see "Initial treatment of stage II to IV follicular lymphoma", section on 'Lenalidomide plus rituximab or obinutuzumab'):

A multicenter, placebo-controlled randomized trial (AUGMENT) evaluated the addition of lenalidomide to rituximab in 358 patients with relapsed and/or refractory FL or marginal zone lymphoma [50]. Patients received lenalidomide or placebo for 12 cycles plus rituximab once per week for four weeks in cycle 1 and on the first day of cycles 2 through 5. The addition of lenalidomide resulted in:

Improved PFS (median 39 versus 14 months; HR 0.46, 95% CI 0.34-0.62). Data regarding overall survival (OS) are immature (estimated two-year OS 93 versus 87 percent; HR 0.61, 95% CI 0.33-1.13).

Higher rates of infection (63 versus 49 percent) and cutaneous reactions (32 versus 12 percent). Rates of neutropenic fever were low (3 versus 1 percent). However, patients assigned to lenalidomide had more grade 3 or 4 neutropenia (50 versus 13 percent) and were more likely to receive growth factors (36 versus 12 percent).  

In a phase II trial, 91 patients with relapsed or refractory FL were randomly assigned to single-agent lenalidomide or to R2 [51]. The addition of rituximab improved the response rate (76 versus 53 percent) and median time to progression (2 versus 1.1 years) but did not improve survival. Among those receiving R2, the most common severe (grade 3/4) toxicities were neutropenia (20 percent), fatigue (13 percent), and rash (4 percent). Thrombosis occurred in 9 out of the 91 patients overall.

There are limited data regarding the use of O-R. In an open-label, phase Ib study, responses to O-R were seen in 12 of 19 patients with relapsed or refractory FL after rituximab-containing therapy [52]. Use as initial therapy is discussed separately. (See "Initial treatment of stage II to IV follicular lymphoma", section on 'Lenalidomide plus rituximab or obinutuzumab'.)

Copanlisib — The phosphoinositide 3'-kinase (PI3K) inhibitor copanlisib is approved by the US Food and Drug Administration (FDA) for use in relapsed or refractory FL. We reserve its use for multiply relapsed disease.

While previously approved by the US FDA, the FL indications for duvelisib, idelalisib, and umbralisib were voluntarily withdrawn by manufacturers in December 2021, January 2022, and April 2022, respectively [53-56]. There have been concerns raised about PI3K inhibitors as some trials have shown an increased risk of death due to toxicity. An FDA report described six randomized trials that suggested higher death rates with PI3K inhibitors despite improvement in other efficacy parameters including response rate and PFS [56]. While there is uncertainty in the OS estimates for each trial given the low number of observed deaths, these data are concerning given the consistency of these observations across multiple trials of different PI3K inhibitors in patients with clinically indolent lymphoid malignancies.

Copanlisib is an intravenous inhibitor of PI3K alpha and delta isoforms that has shown activity in patients with multiply relapsed FL [57-59]. An at least partial response (PR) is seen in approximately half of patients; complete responses (CRs) are uncommon.

Copanlisib is approved by the US Food and Drug Administration as a single agent for the treatment of patients with relapsed FL who have received at least two prior systemic therapies [60]. The starting dose is 60 mg administered as a one-hour intravenous infusion on days 1, 8, and 15 of a 28-day treatment cycle. Suggested dose reductions for hepatic impairment and toxicities are provided in the US prescribing information for copanlisib in addition to dose adjustments for patients taking CYP3A inhibitors/inducers. Copanlisib has a unique toxicity profile due to alpha isoform inhibition. Serious toxicities can be seen, including opportunistic infections, transient bouts of hypertension, hyperglycemia, noninfectious pneumonitis, cutaneous reactions, and neutropenia. Blood pressure and glucose should be monitored before and after each infusion. We offer prophylaxis for P. jirovecii pneumonia.

Efficacy data come from a double-blind, phase 3 trial (CHRONOS-3) that randomly assigned 458 patients with relapsed clinically indolent non-Hodgkin lymphoma (275 with FL) in a 2:1 ratio to receive copanlisib plus rituximab versus placebo plus rituximab [61]. After a median follow-up of 19 months, copanlisib plus rituximab improved PFS (median 22 versus 14 months, HR 0.52, 95% CI 0.39-0.69). The addition of copanlisib increased serious treatment emergent adverse events (47 versus 18 percent) with higher rates of grade 3 or 4 hyperglycemia (56 versus 8 percent) and hypertension (40 versus 9 percent). There was one drug related death due to copanlisib-related pneumonitis. OS data are immature (83 versus 81 percent at 36 months; HR 1.07, 95% CI 0.63-1.82).

Additional data come from a phase II trial (CHRONOS-1) of copanlisib that included 142 patients with clinically indolent subtypes of non-Hodgkin lymphoma (104 with FL) who had received a median of three prior lines of systemic anticancer therapy with the following results [59,62]:

ORR 61 percent, CR rate 17 percent.

Median time to response 1.8 months, median time to CR 4.7 months. Median duration of response 14 months, median duration of CR 26 months.

Median PFS 12.5 months. Estimated median OS 43 months.

Toxicity was significant leading to drug discontinuation in 27 percent, dose reduction in 28 percent, and treatment interruptions or delays in 82 percent. The most common toxicities of all grades were hyperglycemia (50 percent), diarrhea (35 percent), hypertension (30 percent), and fatigue (26 percent). The most common severe (grade 3/4) toxicities were hyperglycemia (40 percent), hypertension (24 percent), and neutropenia (24 percent).

There were three treatment-related deaths (eg, lung infection, respiratory failure, and cerebral thromboembolic event). There were three nonfatal opportunistic infections.

Tazemetostat — Tazemetostat is an oral inhibitor of enhancer of zeste homolog 2 (EZH2) that has shown activity in a small nonrandomized phase 1/2 trial that included patients with multiply relapsed FL [63-65]. Responses are seen in most patients with EZH2 mutations and a smaller percentage of patients with EZH2 wild-type FL. We offer tazemetostat to patients with EZH2 mutation in first relapse and to patients without EZH2 mutation in subsequent relapse.

Tazemetostat is approved by the US Food and Drug Administration as a single agent for the treatment of patients with relapsed or refractory EZH2 mutation positive FL who have received at least two prior systemic therapies [63]. To qualify for tazemetostat, FL tumor specimens should demonstrate one of the following EZH2 mutations: Y646, A682, or A692. Tazemetostat is also approved for patients with relapsed or refractory FL who have no satisfactory alternative treatment options.

Tazemetostat 800 mg is administered orally twice a day until disease progression or unacceptable toxicity. Suggested dose modifications for toxicity are provided in the package insert in addition to dose adjustments for patients taking CYP3A inhibitors [63]. The most common toxicities are fatigue, upper respiratory tract infection, musculoskeletal pain, nausea, and abdominal pain. Tazemetostat increases the risk of secondary malignancies, including T cell lymphoblastic lymphoma, myelodysplastic syndrome, and acute myeloid leukemia.

Efficacy and toxicity data come from a multicenter, open-label single-arm phase 1/2 trial (NCT01897571) [65]. This trial included two cohorts of patients with relapsed or refractory FL after at least two prior systemic therapies:

EZH2 mutated FL – Among the 45 patients with EZH2 mutated FL, ORR was 69 percent, with 13 percent CR and 56 percent PR; median duration of response was 11 months and median PFS was 14 months.

EZH2 wild-type FL – Among the 54 patients with EZH2 wild-type FL, ORR was 35 percent, with 4 percent CR and 31 percent PR; median duration of response was 13 months and median PFS was 11 months.

Responses were delayed with a median time to first response of 3.7 months in both groups. Toxicities were mostly grade 1 or 2 and included nausea, diarrhea, and asthenia/fatigue. Alopecia and rash were noted in 17 and 15 percent, respectively. Usually mild hematopoietic toxicity was seen in a significant minority of patients; other laboratory abnormalities included hyperglycemia (53 percent), increased AST/ALT (20 to 25 percent), increased alkaline phosphatase (18 percent), and increased creatinine (17 percent). There were no treatment-related deaths; eight patients discontinued therapy due to an adverse event.

EZH2 mutations are seen in approximately 20 percent of FL and generally predict for more favorable disease, which responds better to all treatments [66].

Other novel agents — The efficacy and safety of other novel agents requires further study. Often, promising responses in phase 1 studies are not confirmed in subsequent studies. As examples, single-arm phase 2 trials have reported low overall response rates with nivolumab (4 percent [67]), ibrutinib (21 and 38 percent [68,69]), and the combination of venetoclax plus rituximab (35 percent [70]). As such, we do not consider these agents to be effective in this setting.

Chimeric antigen receptor T cells — Chimeric antigen receptor (CAR)-T cell therapy is an option for patients with multiply relapsed FL. The use of CAR-T therapy is individualized weighing disease tempo, availability of other treatments, and expected toxicity. Since most patients with relapsed FL have favorable outcomes with other, less toxic treatment options, we generally reserve CAR-T therapy for patients with multiply relapsed FL with short prior remission durations (eg, <24 months). While initial studies suggest that CAR-T therapy has activity against relapsed or refractory FL, the quality of the evidence is low, treatment is associated with substantial toxicity, and the manufacturing process is complex and expensive.

CAR-T cells are generated from the patient's own T lymphocytes, which are genetically modified (transfected) with a gene that encodes a CAR to direct the patient's T cells against the lymphoma cells. The T cells are genetically modified ex vivo, expanded in a production facility, and then infused back into the patient as therapy. Various CAR-T constructs have subtle structural differences, even when directed against the same antigen, but they have not been directly compared and clinical effects of such differences are not yet clear.

Axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) are CD19-directed CAR-T immunotherapies that have received accelerated approved by the US Food and Drug Administration (FDA) for treatment of adults with relapsed or refractory FL after two or more lines of systemic therapy. They are available in the United States through a risk evaluation and mitigation strategy (REMS), and the US FDA labels carry warnings for cytokine release syndrome (CRS) and neurologic events. Facilities that dispense these agents require special certification, staff must be trained to recognize and manage adverse events, and tocilizumab (a humanized monoclonal antibody against the interleukin-6 receptor [IL-6R]) must be available for immediate administration.

Data regarding the use of CAR-T cells in FL comes from single-arm prospective trials with relatively short follow-up [71-73]. Two single-arm, open label multicenter trials evaluated axi-cel (ZUMA-5) and tisa-cel (ELARA) in adults with relapsed or refractory FL after two or more lines of systemic therapy, including a combination of an anti-CD20 monoclonal antibody and an alkylating agent [73,74]:

Axi-cel – Among the 86 patients with FL treated with axi-cel in ZUMA-5, the ORR was 94 percent (79 percent CR, 15 percent PR) with a median time to first response of one month [74]. Response rates were similar in patients with and without high-risk features, including early treatment failure. The median duration of response was not reached with a median follow-up of 23 months. The estimated PFS at 18 months was 73 percent (95% CI 64-80 percent) and estimated OS at 18 months was 92 percent (95% CI 85-95 percent). CRS of any grade was reported in 78 percent (6 percent ≥grade 3). Management included tocilizumab (50 percent), corticosteroids (18 percent), and vasopressors (5 percent). One patient died of multisystem organ failure prior to the resolution of CRS. A second response was attained in all 11 patients with FL retreated with axi-cel at relapse.

Tisa-cel – Among the 90 patients with FL treated with tisa-cel in ELARA, the ORR was 86 percent (69 percent CR, 17 percent PR) with a median time to first response of 2.9 months [73,75]. The median duration of response was not reached with a median follow-up of 9.1 months. The estimated PFS at 12 months was 71 percent (95% CI 58-80 percent). CRS of any grade was reported in 53 percent, all less than grade 3.

Another trial of CAR-T reported that 10 of 14 patients with relapsed/refractory FL attained a CR by three months [71]. Among patients who achieved CR, all but one remained in CR at a median follow-up of two years.

CAR-T therapy is associated with serious complications, including some fatal neurologic events and CRS, which is a severe systemic response (eg, high fever, flu-like symptoms, hypotension, mental status changes) to the activation and proliferation of CAR-T cells. CRS is observed in nearly all treated patients and may be life-threatening, but it typically responds to treatment with aggressive supportive care that includes tocilizumab and corticosteroids. Neurologic toxicities may also be severe or life-threatening. Other adverse events include hypersensitivity reactions, serious infections, prolonged cytopenias, prolonged hypogammaglobulinemia, and second malignancies. CRS and immune effector cell-associated neurotoxicity syndrome (ICANS) are discussed separately. (See "Cytokine release syndrome (CRS)" and "Immune effector cell-associated neurotoxicity syndrome (ICANS)".)

Mosunetuzumab — Mosunetuzumab is a bispecific T cell engager (BiTE) monoclonal antibody directed at both CD20 on FL cells and CD3 on cytotoxic T cells [76]. Mosunetuzumab is approved by the European Medicines Agency for adults with relapsed or refractory FL who have received at least two prior systemic therapies [77]. Where available, we consider mosunetuzumab an option for patients with multiply relapsed FL with short prior remission durations (eg, <24 months).

Mosunetuzumab is administered intravenously. Following an initial step-up dosing schedule, the drug is administered once every 21 days. Those who achieve a CR receive 8 total cycles, whereas those with a PR or stable disease receive up to 17 cycles. The package insert carries warnings of CRS, serious infection, tumor flare, tumor lysis syndrome, and the need to avoid live and/or live-attenuated vaccines [77]. Facilities that dispense mosunetuzumab must be specially qualified and have appropriate medical support to manage severe reactions such as CRS.

Data regarding the efficacy and safety of mosunetuzumab in FL come from a single-arm, multicenter phase 2 study of 90 patients with relapsed or refractory FL who had received at least two prior lines of treatment (median three), including an anti-CD20 therapy and an alkylating agent [78]. Approximately half had progression within 24 months of initial therapy and 21 percent had prior autologous HCT.

The ORR was 80 percent with 60 percent CR and 20 percent PR; at a median follow-up of 18 months, median duration of response was 23 months and median PFS was 18 months. The CR rate compared favorably to that seen in a historical control group treated with copanlisib (60 versus 14 percent).  

The most common adverse events were CRS (44 percent), fatigue (37 percent), and headache (31 percent). CRS was predominantly grade 1 or 2 and confined to the first cycle. The most common grade 3 or 4 adverse events were decreased neutrophil count (27 percent), hypophosphatemia (17 percent), hyperglycemia (8 percent), and anemia (8 percent).  

Transplantation — We offer high dose chemotherapy with autologous HCT (hematologic rescue) to fit patients who attain a CR following treatment of multiply relapsed disease (algorithm 1), and to patients who attain a CR following treatment of early treatment failure. CAR-T therapy is an alternative for young, fit patients, and has largely supplanted allogeneic HCT in this setting. (See 'Chimeric antigen receptor T cells' above.)

Both high dose chemotherapy with autologous HCT (hematologic rescue) and nonmyeloablative or reduced intensity allogeneic HCT have been used for the treatment of FL. (See "Autologous hematopoietic cell transplantation in follicular lymphoma", section on 'Relapsed disease' and "Allogeneic hematopoietic cell transplantation in follicular lymphoma", section on 'Nonmyeloablative and reduced intensity HCT'.)

Both autologous HCT and allogeneic HCT appear to have a survival benefit for the treatment of relapsed FL, but differing risks:

There is a clear increase in toxicity (ie, short-term treatment-related mortality plus the risk of secondary malignancy) when comparing conventional therapy with autologous HCT and allogeneic HCT, with an approximate risk of treatment-related mortality of <5 percent with conventional therapy (ie, no HCT), 5 to 20 percent with autologous HCT, and 10 to 30 percent with allogeneic HCT.

Although there is shorter follow-up for series of patients who have undergone allogeneic HCT, there appears to be a parallel increase in efficacy, with a chance of possible long-term disease-free remission ranging from zero percent with conventional therapy, 25 to 40 percent with autologous HCT, and 40 to 60 percent with allogeneic HCT.

It is possible that the incremental benefit in each case outweighs the incremental toxicity. Indeed, the results of autologous HCT seem superior to those of salvage chemotherapy alone. (See "Autologous hematopoietic cell transplantation in follicular lymphoma", section on 'Relapsed disease'.)

A comparison of nonrandomized trials of these different procedures is limited by the use of different patient selection criteria for the different regimens [79]. Unfortunately, a randomized trial is difficult to perform in this circumstance. A multicenter trial comparing allogeneic to autologous transplantation was closed early due to poor accrual (NCT00096460).

Small case series have suggested a benefit of allogeneic HCT over autologous HCT [80-82]. Large registry-based analyses have illustrated the decreased relapse rate and increased short-term treatment-related mortality with allogeneic HCT [42,83-86].

One of the largest of these reported the outcomes of 518 adults with relapsed or refractory FL following initial rituximab-based therapy who underwent reduced intensity allogeneic HCT or autologous HCT between 2000 and 2012 [86]. The patients undergoing allogeneic HCT were younger and more heavily pretreated and were more likely to have advanced stage disease and chemotherapy resistance. When compared with allogeneic HCT, autologous HCT was associated with the following:

Lower nonrelapse mortality (5 versus 26 percent at five years)

Higher rates of relapse/progression (54 versus 20 percent at five years)

Inferior PFS (41 versus 58 percent at five years)

Superior OS in the first 24 months (RR 0.41)

Inferior survival beyond 24 months (RR 2.2)

A higher incidence of second hematologic malignancies (7 versus 0 percent at 10 years)

These results are consistent with those seen in other trials. Even in highly selected patients, approximately one-quarter of patients undergoing reduced intensity allogeneic HCT will die of complications of the therapy. However, these deaths usually occur early in the post-transplant period. For those that survive past two years, PFS and OS are better than those seen with autologous HCT. While patients undergoing allogeneic HCT have a lower relapse rate, there is a continued risk of death due to late toxicities from graft-versus-host disease [85].

Radiation for palliation — Radiation therapy (RT) is primarily used for the palliation of patients who have symptoms related to a single disease site. FL is responsive to RT; low dose RT (eg, total dose of 4 Gy) can be used for the palliation of patients who have symptoms related to a single disease site [87-90].

Radioimmunotherapy — Radioimmunotherapy (RIT) uses monoclonal antibodies linked to radioisotopes. Ibritumomab tiuxetan is a murine anti-CD20 monoclonal antibody conjugated to the radioisotope yttrium-90 that is approved by the US Food and Drug Administration for the treatment of patients with relapsed or refractory FL, including patients with rituximab-refractory FL. While RIT is an effective treatment alternative for eligible patients, it is not commonly employed due to the complexity of administration.

Prospective trials of RIT demonstrate response rates of 60 to 80 percent in previously treated disease [91-96]. Median PFS is less than one year, but patients who achieve a CR have a median time to progression of close to four years.

The most profound side effects of RIT are potentially prolonged and significant cytopenias with cell count nadirs ranging from four to nine weeks post-therapy with recovery one to four weeks post-nadir. The most common cytopenias are leukopenia and thrombocytopenia, which are easily managed in the majority of patients. RIT causes a transient depletion of B cells for approximately six to nine months, but has not been associated with significant increases in severe infections or hospitalizations. RIT can be associated with an infusion reaction similar to that seen with other monoclonal antibodies. This is described in more detail separately. (See "Infusion-related reactions to therapeutic monoclonal antibodies used for cancer therapy", section on 'Ibritumomab'.)

Initial reports suggested a possible risk of treatment-related myelodysplastic syndrome (t-MDS) and acute myeloid leukemia (t-AML). Although the rate of t-MDS and t-AML does not appear to be increased in subsequent reports, controversy regarding this potential risk remains [97-101]. Early evidence suggests that patients relapsing following treatment with RIT may tolerate other treatment approaches including chemotherapy, external beam radiation therapy, and autologous HCT [102-104].

CLINICAL TRIALS — Often there is no better therapy 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).

Many agents are under active investigation. These include combinations of agents already used in FL, agents approved for other diseases, new antibodies (eg, blinatumomab, antibody-drug conjugates [105], bispecific antibodies [106,107], anti-PD1 immune checkpoint inhibitors [108], anti-CD47 macrophage immune checkpoint inhibitors [109]), and other novel agents (eg, Bruton tyrosine kinase inhibitors [110,111] and polatuzumab vedotin).

RESPONSE EVALUATION AND SURVEILLANCE FOR RELAPSE — The assessment of disease response to therapy and surveillance for relapse is similar to that used following initial therapy. This is described in more detail separately. (See "Initial treatment of stage I follicular lymphoma", section on 'Evaluation of response to therapy' and "Initial treatment of stage I follicular lymphoma", section on 'Surveillance for relapse'.)

SPECIAL CONSIDERATIONS DURING THE COVID-19 PANDEMIC — The coronavirus disease 2019 (COVID-19) pandemic has increased the complexity of cancer care. Important issues include balancing the risk from treatment delay versus harm from COVID-19, ways to minimize negative impacts of social distancing during care delivery, and appropriately and fairly allocating limited health care resources. Additionally, immunocompromised patients are candidates for a modified vaccination schedule (figure 1), other preventive strategies (including pre-exposure prophylaxis), and the early initiation of COVID-directed therapy. These issues and recommendations for cancer care during the COVID-19 pandemic are discussed separately. (See "COVID-19: Considerations in patients with cancer".)

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

Rule out histologic transformation – For patients with suspected relapse of follicular lymphoma (FL), we have a low threshold to biopsy prior to retreatment to confirm relapse and evaluate for histologic transformation. (See 'Rule out histologic transformation' above.)

Recognize early treatment failure – Most patients have a clinically indolent, relapsing course with survival rates that mirror the general population. Approximately 20 percent have an aggressive course with short remission durations, frequent relapses, and shortened survival.

These aggressive cases can be identified by "early treatment failure," such as progression within 24 months of initial treatment with BR (bendamustine plus rituximab), R-CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab), or R-CVP (cyclophosphamide, vincristine, and prednisone plus rituximab), or within 12 months of single-agent rituximab. (See 'Recognize early treatment failure' above.)

Management – Patients with asymptomatic recurrent FL do not necessarily require immediate treatment, but should be followed closely for the development of symptomatic disease. Patients with symptomatic FL or an increase in disease tempo require treatment. (See 'Indications for treatment' above.)

There is no standard therapy for FL and practice varies; patients should be encouraged to participate in clinical trials. We use a risk-stratified approach, which considers the timing of relapse and results from EZH2 mutation testing (algorithm 1).

Late relapse – For most patients with late relapse, we offer an anti-CD20 monoclonal antibody (rituximab or obinutuzumab), either alone or in combination with chemotherapy or lenalidomide, as follows. (See 'Immunotherapy-based treatment' above.)

For patients with a poor performance status and/or a clinically indolent course, we suggest single-agent rituximab for its relatively low toxicity profile (Grade 2C). (See 'Single-agent rituximab versus obinutuzumab or ofatumumab' above.)

For patients with a good performance status, we suggest obinutuzumab plus combination chemotherapy or lenalidomide rather than rituximab-based combinations for its superior response rates despite greater toxicity and no proven improvement in survival rates (Grade 2C). (See 'Chemoimmunotherapy' above.)

We offer O-CHOP or lenalidomide plus obinutuzumab to those relapsing after bendamustine-based regimens. We offer bendamustine plus obinutuzumab or lenalidomide plus obinutuzumab to those relapsing after CHOP-based regimens.

Our contributors differ in their use of maintenance therapy. (See 'Use of maintenance' above.)

We offer the EZH2 inhibitor tazemetostat in late first relapse to the approximately 20 percent of patients with EZH2 mutation, and we reserve it for subsequent relapse in patients without EZH2 mutation. (See 'Tazemetostat' above.)

Early relapse – For patients with early treatment failure, our approach depends on candidacy for high dose chemotherapy and autologous hematopoietic cell transplantation (HCT) rescue:

For patents who are eligible for HCT, we suggest chemoimmunotherapy with O-CHOP or bendamustine plus obinutuzumab rather than less intensive therapies with the goal of attaining a complete remission (CR) (Grade 2C).

Those who attain a CR may proceed to HCT in an attempt to attain long-term remission. Patients with early treatment failure after single-agent rituximab who achieve CR with chemoimmunotherapy may reasonably defer HCT until subsequent relapse.

For those who are unable to achieve CR, options include serial novel agents (eg, lenalidomide, tazemetostat, copanlisib) with a plan for autologous HCT in CR or chimeric antigen receptor T cell (CAR-T) therapy. (See 'Therapeutic strategy' above.)

For patients who are ineligible for HCT or CAR-T, or do not wish to undergo these procedures, we suggest treatment with serial novel agents rather than chemoimmunotherapy (Grade 2C). This preference is based on short-term follow-up of trials that suggest these novel agents are effective in this setting and an understanding that responses to chemoimmunotherapy are likely to be short-lived.

Subsequent relapse – Novel agents are used for multiply relapsed FL. A choice is made based on the patient's prior treatment, the regimens' expected toxicities, route of administration, and the clinician's experience with the regimens. Fit patients who attain a CR may proceed with autologous HCT or CAR-T in an attempt to attain long-term remission. (See 'Multiply relapsed disease' above.)

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