Newly diagnosed and relapsed follicular lymphoma: EHA Clinical Practice Guidelines for diagnosis, treatment, and follow‐up

Abstract

Follicular lymphoma (FL) is the second most common lymphoma subtype in Europe, with a median age at diagnosis of 60–65 years. It is generally considered an indolent disease, and the median overall survival at diagnosis now likely exceeds 20 years. However, considerable heterogeneity exists. Diagnosis requires adequate biopsy material and a specialized hematopathologist. Staging and prognosis rely on positron emission tomography (PET)‐computed tomography (CT). Prognostication at diagnosis is based on several validated clinical prognostic scores. Localized disease is usually treated with radiotherapy ± Rituximab. The treatment of disseminated disease includes active surveillance (or in selected cases Rituximab monotherapy) for low‐tumor burden patients, and most often immunochemotherapy (or in selected cases chemo‐free therapeutic options), ±antibody maintenance in high‐tumor burden patients. For relapsed or refractory disease, treatment with Rituximab‐Lenalidomide combination ± Tafasitamab or Epcoritamab from the first relapse and single‐agent bispecific antibodies, chimeric antigen receptor T‐cell therapy (CAR‐T) cells, and Zanubrutinib‐Obinutuzumab after second relapse should be prioritized over immunochemotherapy. Given the long natural history and risk of relapse, careful follow‐up is an important part of patient management. Patients should be actively involved in decision‐making. In this guideline, we present current evidence‐based recommendations for diagnosis, staging, treatment, and follow‐up.

METHODOLOGY

These guidelines provide evidence‐based recommendations for the diagnosis, treatment, follow‐up, and supportive care of patients with follicular lymphoma (FL). They are intended for healthcare professionals. A multidisciplinary panel of experts was formed, including hematologists, medical oncologists, pathologists, molecular biologists, radiation oncologists, and patient representatives. Geographic and professional diversity was considered to reflect variations in healthcare systems across Europe. Roles were assigned for drafting, evidence review, and editorial oversight.

A systematic review of the literature was conducted using PubMed. The review prioritized high‐quality evidence. Evidence was graded using the GRADE framework for strength and quality of recommendations. Draft recommendations were developed and circulated among the panel for feedback. Discrepancies were resolved through virtual meetings and consensus discussions. Concerning treatment suggestions, we most often propose drugs that are approved by the European Medicines Agency (EMA); treatments not EMA‐approved but supported by strong scientific evidence are mentioned in the recommendation section with an asterisk (*).

Patient‐centered care, shared decision‐making, quality of life (QoL) issues, and alignment with patient needs were also considered. The need for virtual (on the European Hematology Association [EHA] website) or in extenso revision of guidelines will be assessed annually.

INCIDENCE AND EPIDEMIOLOGY

FL is the second most common non‐Hodgkin lymphoma (NHL) in Western Countries, accounting for 10%–20% of all newly diagnosed NHLs and 70% of all indolent lymphomas. The annual incidence rose from 2 to 3/100,000 during the 1950s, peaked at 4/100,000, and is currently modestly declining without clear explanation. Prevalence, on the other hand, is rapidly growing due to improved overall survival (OS). FL predominantly affects adults, typically in their 60s. It is slightly more common among males and Caucasians. ¹ , ²

DIAGNOSIS, PATHOLOGY, AND MOLECULAR BIOLOGY

Diagnosis requires histological confirmation. An excisional lymph node biopsy remains the gold standard, preferred over core needle biopsies due to its superior diagnostic yield. ³ Fine‐needle aspiration is discouraged. Assessment by an expert hematopathologist should adhere to the WHO/ICC classification. ⁴ , ⁵ Follicular large cell lymphoma (formerly defined as FL Grade 3B) should be treated as aggressive lymphoma. Reporting of histological Grades (1, 2, and 3A) in classical FL is debated optional. ⁴

Classical FL must be distinguished from related rarer variants with different clinical trajectories (described in Table 1).6, 7, 8, 9

Table 1.

Entities/subtypes of follicular lymphoma and related disease.

This guideline	WHO 5th ed.a	ICC nomenclaturea, b	Relevant featuresa
Covered	Classical follicular lymphoma (ICD‐O 9690/3)	Follicular lymphoma	Variable in clinical presentation, immunophenotype, and genetics
	Follicular lymphoma with diffuse growth pattern (ICD‐O 9690/3)	BCL2‐R–negative, CD23‐positive follicle center lymphoma	Definition includes localized stage and site of involvement
	Follicular lymphoma with unusual cytological features (ICD‐O 9690/3)	NA	Clinical significance not definitely defined yet, molecular testing is recommended
Covered: entity‐specific features	Pediatric‐type follicular lymphoma (ICD‐O 9690/3)	Pediatric‐type follicular lymphoma	This guideline only refers to this subtype in patients aged 18 years or older
	Duodenal‐type follicular lymphoma (ICD‐O 9695/3	Duodenal‐type follicular lymphoma	Definition includes localized stage and duodenal localization
Not covered	In situ follicular B‐cell neoplasm (ICD‐O 9695/1)	In situ follicular neoplasia	Mostly incidental finding but may accompany fully developed lymphoma of various types
	Follicular large cell lymphoma (ICD‐O 9698/3)	Follicular lymphoma, Grade 3B	Considered a large cell lymphoma—see guideline for diffuse large B‐cell lymphoma
	Primary cutaneous follicle center lymphoma (ICD‐O 9597/3)	Primary cutaneous follicle center lymphoma	Lymphoma confined to skin molecularly distinct from classical follicular lymphoma—see guideline for primary cutaneous lymphoma

Abbreviations: ICC, International Consensus Classification; NA, not applicable; WHO, World Health Organization.

^a Definitions of entities/subtypes may differ slightly between the two classifications. Harmonization efforts between the two classifications are ongoing, and reconciliation is expected in the near future.

^b Testicular follicular lymphoma mentioned by ICC is a very rare subtype that is not listed here and mostly affects younger patients.

Approximately 85% of FL cases harbor the t(14;18)(q32;q21) translocation, leading to overexpression of the anti‐apoptotic BCL2 protein. Immunohistochemically, FL cells express B‐cell markers (CD19, CD20), germinal center markers (CD10, BCL6), and typically show light chain restriction. In BCL2‐negative cases, BCL2 rearrangement may be confirmed by fluorescence in situ hybridization (FISH) or cytogenetics.

FL commonly has mutations in epigenetic regulators such as KMT2D, CREBBP, and EZH2,10, 11, 12 but these lack validated prognostic/predictive utility and are not routinely tested. ¹³

Exclusion of histological transformation is required in cases of rapid disease progression, or elevated lactate dehydrogenase (LDH)/standardized uptake value (SUV), if transformation is clinically suspected. ¹⁴ The management of histological transformation is described in Large B‐cell lymphoma EHA guidelines. ¹⁵

Rebiopsy must be considered at each relapse to rule out transformation and identify druggable targets.

Recommendations

• FL diagnosis should be based on an excision biopsy when feasible. Large core biopsies are an alternative for difficult anatomical sites.

• Expert hematopathology review is strongly recommended.

• Reporting histological grades is optional, except for FL Grade 3B.

• Mutational profiling currently has no role in routine clinical practice.

• Histological transformation must be ruled out.

STAGING, RESTAGING, AND RISK ASSESSMENT

Staging of newly diagnosed or relapsed/refractory (R/R) FL must follow the Lugano update of the Ann‐Arbor staging system with mention of bulky disease (>10 cm) when applicable. ¹⁶

Risk assessment can be individualized considering long‐established Follicular Lymphoma International Prognostic Index (FLIPI), FLIPI2, or PRIMA Prognostic Index (PI) ¹⁷ , ¹⁸ , ¹⁹ (Table 2). The more recent FLIPI24 calculator can also estimate the probability of progression within 2 years after initiating first‐line treatment (POD‐24). ²⁰

Table 2.

Prognostic scores in follicular lymphoma.

Feature	FLIPI 17	FLIPI‐2 18	PRIMA‐PI 19	FLIPI24 20
Developed in	2004	2009	2018 (from PRIMA trial)	2025
Factors included	1. Age > 60 years 2. Stage III–IV 3. Hb < 12 g/dL 4. >4 nodal sites 5. Elevated LDH	1. β2‐Microglobulin ↑ 2. LN > 6 cm 3. BM involvement 4. Hb < 12 g/dL 5. Age > 60	1. β2‐Microglobulin ↑ 2. BM involvement	1. Hemoglobin 2. Lactate dehydrogenase 3. β‐2 Microglobulin 4. WBC count
Risk categories	‐ Low (0–1) ‐ Int. (2) ‐ High (≥3)	‐ Low (0–1) ‐ Int. (2) ‐ High (≥3)	‐ Low (0) ‐ Int. (1) ‐ High (2)	‐ Low (0) ‐ Int. (1) ‐ High (2)
Features	Imaging needed	Imaging needed BM needed	BM needed

Abbreviations: BM, bone marrow; FLIPI, Follicular Lymphoma International Prognostic Index; LDH, lactate dehydrogenase; LN, lymph node; PI, Prognostic Index; WBC, white blood cell count.

Positron emission tomography (PET) is the reference imaging method for staging (II, A) FL21, 22, 23; however, when possible, both PET and computed tomography (CT) with contrast should be performed. PET is not sensitive enough to exclude bone marrow (BM) involvement. Therefore, bone marrow biopsy (BMB) is recommended to confirm Stage I/II disease (II, A) suitable for radiotherapy. In Stage III–IV advanced stage (AS) disease, BMB can be omitted in the absence of equivocal cytopenias (II, D). ²⁴ When PET is unavailable, full staging should include a contrast‐enhanced CT and an adequately sized BMB (minimum 20 mm) (Table 3).

Table 3.

Patient work‐up according to the Lugano 2014 update of the Ann‐Arbor staging.

Stage	Nodal involvement	Extranodal status	Required procedures
LS
I	One lymphatic localization (lymph node area,a Waldeyer's ring, spleen [IS], or thymus) or two areas of merged, excluding bulky disease	Single, not bulky extranodal lesion without nodal involvement (IE)	History: B symptoms Physical examination: peripheral lymph nodes, liver, and spleen Laboratory tests: complete blood count, lactate dehydrogenase (LDH), creatinine clearance, uric acid, immunoglobulin (Ig) levels, β2‐microglobulin (B2M), human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV) testing Imaging: PET or CT with contrast if PET not available Bone marrow: cytology, histology with immunophenotyping Electrocardiogram, cardiac ultrasound: particularly before doxorubicin and if aged >70 years Reproductive counseling in young patients
II	Two or more lymph node areas on the same side of the diaphragm, can be bulky disease > 10 cm (IIX)	Stage I or II by nodal involvement with limited adjacent or bulky extranodal localization (IIE)
AS
III	Lymph nodes on both sides of the diaphragm or nodes above the diaphragm with spleen involvement (IIIS)	Single extranodal lesion (not bulky, contiguous to known nodal site) with nodal involvement on both sides of the diaphragm (IIIE)	History: B symptoms Physical examination: peripheral lymph nodes, liver, and spleen Laboratory tests: complete blood count, LDH, creatinine clearance, uric acid, Ig levels, B2M tests for HIV, HBV, and HCV Imaging: PET and CT with contrast (possible exceptions described above) Bone marrow: if clinically indicated, cytology, histology with immunophenotyping Electrocardiogram, cardiac ultrasound: before doxorubicin Reproductive counseling in young patients
IV	Lymph nodes on both sides of the diaphragm with extranodal localization	Diffuse or disseminated involvement of one or more extra‐lymphatic organsb with or without nodal lesions

Note: A symptoms: no symptoms listed below. B symptoms: temperature > 38.0°C, drenching night sweats, unexplained loss of >10% of body weight over 6 months.

Abbreviations: CT, computed tomography; PET, positron emission tomography.

^a Lymph node areas, counted as two if bilateral: cervical (pre‐auricular, upper cervical, median or lower cervical, posterior cervical, and supraclavicular), axillary (axillary), mediastinal (paratracheal, mediastinal, hilar, and retrocrural), mesenteric (celiac, splenic hilar, hepatic hilar, portal, and mesenteric), para‐aortic (para‐aortic, common iliac, and external iliac), inguinal (inguinal, femoral), and others (epitrochlear, popliteal).

^b Any involvement of the liver, bone marrow, cerebrospinal fluid, or lungs (other than by direct extension from another site).

Laboratory testing should include at least: complete blood count, routine blood chemistry: immunoglobulin (Ig) levels, LDH, β2‐microglobulin (B2M), creatinine clearance, uric acid, and serology for human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV).

Elevated SUVmax values may support the decision to biopsy when transformation is suspected, and therefore, SUVmax should be included in FDG‐PET reports (IV, B). Nevertheless, PET imaging cannot replace histological confirmation of transformation (III, E). ²⁵ , ²⁶ In the absence of clinical concerns for HT (highly discrepant SUVmax, elevated LDH, rapid growth, etc.), a repeat biopsy at sites of greatest SUVmax is generally not needed. Regarding response assessment, the Deauville five‐point score (DV 5PS) should be included in the end‐of‐induction PET report, with DS 4 and 5 identifying disease persistence at specific sites. ¹⁶

When planning additional lines of non‐intensive treatment, restaging should follow the same approach used at diagnosis. Although some prognostic markers remain relevant at relapse, ²⁷ early disease progression (often measured as POD24) is considered a useful parameter for guiding therapeutic decisions at first relapse, especially after immunochemotherapy. ²⁸ , ²⁹

Recommendations

• The Lugano update of the Ann‐Arbor staging system should be used for initial staging.

• FLIPI/FLIPI2/PRIMA‐PI and FLIPI24 risk scores may be used for prognostic assessment.

• A complete blood count, routine blood chemistry including Ig levels, LDH, B2M, creatinine, uric acid, HIV, HBV, and HCV virology are required.

• PET‐CT is more sensitive than CT for staging (II, A). In PET‐CT staged patients, BMB is recommended to confirm Stage I/II disease (II, A) but may be omitted in patients with Stage III–IV disease (II, D).

• PET‐CT with Deauville scoring is recommended for response assessment at the end of systemic therapy.

• At retreatment, early disease progression is the most important prognostic factor.

MANAGEMENT OF NEWLY DIAGNOSED FL

At every treatment line, screening for enrollment into well‐designed clinical trials should be considered and discussed with the patient, where available.

Treatment of localized stage FL

In patients with localized stage (LS) and low‐tumor burden (LTB), radiotherapy should be considered. The preferred dose to involved sites is 24 Gy in 2 Gy single doses (II, B). ³⁰ For smaller lymph nodes and special situations (lacrimal gland, parotid, etc.) 2 × 2 Gy may be an alternative option to minimize side effects (II, C). ³¹ , ³² FDG‐PET/CT is suggested for precise definition of the target volume. ³³

Combining radiotherapy with an anti‐CD20 antibody improves progression‐free survival (PFS) ³⁴ , ³⁵ and may provide the best balance between efficacy and side effects (III, B). The antibody can be administered synchronously. Minimal residual disease (MRD)–driven administration after radiotherapy has practical limitations and lacks standardization (III, C). ³⁶

Active surveillance may be considered in selected cases (III, C) (e.g., limited life expectancy). ²¹ Where available, R monotherapy offers an alternative to prolong PFS and delay immunochemotherapy ³⁷ (III, C).

Treatment of AS FL

Most FL patients present with AS, and no current therapy has been proven to be curative. Given their generally favorable prognosis, OS differences between treatments are difficult to discern, supporting a broad range of acceptable management options.

The need for treatment is historically based on criteria described in Table 4,38, 39, 40 but flexibility is often needed. Clinical evaluation, especially noting the presence of symptomatic disease, is the main criterion. Generally, asymptomatic patients without high‐tumor burden disease are candidates for active surveillance (I, A). Follow‐up should include physical examination, laboratory tests and judicious imaging (ultrasonography where appropriate); the median time to needing treatment is approximately 3 years. ³⁷ , ⁴¹

Table 4.

High‐tumor burden criteria in follicular lymphoma, modified from GELF and British National Lymphoma Investigation (BNLI) guidelines.

Criterion	High‐tumor burden indication
Any lymph node or nodal mass ≥ 7 cm in diametera	Indicates bulky disease
Involvement of ≥3 nodal sites, each ≥3 cm	Suggests disseminated nodal burden
Symptomatic splenomegaly	Pain, early satiety, or cytopenias due to spleen enlargement
Compressive symptoms (e.g., ureteral obstruction, organ compression) or painful lesions	Functional compromise of organs
Pleural effusion or ascites attributable to lymphoma	Indicates extranodal spread with symptomatic serous effusions
Cytopenias due to marrow or splenic infiltration: – hemoglobin < 10 g/dL – platelets < 100 × 109/L	Bone marrow or spleen involvement impairing hematopoiesis
B symptoms: – unexplained fever > 38°C – night sweats – weight loss > 10% over 6 months	Reflects systemic disease activity
Rapidly progressive disease (within 3 months)	Clinical or radiographic progression over weeks/months

Abbreviation: GELF, Groupe d'Étude des Lymphomes Folliculaires (French Study Group for Follicular Lymphoma).

^a Alternative cut‐offs have been considered (7, 6, and 10 cm).

An alternative to active surveillance is Rituximab monotherapy (I, B). A randomized trial,42, 43, 44 compared observation versus four doses of Rituximab versus four doses of Rituximab plus maintenance. As expected, Rituximab prolonged PFS and time to next treatment (TTNT) compared to observation, but no differences in the risk of histological transformation or OS were observed.

Thus, both options are appropriate and need to be carefully discussed with patients, with potential for improved QoL favoring Rituximab (II, C). ⁴⁵

Patients with high‐tumor burden, either at initial presentation or after active surveillance, require treatment. There is no consensus on the optimal regimen, and the patient's perspective is central to an individualized approach.

Rituximab (R) monotherapy has been used, yielding modest outcomes of complete response (CR) and PFS, but with minimal toxicity and OS exceeding 15 years46, 47, 48 (I, B). Subsequent R maintenance may improve PFS (I, B). ⁴⁹ In most EU countries, R monotherapy is usually reserved for selected patients with significant comorbidities or advanced age, when minimizing toxicity is prioritized over prolonging PFS.

Immunochemotherapy incorporating an anti‐CD20 monoclonal antibody (MoAb) is more effective than chemotherapy alone. Therefore, unless there is an absolute contraindication, these agents should be delivered in combination (I, A). ⁵⁰

Regarding the chemotherapy backbone, several studies51, 52, 53, 54 have evaluated different first‐line treatment options. Fludarabine‐based combinations are more toxic, offer no significant benefit, and are no longer appropriate (I, E). Studies comparing R‐B with R‐CHOP demonstrated the non‐inferiority of R‐B in terms of efficacy, with reduced neutropenia and stomatitis and no significant difference in OS. Therefore, R‐B, R‐CHOP, or R‐CVP are commonly selected as first‐line treatments (I, A).

The third‐generation Type 2 anti‐CD20 MoAb, Obinutuzumab (O), was compared with R in combination with either CHOP, CVP, or bendamustine in the randomized phase 3 GALLIUM trial. ⁵⁵ , ⁵⁶ Although PFS was improved, OS was comparable. Toxicity was higher in the O arm with an increased non‐relapse mortality due to infections when combined with bendamustine, particularly in elderly patients during maintenance. In a subset analysis, the benefit of O appeared limited to intermediate and high‐risk FLIPI patients ⁵⁷ and may therefore be preferred in this subgroup, with careful consideration when combined with bendamustine (I, B).

The randomized Phase 3 RELEVANCE study compared the chemo‐free combination of Rituximab with lenalidomide (R2) + R maintenance versus immunochemotherapy (R‐CHOP, R‐B, and R‐CVP) and R maintenance. There were no significant differences in overall response rate (ORR), CR rate, PFS, or OS. ⁵⁸ , ⁵⁹ As the trial was designed to demonstrate superiority of R2, it did not meet its primary endpoint. Nevertheless, the comparable results of the two arms suggest the potential use of R2 in certain circumstances (I, B).

The concept of anti‐CD20 maintenance therapy is long‐standing in FL. In the PRIMA trial, ⁶⁰ , ⁶¹ those responding to induction immunochemotherapy were randomized to either observation or to Rituximab 375 mg/m² every 8 weeks for a total of 12 doses. The updated results indicate a substantial PFS advantage of maintenance therapy (median 4 vs. 10 years). Similarly, the results of the GALLIUM trial confirm the benefit of antibody maintenance, using the same antibody administered in induction. ⁵⁵ , ⁵⁶ Therefore, maintenance with an anti‐CD20 antibody after induction is considered a standard approach (I, B). However, given the lack of OS benefit, it is reasonable to delay, avoid, or curtail maintenance in patients at high risk of, or with recurrent infections or at high risk of SARS‐CoV‐2 complications, particularly when bendamustine is used ⁶² , ⁶³ (IV, C). Attempts to use a response‐adapted postinduction strategy have not been successful so far as shown by the FIL‐FOLL 12, and should not be performed (I, D). ⁵⁴ However, additional studies in this setting, including the PETReA trial, are ongoing. ⁶⁴

FL variants

Pediatric FL is a variant originally described in children that rarely occurs in adults. It is characterized by localized disease, absence of BCL2 aberrations, lack of t(14;18), Grade III histology, and high proliferation rate. It follows a very indolent course and can be managed with local therapy only, despite displaying histologically aggressive features (IV, B). ⁶⁵ Similarly, duodenal‐type FL is usually a localized disease most often managed with observation or alternatively radiotherapy or R monotherapy if symptomatic (IV, B). ⁷

Recommendations

• In LS, 24‐30 Gy ISRT ± R* is the preferred approach (II, B). In selected cases, active surveillance (III, C) or 2 × 2 Gy ISRT (II, C) or R monotherapy* might be considered (III, B).

• Stage I–II patients should receive systemic therapy akin to AS FL if there is high‐tumor burden or adverse clinical prognostic features, or if bulky Stage II disease is unsuitable for ISRT (IV, B).

• In patients with AS FL without treatment criteria (LTB), active surveillance is recommended until treatment criteria are met (I, A). R* monotherapy is an alternative selection (I, B).

• Induction treatment in advanced FL who meet treatment criteria (high‐tumor burden) is generally immunochemotherapy with R or O (I, A). O is superior in terms of PFS in high‐risk FLIPI patients but more toxic.

• The anti‐CD20 MoAb should be combined with CHOP, CVP, or bendamustine (I, A).

• R monotherapy is an alternative non‐toxic option, if PFS prolongation is not the top priority (II, B).

• R2 is an alternative first‐line option, where available (II, B)*.

• In patients with FL who respond (CR or PR) to immunochemotherapy, maintenance treatment with the same anti‐CD20 MoAb used in induction is recommended to prolong PFS, balancing the potential benefits and risks in individual patients (I, B) (Figure 1).

Figure 1.

Therapeutic treatment algorithm for untreated follicular lymphoma (FL).

MANAGEMENT OF FIRST RELAPSE/REFRACTORY DISEASE

The choice of 2L regimen after a first‐line systemic therapy is based on the following: (a) patient's fitness and underlying comorbidities; (b) depth and duration of response (DOR) and toxicity of previous therapy; (c) disease kinetics; (d) accessibility of novel therapies for subsequent treatment; and (e) patient priorities. In case of relapse after radiotherapy only, systemic therapies will be delivered as outlined for 1L treatment.

New therapies including chimeric antigen receptor T‐cell therapy (CAR‐T), ⁶⁶ , ⁶⁷ , ⁶⁸ bispecific antibodies (BsAbs), ⁶⁹ , ⁷⁰ , ⁷¹ and Zanubrutinib in combination with O ⁷² are currently employed in the management of R/R FL patients who had failed at least two prior lines of therapy (3L+). Preliminary Phase 2 results of some of these agents at the 2L are promising. Phase III results are available for Tafasitamab and Epcoritamab in combination with Lenalidomide and Rituximab. ⁷³ , ⁷⁴ Availability of these combinations will have a growing impact on the management of patients with R/R FL after first‐line treatment. ⁷⁵ , ⁷⁶ , ⁷⁷ , ⁷⁸

Radiotherapy in 2L

Some patients with a late, non‐bulky, localized relapse may be candidates for radiotherapy, if the site is accessible. The decision to irradiate should be individualized, considering the patient's preferences. In most cases, a palliative 2 × 2 Gy dose is the preferred option (II, B). ⁷⁹ , ⁸⁰ A dose of 24 Gy is highly effective; however, its curative potential at relapse is unknown (IIC). ⁷⁹ , ⁸⁰ , ⁸¹ Active surveillance and R monotherapy are also acceptable options.

Low‐tumor burden at relapse or progression

Patients with documented disease progression with LTB who are asymptomatic can undergo active surveillance (IV, B). ⁸² , ⁸³ Early disease progression is strongly associated with poor outcomes, necessitating close follow‐up. A short course of anti‐CD20 monotherapy (4–8 weeks) (III, C) ⁸³ , ⁸⁴ may be considered for patients uncomfortable with active surveillance or if delaying more intensive systemic therapy is desired (e.g., durable remission with previous anti‐CD20 monotherapy, unfit patients).

High‐tumor burden after a late first relapse

If immunochemotherapy is chosen, any non‐cross–resistant regimen to that delivered at first line is usually considered (IV, C). The Rituximab‐Lenalidomide (R2) ⁸⁵ combination is an established chemotherapy‐free option (I, B). Recently, Tafasitamab Rituximab‐Lenalidomide (T‐R2) ⁷³ (I, B) and Epcoritamab Rituximab‐Lenalidomide (E‐R2) (1, A) ⁷⁴ combinations proved substantially superior to R2 in large well‐conducted phase III trials in terms of CR rate, PFS, and TTNT. Due to their novelty, availability of these regimens is still pending in some countries, but where available they represent excellent treatment options.

High‐tumor burden and early disease progression

Early progression (<12–24 months) after 1L anti‐CD20 monotherapy is also linked to inferior survival and should be managed as aggressive disease. Early progressors are unlikely to maintain long‐lasting remissions following SOC regimens. Therefore, bendamustine is discouraged in this setting to avoid the potential impact on harvesting of CAR‐T cells as a subsequent therapy (V, D). ⁸⁷ R2 has until recently been considered the SOC for patients with early disease progression (II, B). ⁸⁵ , ⁸⁸ Although PFS in these patients remains unsatisfactory (IB). In addition to the aforementioned T‐R2 (I, B) and E‐R2 (I, A) combinations, other promising alternatives such as Mosunetuzumab‐Lenalidomide, ⁸⁹ Loncastuximab Tesirine‐Rituximab, ⁹⁰ and Lisocaptagene‐maraleucel ⁶⁸ are currently under evaluation. Autologous Stem Cell Transplantation (ASCT) is still employed as consolidation at many institutions based on historical data ⁹¹ , ⁹² ; however, its benefit and curative potential are not proven in the rituximab era, and the approach is associated with significant acute and late toxicities. ⁹³ , ⁹⁴ Therefore, its use should be limited to selected cases (II, D) such as rapidly progressive disease when novel therapies are not available.

Anti‐CD20 maintenance

The evidence for anti‐CD20 maintenance for R/R FL in today's treatment landscape is limited.95, 96, 97 Maintenance is discouraged for patients progressing during or soon after maintenance in the frontline setting (V, D). For patients who did not previously receive maintenance or with late relapses, the decision to administer maintenance is reasonable, especially in the absence of infections during re‐induction (I, B). ⁹⁶

Recommendations for the 2L management of FL

• Active surveillance is an option for asymptomatic disease with LTB. Early progressors should be followed closely for progression (IV, B).

• The choice of regimen should be directed by disease‐related variables, including duration of previous response, clinical characteristics, treatment availability, and patient priorities. Options include R monotherapy (III, C), R2 (II, B), T‐R2 (I, B), E‐R2* (I, A) or in selected cases immunochemotherapy (IV, C).

• Anti‐CD20 maintenance can be considered if not previously given, after careful weighing of benefit/risk ratio (I, B).

• Radiotherapy may be considered for localized Stage I disease (IV, C).

• ASCT consolidation in 2L should not be routinely implemented given the new treatment options but may be appropriate where CAR‐T, BsAbs or other novel therapies are not available (II, D) (Figure 2).

Figure 2.

Therapeutic treatment algorithm for relapsed/refractory (R/R) follicular lymphoma (FL).

MANAGEMENT OF R/R DISEASE AT LATER RELAPSE

A key consideration in the management of third‐line or later (3L+) relapsed FL is the optimal sequencing of available therapies, based on treatment goals to maximize PFS and OS, alleviate symptoms, treat cytopenias, and improve QoL. ⁹⁸

Critical disease‐related factors are (1) clinical presentation (±symptoms); (2) the timing of relapse (particularly early progression and refractory disease); (3) tumor burden; (4) disease stage; and (5) previous treatments and response, including the “double refractory” status. ⁹⁹ In addition, patient‐related factors such as performance status, age, comorbidities, frailty, and personal preferences must be carefully assessed.

Therefore, the choice of therapy for (3L+) relapsed FL is more nuanced than in earlier lines.

Low‐tumor burden asymptomatic/early stage

LTB asymptomatic and early‐stage patients should follow the same recommendations described for first relapse with a high degree of individualization.

Low‐tumor burden patients requiring treatment

Repeating R monotherapy (III, C) or delivering R2 (II, B) or T‐R2 (II, A) are valid options if durable remission to previous therapies was achieved, but DOR is usually shorter compared to earlier lines. ⁷³ , ⁸⁵ Zanubrutinib combined with O is another option, particularly in Rituximab‐refractory cases (II, B). ⁷² , ¹⁰⁰

High‐tumor burden

Patients with asymptomatic high‐tumor burden R/R FL may defer therapy without compromising survival, risk of transformation or responsiveness to subsequent therapy if there are no other indications for treatment, such as organ compromise, significant cytopenias, or poor risk features such as early relapse or Rituximab‐refractoriness. ⁹⁹

Symptomatic high‐tumor burden relapsed FL requires treatment, and choice is determined by previous history and timing of relapse. Re‐treatment with R monotherapy for four doses followed by 2‐monthly maintenance for 2 years offers modest ORR and CR rates (ORR 26%–55%/CR 4%–20%). ⁸⁵ , ⁹⁷ PFS is shorter for patients with high‐tumor burden disease, chemo‐resistant, and/or AS disease. Therefore, this option is reasonable only in frail patients or to gain a short‐term benefit (i.e., to access emerging therapies) (III, C). Chemosensitive relapsed FL may still be considered for further immunochemotherapy but, given the availability of several novel alternatives, this should be limited to selected cases or countries without access to novel options (IV, D). Moreover, given the short PFS at 3L+, the use of highly immunosuppressive agents such as bendamustine is discouraged (V, E).

Chemotherapy‐free approaches, such as R2, T‐R2, ⁷³ E‐R2, ⁷⁴ Zanubrutinib with O, ⁷² single‐agent BsAbs,69, 70, 71 and CAR‐T cells66, 67, 68 deliver unprecedented efficacy in all patients with R/R FL beyond second relapse, particularly those with chemo‐refractory FL and those less likely to respond to CIT due to high‐risk features.

Zanubrutinib with O was approved based on pivotal data from the Phase II randomized ROSEWOOD trial, ⁷² reporting median PFS of 22.1 months at a median follow‐up of 34.6 months (II, B). ⁷² , ¹⁰⁰ In general, R2 (II, B), T‐R2 (I, B), and Zanubrutinib‐O (II, B) provide well‐tolerated options suitable for patients with comorbidities or preferring less intensive treatment.

Three CD20 and CD3 dual targeting BsAbs are currently EMA approved for R/R FL—Epcoritamab, Mosunetuzumab, and Odronextamab—based on pivotal trials in heavily pre‐treated populations reporting ORR and CR rates between 80%–83% and 60%–73%, respectively,69, 70, 71 with CRs exceeding 50%–60% even in high‐risk subsets (early disease progression at last line and double refractory) (III, A).69, 70, 71 Encouraging durability of disease control has been demonstrated, with median DOR of 46.4 months at 54 months of follow‐up for Mosunetuzumab, the agent with the longest follow‐up. ¹⁰¹

Indirect comparative effectiveness studies showed no significant difference in clinical outcomes between approved BsAbs. ¹⁰² , ¹⁰³ , ¹⁰⁴ , ¹⁰⁵ Epcoritamab can be administered subcutaneously and has a favorable safety profile. Mosunetuzumab has the advantage of a fixed duration schedule and is efficacious as retreatment in at least 50% of patients. ¹⁰³ Collectively, BsAbs represent excellent choices for a sizeable proportion of patients (III, A), and choosing between BsAbs should be individualized. BsAb combinations with lenalidomide or R2 (such as E‐R2) ⁷⁴ are possibly more effective and may be preferred over BsAbs monotherapy in lenalidomide‐naïve patients, subject to local availability as shown by the good efficacy of E‐R2 in the EPCORE FL‐1 also at later treatment lines ⁷⁴ (I, A).

CAR‐T therapies are highly active in R/R FL with ORR and CR rates of 86%–97% and 69%–94%, respectively, in pivotal trials ⁶⁶ , ⁶⁷ , ⁶⁸ (III, A). Candidates for CAR‐T treatment previously treated with an anti‐CD19 agent need rebiopsy to confirm ongoing CD19 expression. Notably, efficacy is preserved even in later lines of therapy for Axicabtagene ciloleucel (axi‐cel), ⁶⁶ in contrast to numerically lower response rates and DOR after four or more lines reported for BsAbs. ⁶⁹ , ⁷⁰ Axi‐cel is approved in the EU for treatment of FL after three or more prior lines of therapy, while two other approved agents—Tisagenlecleucel (tisa‐cel) ⁶⁷ and Lisocabtagene maraleucel (liso‐cel) ⁶⁸ are options after two or more prior lines. In the absence of head‐to‐head comparisons, choosing between CAR‐T therapies is challenging. Axi‐cel has the most mature data and delivered durable disease control with a median PFS and DOR of 57 and 60 months, respectively (III, A). ¹⁰⁶ Moreover, it has the shortest manufacturing time and delivers rapid disease control; it should be considered when bridging therapy is not needed or desirable. Due to higher rates of Grade ≥3 CRS/ICANS, Axi‐cel is less suited to older/frailer patients and those with neurological comorbidities, whereas Tisa‐cel ⁶⁷ and Liso‐cel ⁶⁸ have more favorable safety profiles (III, A).

There is no consensus on the optimal sequencing of BsAb and CAR‐T therapies to achieve maximal efficacy and safety in FL. Based on current evidence, in high‐risk patients such as those with chemo‐resistant or early disease progression, CAR‐T therapy may deliver the most durable disease control. ¹⁰⁷ BsAbs are effective after CAR‐T therapy. For patients unfit for CAR‐T therapy, BsAbs offer a more accessible, safer, and less complex option. For many patients, CAR‐T can be reserved for post‐BsAb failure, with no evidence to date that earlier BsAbs impact subsequent CAR‐T efficacy. ¹⁰⁸ Furthermore, given the rapid shift of BsAb toward earlier treatment lines, it is expected that the majority of pts will receive BsAb before CAR‐T.

As in second line, the advent of highly effective novel therapies has largely replaced ASCT, which should not be routinely considered (II, D). ⁹³ , ⁹⁴

Allogeneic stem cell transplantation remains the only approach with confirmed curative potential in r/r FL ¹⁰⁹ , ¹¹⁰ and is feasible for selected patients with post CAR‐T relapse, or post ASCT relapse where CAR‐T are not available (III, C). ¹¹¹ However, decisions must balance efficacy and curative potential against early and high toxicity and non‐relapse mortality rates.

Recommendations for 3L+ R/R FL

• Observation is appropriate for LTB r/r FL (IV, A) and in selected asymptomatic high‐tumor burden cases, particularly for late relapses and in the absence of organ compromise, significant cytopenias or high‐risk features (IV, C).

• R2 (II, B), T‐R2 (I, B), or Zanubrutinib ‐ O (II, B) are recommended when a low toxicity option is sought.

• Single‐agent Mosunetuzumab (III, A), Epcoritamab (III, A), or Odronextamab (III, A) as well as E‐R2* (I, A) are appropriate options to deliver maximal response and PFS benefit.

• CAR‐T cell therapy is recommended after ≥2–3 prior lines particularly for high‐risk or chemo‐refractory FL (III, A).

• There are no definitive sequencing rules for BsAbs versus CAR‐T, and each can be used after the other (IV, C).

• Immunochemotherapy may be considered in selected patients with chemosensitive relapse, particularly if CAR‐T or BsAbs are not available (III, D).

• R monotherapy is an option for frail patients with low‐burden disease who are ineligible for intensive treatments, with modest PFS expectations (III, C).

• Radiotherapy is an option in the rare situation of Stage I localized disease relapse (IV, B).

• ASCT has a very limited role in 3L+ R/R FL (II, D).

• Allogeneic SCT should be reserved for highly selected patients relapsed post‐CAR‐T (III, C) (Figure 3).

Figure 3.

Relapsed/refractory (R/R) follicular lymphoma (FL) therapy third or later lines (second or later relapse/progression).

FOLLOW‐UP, LONG‐TERM IMPLICATIONS, AND SURVIVORSHIP

Follow‐up and survivorship

Patients receiving treatment for multiply relapsed FL1, 2, 3 should undergo close, long‐term specialist follow‐up. Conversely, after first‐line therapy, indefinite hematology review is not warranted for the ~90% who achieve CMR. ⁴ , ⁵ Collectively, even with limited follow‐up, institutional, population, and clinical trial data indicate that a significant proportion of patients achieve a “functional cure” after initial therapy ²⁸ , ¹¹² with survival estimates for many comparable to age‐ and gender‐matched populations. ¹¹³ For such patients, informed by age, fitness, and FL prognosis, hematologist review every 3–6 months over the following 2 years provides both clinical assessment and the opportunity to address healthy survivorship management of other comorbidities, infection prophylaxis, monitoring for long‐term cardiac and secondary malignancy risks, and attention to QoL and well‐being (Table 5). Having established the patient's needs during induction, the hematologist can tailor medical advice of remission duration to assist this life‐planning.

Table 5.

Suggested follicular lymphoma survivorship follow‐up.

Immediate post‐therapy considerations/transitioning from active treatment	Considerations	Actions
Treatment summary and shared care follow‐up plan for the local medical practitioner
	Infection prophylaxis	Trimethoprim/sulfamethoxazole 80/400 mg or other PJP prophylaxis until CD4 count 0.2 × 109/L
		Shingrix vaccination ± valaciclovir 500 mg bd
		Annual influenza, optional RSV vaccination
		Immunoglobulin replacement therapy per national guidelines
	Cardiac assessment	Repeat echocardiogram in elderly and patients at risk, or if symptomatic after CHOP (anthracycline chemotherapy)
	Metabolic needs	Address fatigue, obesity, and sedentary lifestyle, supporting informed decisions about lifestyle behaviors that promote wellness and improve QoL
	Psychosocial needs	Address stress, fear of lymphoma recurrence, and lymphoma/treatment‐related fatigue, pain, distress, anxiety, depression, cognitive changes and sleep issues 114 , 115 Offer referral to local psycho‐oncology or community‐based psychology services. Provide practical fatigue self‐management strategies and referral to exercise physiology or survivorship programs where needed Assess ongoing impact on work, family, and financial well‐being and signpost to resources if appropriate Referral to patient advocacy groups, especially when local services are lacking
	Patient‐specific needs	Referral to physiotherapy, occupational therapy, social work, dietetics, fertility, clinical psychology, or palliative care clinicians as appropriate Practical guidance for patient‐initiated follow‐up, including examples of red flag symptoms Involve care partners in survivorship education and planning, with patient consent
Long‐term considerations		Encourage healthy survivorship: comorbidity management, infection prophylaxis, cardiac surveillance, and vaccination Annual influenza vaccination, COVID boosters as required
	General cancer screening and reduction of risk of a second primary cancer	Nonsmoking, healthy diet, being sun smart, limiting alcohol intake, being physically active, and maintaining a healthy body weight may help reduce the risk of a second primary cancer. However, none of these factors have been shown to affect the risk of relapse for follicular lymphoma
	Post radiotherapy	Evaluation of localized second cancer risk and thyroid function yearly in patients who receive radiotherapy to the neck 116
	Endocrinology	Consider gonadal insufficiency (incl. premature menopause) and evaluation for bone density loss
Specific considerations after relapse(s)	Living with lymphoma needs	Close follow‐up by lymphoma specialist
		Reassessment of supportive care issues
		Advance care planning and engagement with palliative care team as appropriate for symptom management and end‐of‐life planning

Abbreviations: PJP, pneumocystis jirovecii pneumonia; QoL, quality of life; RSV, respiratory syncytial virus.

Beyond the initial 2 years, tapered clinic follow‐up with minimal surveillance imaging is appropriate. With documented education and guidance to contact the hematology service in the event of suspected relapse, patient‐initiated follow‐up may be appropriate for many patients. This strategy reassures patients and underscores the importance of addressing survivorship issues, physical, psychological, social, work and financial impacts of FL, as well as the promotion of health and well‐being.

Recommendations

Recommended survivorship follow‐up is outlined in Table 5.

AUTHOR CONTRIBUTIONS

Marco Ladetto: Conceptualization; methodology; data curation; supervision; validation; project administration; writing—review and editing; writing—original draft. Natacha Bolaños: Conceptualization; methodology; data curation; validation; writing—review and editing; writing—original draft. Guy Bouguet: Conceptualization; methodology; data curation; writing—original draft; writing—review and editing; validation. Klaus Herfarth: Conceptualization; writing—original draft; writing—review and editing; validation; methodology; data curation. Wolfram Klapper: Conceptualization; writing—original draft; writing—review and editing; methodology; validation; data curation. Sirpa Leppa: Data curation; methodology; validation; conceptualization; writing—original draft; writing—review and editing. Kim Linton: Conceptualization; writing—original draft; writing—review and editing; methodology; validation; data curation. Armando Lopez‐Guillermo: Conceptualization; methodology; validation; writing—original draft; writing—review and editing; data curation. Stefano Luminari: Conceptualization; writing—original draft; writing—review and editing; methodology; data curation; validation. Franck Morschhauser: Conceptualization; methodology; validation; writing—original draft; writing—review and editing; data curation. Jessica Okosun: Data curation; writing—review and editing; methodology; validation; conceptualization; writing—original draft. Ewa Paszkiewicz‐Kozik: Conceptualization; writing—original draft; writing—review and editing; methodology; validation; data curation. Catherine Thieblemont: Data curation; methodology; validation; conceptualization; writing—original draft; writing—review and editing. Sanne Helene Tonino: Data curation; methodology; validation; writing—review and editing; writing—original draft; conceptualization. Marek Trneny: Conceptualization; writing—original draft; methodology; writing—review and editing; data curation; validation. Judith Trotman: Conceptualization; methodology; writing—original draft; writing—review and editing; data curation; validation. Umut Yilmaz: Data curation; methodology; validation; writing—review and editing; writing—original draft; conceptualization. Martin Dreyling: Conceptualization; writing—original draft; writing—review and editing; methodology; validation; data curation; supervision; project administration.

CONFLICT OF INTEREST STATEMENT

M.L.: Personal fees from AbbVie, Amgen, ADC Therapeutics, Sobi, BeOne, BMS, Eusapharma, GSK, Gentili, Gilead/Kite, Novartis, Incyte, Janssen, Jazz, Lilly, Regeneron, Roche, Ellipses, MSD, Genmab, Astrazeneca. Research grants from Roche, Beone, Sobi, Abbvie, Incyte, Astra Zeneca and J&J. N.B.: Member of the 2024 Ipsen Global Patient Organisations Advisory Board and Member of the Sobi Global Unite4Rare Council. G.B.: None. K.H.: Research support: Roche. W.K.: Research support: Roche, Janssen, InCyte, Amgen. S.L.: Consultancy: AbbVie, AstraZeneca, Genmab, Gilead, Incyte, and Roche; Honoraria: AbbVie, BMS, Gilead, Incyte, and Roche; Research support to the Institute: BMS, Galapagos, Genmab, Novartis, and Roche. K.M.L.: Reports consultancy for AbbVie, BeOne, Bristol Myers Squibb, Celgene, Genmab, Kite/Gilead, and Roche; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from AbbVie, Bristol Myers Squibb, and Celgene; travel support from Bristol Myers Squibb, Abbvie and Celgene, and participation on a data safety monitoring board or advisory board for Genmab and Abbvie; and research funding from ADC Therapeutics, AstraZeneca, BeOne, Bristol Myers Squibb, Celgene,CellCentric, Genmab, Janssen, Kite/Gilead, MorphoSys, MSD, Nurix, Regeneron, Roche, Step Pharma, Viracta and National Institute for Health and Care Research (NIHR) Manchester Biomedical Research Centre (BRC) (NIHR203308). A.L.‐G.: Research support from Roche, Gilead/Kite. Advisory/Consultancy for: Roche, Astra Zeneca, BMS, Gilead/Kite, Incyte, Abbvie. S.L.: Research support from BeOne, Roche. Speaker bureau for: Roche, Incyte, Abbvie, BeOne, Regeneron, Novartis, BMS, Kite. Advisory board for: Astrazeneca, BMS, Kite, Incyte, BeOne, Regeneron, Abbvie. F.M.: Consulting/Advisory role ‐ Bristol Myers Squibb, Roche/Genentech, Janssen, Ipsen,Takeda, AstraZeneca, Abbvie, Kite/Gilead. Research funding ‐ Bristol Myers Squibb, Roche/Genentech, Abbvie, Kite/Gilead. J.O.: Reports personal fees for advisory board membership from AbbVie, AstraZeneca, BeOne, Genmab and Incyte; personal fees as an invited speaker for AbbVie, AstraZeneca and Roche; personal fees for a consulting/advisory role from Incyte; and institutional research grants from AstraZeneca, BeOne, Genmab and Kite Gilead. E.P.K.: Advisory/Consultancy: Roche, Takeda, ABBvie. Speaker Bureau:Kite Gilead, Roche, Takeda, AstraZeneca, BE ONE Med, ABBVIE. Travel/Accomodation: Roche, Takeda. C.T. reports membership on an entity's: Board of Directors or advisory committees of Kite, Amgen, AbbVie, Novartis, Roche, Gilead, Takeda, BMS/Celgene, Incyte, and Cellectis; consultancy for Kite, Amgen, AbbVie, Novartis, Gilead, Cellectis, Roche, and BMS/Celgene; honoraria from Takeda, Incyte, Bayer, Kite, Gilead, Novartis, BMS, Abbvie, F. Hoffmann‐La Roche Ltd, Amgen, Cellectis, and Janssen; research funding from Hospira and BMS/Celgene; and support for attending meetings and/or travel from Kite Pharma / Gilead, Amgen, AbbVie, Novartis, Gilead, Cellectis, Roche, BMS/Celgene, and Janssen. S.H.T.: None. M.T.: Roche, Gilead, AstraZeneca, Sobi, Takeda, Incyte, Lilly, BMS, Novartis, AbbVie, Janssen, Swixx, Carbou Sciences, and Autolus. J.T.: Research funding to her institution from Takeda, BeOne, Roche, and Cellectar. U.Y.: Speaker Honoraria: AbbVie, J&J. Advisory Board Participation: AstraZeneca. Travel Support: J&J, Abbvie, Takeda, BMS. Research Funding: AbbVie. M.D.: Research support: Abbvie, Gilead/Kite, Janssen, Lilly, Roche. Speakers' honoraria: Abbvie, Astra Zeneca, BeOne, BMS, Gilead/Kite, Janssen, Lilly, Roche, Novartis, Sobi. Scientific advisory board: Abbvie, Astra Zeneca, AvenCell, BeOne, BMS, Genmab, Gilead/Kite, Incyte, Janssen, Lilly, Novartis, Roche, Sobi.

FUNDING

The authors acknowledge the support from the grant no. MCL 7005‐24 of Leukemia and Lymphoma Society (LLS) and Progetto di Ricerca Sanitaria Finalizzata 2021 (RF‐2021‐12371972).

Supporting information

Supplementary Information

DATA AVAILABILITY STATEMENT

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.