The European Hematology Association (EHA) published updated follicular lymphoma (FL) guidelines in HemaSphere (Ladetto et al., 2026). They cover diagnosis, staging, frontline and relapsed treatment, follow-up, and incorporate randomized evidence for novel immunotherapies.
The largest changes are in relapsed disease. Tafasitamab or epcoritamab plus rituximab and lenalidomide are recommended from first relapse on phase III evidence. Bispecific antibodies, CAR T-cell therapy, and zanubrutinib plus obinutuzumab are prioritized in later lines, and autologous stem cell transplantation (ASCT) has a more limited role. Median overall survival from diagnosis likely exceeds 20 years, so the guidelines favor individualized decisions.
Diagnosis and Staging
Excisional lymph node biopsy is preferred. Large core needle biopsy is acceptable when excision is impractical. Expert hematopathology review is strongly recommended. Follicular large cell lymphoma, previously grade 3B FL, should be managed as an aggressive B-cell lymphoma, and reporting classical FL grades 1, 2 and 3A is optional.
About 85% of FL cases carry t(14;18), and mutations in KMT2D, CREBBP and EZH2 are common, but routine mutational profiling is not recommended because these alterations lack validated prognostic or predictive value. Rapid progression, elevated lactate dehydrogenase, or unexpectedly high PET uptake should prompt biopsy for transformation. Rebiopsy at relapse can exclude transformation and identify actionable targets.
PET-CT is the reference method for staging and response assessment, with the Deauville five-point score reported at the end of treatment (4-5 indicates persistent metabolic activity). It cannot reliably exclude marrow involvement: bone marrow biopsy remains recommended in apparently localized stage I-II disease that may receive radiotherapy, and can generally be omitted in stage III-IV disease unless cytopenias or other findings warrant it.
Risk assessment can use FLIPI, FLIPI2 and PRIMA-PI. The guidelines add FLIPI24, which estimates the probability of progression within two years of frontline treatment. None of these scores replaces clinical judgment.
Frontline Follicular Lymphoma: Treatment Follows Disease Burden
For most patients with localized FL, involved-site radiotherapy at 24-30 Gy remains preferred. Adding rituximab may improve progression-free survival at the cost of more treatment. Observation, rituximab monotherapy or very-low-dose radiotherapy are options when minimizing toxicity matters most, and bulky stage II disease may call for systemic treatment.
Active surveillance remains recommended for asymptomatic, low-tumor-burden advanced disease. Median time to first treatment is about three years, and immediate treatment has not shown an overall survival advantage. Rituximab monotherapy prolongs PFS and delays subsequent therapy, but randomized data show no reduction in transformation and no overall survival gain.
For patients who need treatment, anti-CD20-based immunochemotherapy (bendamustine, CHOP or CVP with rituximab or obinutuzumab) remains standard. In GALLIUM, obinutuzumab improved PFS over rituximab without improving overall survival, and toxicity was higher, including infection-related non-relapse mortality, particularly with bendamustine in older patients. The PFS advantage appeared mainly with intermediate- or high-risk FLIPI scores. Rituximab plus lenalidomide is a chemotherapy-free option: in RELEVANCE it produced outcomes comparable to immunochemotherapy but did not meet its prespecified superiority endpoint.
Anti-CD20 maintenance remains recommended after response to immunochemotherapy, using the induction antibody. In long-term PRIMA follow-up, rituximab maintenance extended median PFS from about four to ten years with no overall survival benefit. It may be delayed, shortened or omitted in patients with recurrent infections, particularly after bendamustine. The guidelines advise against the response-adapted strategy tested in FIL-FOLL12.
First Relapse: Randomized Data Change Selection
Treatment choice depends on the duration and quality of the prior response, disease kinetics, toxicity, comorbidities, availability and patient preference, with reassessment for transformation when indicated. Asymptomatic, low-tumor-burden relapse can continue under surveillance, and localized relapse can sometimes be treated with radiotherapy.
When systemic therapy is needed, rituximab plus lenalidomide (R2) remains an established option. Tafasitamab plus R2 (T-R2) and epcoritamab plus R2 (E-R2) each showed higher complete response rates, longer PFS and longer time to next treatment than R2 in large randomized trials. The guidelines grade T-R2 as I, B and E-R2 as I, A. These combinations may not be available in every European country, and some recommended agents lack European Medicines Agency approval for the relevant indication.
Patients who progress within 12-24 months of anti-CD20-based treatment are less likely to achieve prolonged control with conventional salvage. The guidelines discourage bendamustine in this setting when CAR T-cell therapy may follow, because prior exposure can compromise T-cell collection. ASCT receives a narrower recommendation, its benefit and curative potential are not established in the rituximab era.
Third Line and Beyond: BsAbs and CAR T
For symptomatic, high-tumor-burden disease after second relapse, the guidelines prioritize bispecific antibodies, CAR T-cell therapy, zanubrutinib plus obinutuzumab, and lenalidomide-based combinations. Immunochemotherapy remains an option for selected chemosensitive patients where novel agents are inaccessible. Repeated use of bendamustine is discouraged.
Three CD20×CD3 bispecific antibodies are approved in Europe for relapsed or refractory FL: mosunetuzumab, epcoritamab and odronextamab. In pivotal studies they produced overall response rates of about 80%-83% and complete response rates of 60%-73%, including in early-progressing and multiply refractory disease. Mosunetuzumab has the longest follow-up, with a median duration of response of 46.4 months at 54 months.
Indirect comparisons show no clear efficacy advantage for any one agent. Mosunetuzumab has a fixed-duration schedule and has shown activity on retreatment. Epcoritamab is given subcutaneously and has a favorable safety profile. In some lenalidomide-naive patients, E-R2 may be preferable to bispecific monotherapy.
Pivotal studies of axicabtagene ciloleucel, tisagenlecleucel and lisocabtagene maraleucel reported CAR T overall response rates of 86%-97% and complete response rates of 69%-94%. Axicabtagene ciloleucel has the most mature follow-up: median PFS of 57 months and median duration of response of 60 months.
These come from different trials and populations, with no randomized comparison. Axicabtagene ciloleucel carries higher rates of severe cytokine release syndrome and neurotoxicity, which makes it less suitable for older or frailer patients and those with neurologic comorbidities. After an anti-CD19 agent, rebiopsy should confirm CD19 expression before CAR T-cell therapy.
No optimal sequence of bispecifics and CAR T is established. For chemotherapy-resistant or early-progressing disease, CAR T-cell therapy may give the most durable control. Current evidence doesn’t show that prior bispecific treatment compromises later CAR T efficacy, so CAR T can be reserved until after a bispecific in many patients, but not in rapidly progressive or particularly high-risk disease. The evidence is largely indirect.
Follow-Up and Survivorship
About 90% of patients reach complete metabolic response after successful frontline therapy, and many don’t need indefinite specialist follow-up. Clinical review every three to six months during the first two years covers recurrence, complications, infection risk and quality of life, after which follow-up can be reduced, with minimal routine imaging and more patient-initiated review. Patients with multiply relapsed disease need closer, longer monitoring.
Survivorship care should address infections, immunoglobulin deficiency, vaccination, cardiovascular risk after anthracyclines, secondary malignancies, fertility and endocrine effects, fatigue and psychological well-being. Employment, financial strain and relapse anxiety also bear on the choice between maintenance, repeated fixed-duration therapy and cellular approaches.
