Updated ESMO guidelines for diagnosis, treatment, and follow-up of newly diagnosed and relapsed follicular lymphoma

In November 2020, the European Society for Medical Oncology (ESMO) Guidelines Committee issued an update of their Clinical Practice Guidelines for newly diagnosed and relapsed follicular lymphoma (FL), which was published in the March 2021 edition of Annals of Oncology.¹

Below, we highlight the key recommendations from the ESMO Guidelines Committee regarding the diagnosis, staging, treatment, and follow-up for FL.

Diagnosis and pathology/molecular biology

• Diagnosis should be based on a surgical specimen/excisional lymph node biopsy, with rebiopsy advised if the material is inadequate.
• Core biopsies should be restricted to patients without easily accessible lymph nodes.
• Pathological review by an expert hematopathologist is recommended, particularly for Grade 3A or 3B
• Grades 1, 2, and 3A should be treated as indolent disease, and Grade 3B as aggressive lymphoma.

Staging and risk assessment

• Thorough initial staging following the Ann Arbor classification system is important, and bone marrow aspirate and biopsy, alongside a computerized tomography (CT) scan of the neck, thorax, and abdomen, should be included in the work-up.
• Positron emission tomography (PET)-CT scanning is mandatory to confirm localized Stage I/II disease before involved-site radiotherapy (ISRT) and is also recommended for routine staging.
• Complete blood count, routine blood chemistry (including measurement of immunoglobulin [Ig], lactate dehydrogenase, β2-microglobulin, and uric acid levels), and screening for human immunodeficiency virus and hepatitis B and C are all required.
• Regarding prognosis, the FL International Prognostic Index (FLIPI), FLIPI2, and the simplified PRIMA Prognostic Index (PRIMA-PI) can be used.

Treatment of localized FL (Stages I–III)

• In patients with low tumor burden and Stage I–II FL, ISRT with 24–30 Gy is preferred, combined with single-agent rituximab.
• In cases such as limited life expectancy or large abdominal fields, an observational approach or rituximab monotherapy can be considered.
• In patients with Stage I–II FL and high tumor burden, adverse clinical prognostic features, or where ISRT is not feasible, systemic therapy should be discussed.

Treatment of advanced FL (Stages III–IV)

First-line treatment

Induction

• Therapy should only be initiated upon the development of symptoms such as B symptoms (unexplained fever > 38°C, night sweats or loss of > 10% body weight within 6 months), hematopoietic impairment, bulky disease, vital organ compression, ascites, pleural effusion, or rapid lymphoma progression.
• If the therapeutic goals are complete remission and long progression-free survival, then treatment is to include obinutuzumab or rituximab in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or bendamustine.
• With evidence of an aggressive clinical course, obinutuzumab/rituximab-CHOP should be administered.
• Consider extended prophylaxis with an anti-infective agent if induction therapy includes bendamustine.
• For patients with a low risk profile, or if conventional chemotherapy is contraindicated, antibody monotherapy (rituximab, radioimmunotherapy) or chlorambucil plus rituximab are favored alternatives.
• Prophylaxis with antiviral medication for up to 2 years after last rituximab exposure is strongly recommended in patients with positive hepatitis B serology.

Consolidation/maintenance

• Rituximab maintenance every 2 months for 2 years is suggested post induction or radioimmunotherapy.
• Myeloablative consolidation followed by autologous hematopoietic stem cell transplant (auto-HSCT) is not recommended first line in responding patients.

Relapsed disease

• A confirmatory biopsy should be obtained if disease relapse or progression is suspected.
• In asymptomatic patients with low tumor burden, an observational approach is acceptable.

Induction

• Localized symptomatic disease can be managed with low-dose ISRT.
• In early systemic relapses of up to 2 years, a regimen which is not cross-resistant is preferred.
• If the previous antibody-containing regimen achieved > 6–12 months of remission then rituximab should be added, however in rituximab-refractory cases or remissions lasting < 6 months, obinutuzumab-bendamustine plus obinutuzumab maintenance is recommended.
• Rituximab monotherapy may be sufficient if tumor burden is low.
• In patients with short remissions following chemotherapy, lenalidomide plus rituximab can be considered.
• Radioimmunotherapy can be effective in elderly patients with comorbidities.
• A non–chemotherapy-based approach is favored for later relapses, such as lenalidomide plus rituximab or idelalisib in double-refractory FL, however anti-infectious prophylaxis with co-trimoxazole/acyclovir and cytomegalovirus monitoring are strongly recommended.

Consolidation/maintenance

• Rituximab maintenance every 3 months for up to 2 years is recommended.
• Discuss high-dose chemotherapy with auto-HSCT, particularly in patients who experience brief first remissions after regimens with rituximab.
• Allogeneic HSCT in selected younger patients with a high-risk profile and later relapses, or those who relapse after auto-HSCT, may be curative.

Response evaluation

• Structural imaging should be performed mid-treatment and on completion of chemotherapy, with early salvage regimens considered in patients with inadequate responses.

Personalized medicine

• Treatment selection is currently based on clinical risk factors, symptoms, and the wishes of the patient.
• Pediatric FL should be managed with local therapy, despite its histologically aggressive features.
• An observational approach is suitable for duodenal-type FL if asymptomatic.

Follow-up, long-term implications, and survivorship

• Recommendations for post-therapy follow-up are based on consensus rather than evidence.
• After local radiotherapy, history and physical examination should take place every 6 months for 2 years, then once a year if clinically indicated.
• In patients with irradiation of the neck, thyroid function should be assessed 1, 2, and 5 years after treatment.
• After systemic treatment, history and physical examination should be performed every 3–6 months for 2 years, then every 6–12 months.
• Assessment of blood count and routine laboratory parameters, including IgG levels, every 6 months for 2 years was suggested, then as needed if symptoms are suspicious.
• Radiological and other examinations should take place every 6 months for 2 years, then annually for up to 5 years if necessary, however it was noted that regular CT scans are not mandatory, and PET-CT should not be used for surveillance.
• Screening of measurable (minimal) residual disease to guide therapeutic strategies is not recommended in clinical settings yet, although this may occur within clinical trials.
• In patients with symptomatic recurrent infections, adequate prophylaxis with antibiotics and/or IgG supplementation is supported, based on prior treatment, alongside annual seasonal flu vaccination.