Guideline sources The following summarized guidelines for the evaluation and management of follicular lymphoma (FL) are prepared by our editorial team based on guidelines from the European Society of Medical Oncology (ESMO 2021), the British Society for Haematology (BSH 2020), the Italian Group for Bone Marrow Transplantation (GITMO/SIES/SIE 2013), and the Spanish Society of Hematology and Hemotherapy (SEHH 2011). 1 2 3 4 Calculator Calculator Calculat Eastern Cooperative Oncology G Follicular Lymphoma Internation Karnof Guidelines 1. Classification and risk stratification Staging: https://web.pathway.md/diseases/recDXKYKrAxy8Ttc2 1/8 6/29/23, 4:07 AM Follicular lymphoma Pathway As per ESMO 2021 guidelines, use the Ann Arbor classification system for the initial staging of FL. E As per SIE 2013 guidelines, use the Ann Arbor system for staging FL. E Prognostic scores: As per ESMO 2021 guidelines, consider using the Follicular Lymphoma International Prognostic Index 1/2 and PRIMA prognostic index risk factors for prognostic purposes. E As per SIE 2013 guidelines, assess the Follicular Lymphoma International Prognostic Index prognostic score in all patients with FL. E 2. Diagnostic investigations Imaging for staging: As per ESMO 2021 guidelines: Obtain CT of the neck, chest, and abdomen in the initial evaluation of patients with FL. E Obtain positron emission tomography-CT for routine staging B and to confirm localized stage I/II disease before involved-site radiotherapy. E As per BSH 2020 guidelines, obtain FDG-positron emission tomography/CT before initiating treatment in patients with newly diagnosed FL. Consider obtaining contrast-enhanced CT. E As per SIE 2013 guidelines: Obtain CT of the neck, chest, abdomen, and pelvis in the initial evaluation and staging of patients with FL. Obtain positron emission tomography for staging of patients with a limited- stage disease on CT and possibly being candidates for radiotherapy only. Recognize that FL is a FDG-avid disease and positron emission tomography allows the identification of a higher number of nodal and extranodal areas compared with CT. E Consider obtaining pre-treatment positron emission tomography to allow an optimal assessment of response in patients requiring chemotherapy if an early-stage disease (stage II) and therapy fitness make the probability of complete remission high. E Laboratory evaluation: As per ESMO 2021 guidelines, obtain CBC, routine blood chemistry (including immunoglobulin levels, LDH, -2-microglobulin, and uric acid), and screening tests for human immunodeficiency virus, HBV, and HCV in patients with FL. E As per BSH 2020 guidelines, obtain the following baseline laboratory tests before initiating immunochemotherapy in patients with FL: CBC flow cytometry on blood (or bone marrow aspirate) if peripheral blood lymphocytosis or abnormal lymphocytes are seen on blood film urea, creatinine, and electrolytes LFTs including albumin calcium, phosphate uric acid LDH https://web.pathway.md/diseases/recDXKYKrAxy8Ttc2 2/8 6/29/23, 4:07 AM Follicular lymphoma Pathway -2 microglobulin hepatitis B (surface antigen and core antibody), hepatitis C and human immunodeficiency virus. E As per SIE 2013 guidelines, obtain CBC and routine blood chemistry, including LDH, -2 microglobulin, and uric acid in patients with FL. E Show 2 more Cardiac evaluation: as per BSH 2020 guidelines, consider obtaining an ECG and echocardiography before initiating anthracycline-containing chemotherapy in patients aged > 70 years and/or with a history of cardiac disease including ischemic heart disease, hypertension, or diabetes. E 3. Diagnostic procedures Biopsy and histopathology: As per ESMO 2021 guidelines, perform surgical specimen/excisional lymph node biopsy for the diagnosis of FL. Consider performing core biopsies if lymph nodes are not easily accessible. E Show 2 more As per BSH 2020 guidelines, perform bone marrow aspiration and trephine biopsy for staging in patients with newly diagnosed FL. Consider reviewing this after discussion with the patient if it will not alter therapy. Take into consideration the impact of this decision on prognostic score calculations and access to clinical trials. E As per SIE 2013 guidelines, perform a bone marrow biopsy in the initial evaluation and staging of patients with FL. E Show 2 more 4. Medical management General principles: treat FL grade IIIb as an aggressive lymphoma, whereas grades 1, 2, and 3A as an indolent disease. E Management of localized disease, watchful waiting: As per ESMO 2021 guidelines: Consider offering a watch-and-wait strategy or rituximab monotherapy in selected patients with localized (stage I-II) FL. C Offer observation in patients with duodenal-type FL only as long as asymptomatic. B As per BSH 2020 guidelines, consider offering observation without involved-site radiotherapy in patients with limited stage FL undergone localized excision and where there may be concerns by the clinician or patient about radiotherapy to a particular site. E As per GITMO/SIES/SIE 2013 guidelines, do not offer watchful waiting in patients with stage I-II disease, with the exception of patients with a short life expectancy due to severe comorbidity or with contraindications to therapy. D Management of localized disease, involved-site radiotherapy: https://web.pathway.md/diseases/recDXKYKrAxy8Ttc2 3/8 6/29/23, 4:07 AM Follicular lymphoma Pathway As per ESMO 2021 guidelines, offer involved-site radiotherapy with a dose of 24-30 Gy as the preferred approach in patients with localized FL, B and consider combining with single- agent rituximab. B As per BSH 2020 guidelines, offer involved-site radiotherapy with a dose of 24 Gy in 12 daily fractions in patients with limited stage FL that can be encompassed within a radiotherapy field. E As per GITMO/SIES/SIE 2013 guidelines, offer external involved-field radiotherapy at the dose of 24 Gy in patients with stage I-II disease, low tumor burden, and with documented contiguity of involved lymph nodes treatable in the same radiotherapy field. B Management of localized disease, systemic therapy: As per ESMO 2021 guidelines, offer systemic therapy (as indicated in patients with advanced stages) in patients with stage I-II FL with a high tumor burden, adverse clinical prognostic features, or if involved-site radiotherapy is not feasible. B As per GITMO/SIES/SIE 2013 guidelines, offer chemoimmunotherapy in patients with stage II disease when there is a high tumor burden or a high-risk scoring system. B Management of advanced disease, general principles: As per BSH 2020 guidelines: Consider offering enrolment in a clinical trial, if available. E Assess the GELF criteria in all patients with advanced stage FL to assess the requirement of treatment. E As per GITMO/SIES/SIE 2013 guidelines, consider initiating treatment in patients with stage II-IV disease in case of any of the following: systemic symptoms high tumor burden (> 3 lymph nodes measuring > 3 cm or a single lymph node > 7 cm) extranodal disease cytopenia due to marrow involvement spleen involvement ( 16 cm by CT) leukemic phase serous effusion symptomatic or life-endangering organ involvement rapid lymphoma progression consistently increased LDH levels. E Management of advanced disease, watchful waiting: As per ESMO 2021 guidelines, offer a watch-and-wait strategy as a standard approach in patients with asymptomatic advanced (stage III-IV) FL. A As per BSH 2020 guidelines, consider offering observation alone or rituximab monotherapy in patients with asymptomatic, advanced-stage FL. E As per GITMO/SIES/SIE 2013 guidelines, offer watchful waiting as the standard of care in patients with asymptomatic, stage II-IV, non-bulky disease. B Management of advanced disease, induction of remission: https://web.pathway.md/diseases/recDXKYKrAxy8Ttc2 4/8 6/29/23, 4:07 AM Follicular lymphoma Pathway As per ESMO 2021 guidelines, initiate therapy only upon the development of symptoms, including B symptoms, hematopoietic impairment, bulky disease, vital organ compression, ascites, pleural effusion, or rapid lymphoma progression. A Show 4 more As per BSH 2020 guidelines: Consider offering induction rituximab monotherapy in patients with asymptomatic, advanced-stage FL. E Offer rituximab or obinutuzumab with chemotherapy in patients requiring treatment. Decide on the chemotherapy options with which the antibody should be paired (such as bendamustine, chlorambucil, CHOP, CVP) depending on patient factors and clinician choice. E As per GITMO/SIES/SIE 2013 guidelines, offer front-line chemoimmunotherapy in patients with stage III-IV disease. B Show 3 more Management of advanced disease, maintenance of remission: As per ESMO 2021 guidelines: Offer rituximab maintenance every 2 months for 2 years after immunochemotherapy. B Consider offering radioimmunotherapy consolidation after chemotherapy as an alternative. B Do not offer myeloablative consolidation followed by ASCT after chemotherapy as first-line therapy in responding patients. D As per BSH 2020 guidelines: Consider offering rituximab or obinutuzumab (whichever antibody was used in induction) maintenance for a period of 2 years in patients responding to therapy (partial or complete response) after discussing the risks and benefits with the patient. E Do not offer high-dose therapy with ASCT as first-line therapy in patients with FL. D As per GITMO/SIES/SIE 2013 guidelines, offer maintenance therapy with rituximab in patients reaching at least a partial response at the end of first-line therapy. A 5. Preventative measures Antibiotic prophylaxis: administer adequate prophylaxis (antibiotics and/or IgG) in patients with symptomatic recurrent infections based on prior treatment (such as with fludarabine or bendamustine). E Routine immunizations: consider offering annual seasonal influenza vaccination in patients with FL. E 6. Follow-up and surveillance Serial clinical assessment: As per ESMO 2021 guidelines: https://web.pathway.md/diseases/recDXKYKrAxy8Ttc2 5/8 6/29/23, 4:07 AM Follicular lymphoma Pathway Obtain clinical monitoring every 6 months for 2 years after local radiotherapy, and once a year subsequently if clinically indicated. E Obtain clinical monitoring every 3-6 months for 2 years after (during continuous) systemic treatment, and every 6-12 months subsequently. B As per BSH 2020 guidelines, obtain regular clinical assessments modified according to the disease behavior. E Serial laboratory assessment: As per ESMO 2021 guidelines: Obtain CBC and routine chemistry including IgG levels every 6 months for 2 years, thereafter only as needed for evaluation of suspicious symptoms. E Obtain evaluation of thyroid function at 1, 2, and 5 years after neck irradiation. E As per BSH 2020 guidelines: Consider obtaining CBC, urea, creatinine, and LFTs at each clinical visit. Do not measure LDH levels routinely. E Obtain annual thyroid function testing in patients undergone neck irradiation. E As per SIE 2013 guidelines, do not obtain routine assessments of molecular response. D Serial imaging assessment: As per ESMO 2021 guidelines: Obtain minimal adequate radiological or other examinations every 6 months for 2 years, and optionally annually up to 5 years. B Avoid obtaining regular CT outside of clinical trials, and do not obtain positron emission tomography-CT for surveillance. D As per BSH 2020 guidelines, obtain post-treatment cross-sectional imaging only in case of suspicion of relapse requiring treatment (such as clinically significant lymphadenopathy not attributable to another cause, or B symptoms). E As per SIE 2013 guidelines: Insufficient evidence to recommend interim positron emission tomography for guiding treatment decisions. I Do not obtain routine positron emission tomography for follow-up. D Assessment of minimal residual disease: consider obtaining minimal residual disease screening in a clinical trial setting but not for guiding therapeutic strategies in clinical practice. E Management of relapse, biopsy: As per ESMO 2021 guidelines, perform a new confirmatory biopsy in patients with suspected disease relapse or progression. E As per BSH 2020 guidelines, perform biopsy, wherever practicable, to assess for high-grade transformation in patients with suspected relapsed FL. E Management of relapse (watchful waiting): consider offering observation alone in asymptomatic patients with relapsed disease lacking standard indications for therapy. E Management of relapse, radiotherapy: https://web.pathway.md/diseases/recDXKYKrAxy8Ttc2 6/8 6/29/23, 4:07 AM Follicular lymphoma Pathway As per ESMO 2021 guidelines, consider offering low-dose involved-site radiotherapy (2 2 Gy) for the management of patients with localized symptomatic disease. E As per BSH 2020 guidelines, consider offering low-dose radiotherapy for symptom control in patients with relapse. E Management of relapse, systemic therapy: As per ESMO 2021 guidelines, offer a non-cross-resistant regimen in early systemic relapses (< 12-24 months). E Show 8 more As per BSH 2020 guidelines, consider offering enrolment in a clinical trial, especially in patients with early progression following primary therapy. E Show 7 more As per GITMO/SIES/SIE 2013 guidelines, add rituximab to chemotherapy as reinduction if there is no evidence of resistance to rituximab in fit patients relapsing after first-line chemoimmunotherapy and requiring treatment. B Show 2 more Management of relapse, stem cell transplantation: As per ESMO 2021 guidelines, consider offering allo-SCT in selected younger patients with later relapses with a high-risk profile or relapse after ASCT. C As per BSH 2020 guidelines, consider offering early referral for transplantation in fit patients with shorter durations of response following first-line therapy. E Show 7 more As per GITMO/SIES/SIE 2013 guidelines, offer ASCT is recommended in young (< 65 years old) fit patients relapsing within 12 months from the end of front-line chemoimmunotherapy and achieving a response to chemoimmunotherapy reduction. E Show 2 more Clinical findings Symptoms Past medical history Fatigue Gastrointestinal bleeding Fever Abdominal exam Night sweats Weight loss Ascites Hepatomegaly Head and neck exam Palpable abdominal mass Neck mass Splenomegaly Lymphatic exam Lab findings Axillary lymphadenopathy serum LDH Cervical lymphadenopathy Imaging findings Femoral lymphadenopathy Inguinal lymphadenopathy Epidural mass https://web.pathway.md/diseases/recDXKYKrAxy8Ttc2 7/8 6/29/23, 4:07 AM Follicular lymphoma Pathway Lymphadenopathy Hilar lymphadenopathy Mediastinal lymphadenopathy Hematological findings Pleural effusion Spinal cord compression Anemia blood leukocyte count blood platelet count Studies 2020 TRIST In patients with hematologic malignancies requiring hematopoietic cell transplantation, restrictive strategy was noninferior to liberal strategy with respect to a health-related quality of life measured by Functional Assessment of Cancer Therapy-BMT score at day 100. Jason Tay et al. J Clin Oncol. 2020 May 1. References 1. M Dreyling, M Ghielmini, S Rule et al. Newly diagnosed and relapsed follicular lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2021 Mar;32 3 298 308. Open 2. Armando L pez-Guillermo, Dolores Caballero, Miguel Canales et al. Clinical practice guidelines for first-line/after-relapse treatment of patients with follicular lymphoma. Leuk Lymphoma. 2011 Dec;52 Suppl 3 1 14. Open 3. Christopher McNamara, Silvia Montoto, Toby A Eyre et al. The investigation and management of follicular lymphoma. Br J Haematol. 2020 Nov;191 3 363 381. Open 4. Pier Luigi Zinzani, Monia Marchetti, Atto Billio et al. SIE, SIES, GITMO revised guidelines for the management of follicular lymphoma. Am J Hematol. 2013 Mar;88 3 185 92. Open 5. Qiushi Chen, Turgay Ayer, Loretta J Nastoupil et al. Initial management strategies for follicular lymphoma. Int J Hematol Oncol. 2012 Oct; 1 1 35 45. Open 6. M Hutchings, M Ladetto, C Buske et al. ESMO Consensus Conference on malignant lymphoma: management of 'ultra-high-risk' patients. Ann Oncol. 2018 Aug 1;29 8 1687 1700. Open 7. Abraham S Kanate, Ambuj Kumar, Peter Dreger et al. Maintenance Therapies for Hodgkin and Non- Hodgkin Lymphomas After Autologous Transplantation: A Consensus Project of ASBMT, CIBMTR, and the Lymphoma Working Party of EBMT. JAMA Oncol. 2019 May 1;5 5 715 722. Open 8. Steven H Kroft, Cordelia E Sever, Adam Bagg et al. Laboratory Workup of Lymphoma in Adults: Guideline From the American Society for Clinical Pathology and the College of American Pathologists. Arch Pathol Lab Med. 2021 Mar 1;145 3 269 290. Open 9. C Buske, M Hutchings, M Ladetto et al. ESMO Consensus Conference on malignant lymphoma: general perspectives and recommendations for the clinical management of the elderly patient with malignant lymphoma. Ann Oncol. 2018 Mar 1;29 3 544 562. Open 10. Philippe Solal-C ligny, Pascal Roy, Philippe Colombat et al. Follicular lymphoma international prognostic index. Blood. 2004 Sep 1;104 5 1258 65. Open https://web.pathway.md/diseases/recDXKYKrAxy8Ttc2 8/8