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Follicular Lymphoma

Lead: Lisa Chodirker
Date of last revision: August 31, 2020

Terms of use: These guidelines are a statement of consensus of the OCC Hematology site group regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult the Guidelines is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient's care or treatment. Use of this site and any information on it is at your own risk.

  1. Diagnosis and pathologic classification:

    Follicular Lymphoma (FL) is the second most frequent type of non-Hodgkin’s lymphoma (NHL), accounting for 20-25% of all presentations. It effects mainly older adults, with a median age of 65 years.

    The diagnosis of follicular lymphoma (FL) is dependent on an adequate biopsy specimen (incisional or excisional biopsy) of an involved lymph node or other extra-nodal tissue. The biopsy is evaluated for morphology, immunohistochemistry and flow cytometry.

    Follicular lymphoma grading, based on the number of centroblasts per high-power field(HPF):

    • Grade 1, 0-5 centroblasts/HPF
    • Grade 2, 6-15 centroblasts/HPF
    • Grade 3A, >15 centroblasts/HPF, centrocytes present
    • Grade 3B, >15 centroblasts/HPF, sheets of centroblasts
      • Grade 3B is managed as diffuse large B-cell lymphoma

  2. Baseline testing:

    • Full history and physical including performance status/frailty index and documentation of B symptoms
    • CBC, electrolytes, creatinine, LFTs (Bilirubin, ALT, ALP), albumin, LDH
    • Hepatitis B (including core antibody) & C screening
    • HIV serology if risk factors present
    • CT head, neck, chest, abdomen & pelvis
    • FDG-PET if limited stage by CT and potential candidate for curative radiation
    • Bone marrow aspirate and biopsy
    • TB skin test
    • MUGA scan or 2D echo ( if doxorubicin appropriate, age >60 or with cardiovascular risk factors)
    • Pathology review if not reported at Sunnybrook or UHN

  3. Staging and prognostic factors:

    Patients should be staged according to the Ann Arbor staging system:

    Stage:

    1. Single lymph node region (1) or single localized extranodal site (1E)
    2. Two or more lymph node regions, same side of the diaphragm (2) or local extranodal involvement in two or more regions, same side of the diaphragm (2E)
    3. Lymph node regions on both sides of the diaphragm (3) which may be accompanied by local extranodal extension (3E)
    4. Diffuse involvement of one or more extranodal organs or sites (4)

    Symptoms

    1. = no B symptoms
    2. = presence of at least one of these
      1. unexplained weight loss > 10% baseline during 6 months prior to staging
      2. recurrent unexplained fever > 38oC
      3. recurrent night sweats
      Bulky tumour is defined as a single mass of tumour tissue 10 cm or larger in largest diameter.

    Prognosis

    The Follicular Lymphoma International Prognostic Index (FLIPI)

    Five adverse prognostic factors were identified:

    1. Age > 60 years
    2. Stage – III/IV
    3. LDH above normal
    4. Number of Nodal areas > 4
    5. Hemoglobin < 120g/L


    Outcome and relative risk of death according to risk group as defined by the Follicular Lymphoma International Prognostic Index:

    Risk Group Number of adverse factors Distribution of patients, % 5-year OS, % 10-year OS, % RR 95% CI
    Low 0-1 36 90.6 70.7 1.0 NA
    Intermediate 2 37 77.6 50.9 2.3 1.9-2.8
    High >= 3 27 52.5 35.5 4.3 3.5-5.3

    The FLIPI was developed prior to the routine use of Rituximab containing regimens as initial therapy. The Follicular Lymphoma International Prognostic Index 2 (FLIPI-2) This prognostic index was developed using a cohort of patients that largely received chemoimmunotherapy with Rituximab and is applied at the time of first therapy. Similar to the FLIPI, 5 prognostic factors were identified:
    • Age > 60
    • Lymph node diameter > 6cm
    • Hemoglobin < 120 g/L
    • Bone marrow involvement
    • Elevated B-2 microglobulin

    Risk Group Number of adverse factors 3-year PFS, % 5-year PFS, %
    Low 0 91 80
    Intermediate 1-2 69 51
    High 3-5 51 19

  4. Treatment:

    Follicular lymphoma

    Stage I/II:

    Involved field radiotherapy (IFRT) 24 Gy in 12 fractions

    Consider chemotherapy alone for patients with B symptoms, IIA with extensive disease or bulk > 5cm

    Patients with localized disease (stage I/II) at presentation may be cured with radiotherapy.

    Stage III/IV:

    The majority of patients with FL have advanced disease at presentation and remain incurable with present therapeutic approaches. Management options include:

    Observation (“watch and wait”)

    Multiple trials have demonstrated that initial therapy offers no advantage in patients with advanced, but asymptomatic disease ref. However, this does not apply to patients who fulfill any of the below criteria:

    BNLI Criteria

    • Hematopoietic impairment (Hb<100g/L, WBC<3x109/L, platelets <100 x 109/L)
    • Pruritis or B symptoms
    • Rapidly progressing lymphoma within three months
    • Life endangering organ involvement
    • Localized bone lesions
    • Renal infiltration
    • Macroscopic liver involvement


    GELF Criteria

    • Involvement of 3 nodal sites each with diameter of 3cm
    • Any nodal or extra-nodal mass 7cm in diameter
    • B symptoms
    • Splenomegaly
    • Pleural effusion or ascites
    • Cytopenias: WBC <1.0 x109/L or platlets ,100x109/L
    • Leukemic phase of disease with >5.0x109/L

    Systemic Therapy
    • If symptomatic or meeting above criteria
    • Bendamustine 90mg/m2 days 1+2 and Rituximab 375mg/m2 day 1, q28 days x 6 cycles (BR)
    • For patients with CR/PR – maintenance Rituximab 375mg/m2 q3mos x 8 cycles (2 years)
    • Other options for treatment include R-CVP, R-lenalidomide or oral alkylating agents such as chlorambucil if the patient is not suitable for BR

    Radiation Therapy
    • IFRT 4Gy in 2 fractions for symptom control or 20-30Gy in 5-15 fractions for local control, for patients with bulky disease

    Response assessment:

    • At 1 month post treatment
    • Perform CT scans of previously involved areas and physical examination
    • Consider a repeat BM biopsy if previously positive, to document CR or to investigate persistent cytopenias
    • Consider CT scans after one year of maintenance Rituximab to ensure ongoing benefit or following completion of maintenance treatment to document new baseline


    Follow-up:

    • Patients with advanced stage disease should have indefinite follow up as recurrence is inevitable
    • Patients should be followed every 3-4 months for the first 2 years and every 6-12 months thereafter
    • Assessment at each visit should include: history and physical exam, ECOG status, CBC, Creatinine, LDH
    • Imaging should be reserved for symptomatic patients or those with evidence of biochemical abnormalities that may suggest disease relapse
    • Counselling on physical and psychosocial issues, smoking cessation, age-appropriate cancer screening, immunizations

    Relapsed Disease

    • Relapse with follicular lymphoma is inevitable in patients with advanced disease. Relapse with both indolent or aggressive histology (transformation) may occur.
    • Biopsy should be performed if suspicion of transformation based on clinical behaviour, evidence of rapid growth or discordant growth between various disease sites
    • Early relapse, which occurs in approx. 20% of patients, is defined as FL recurrence within 2 years of chemoimmunotherapy or within 2 years of diagnosis and is one of the best predictors of poor survival


    Treatment of relapsed disease

    • There is currently no standard second line treatment for FL – options include:
    • Clinical trials
    • Bendamustine and Obinutuzumab with Obinutuzumab maintenance – for Rituximab refractory, currently funded in Ontario
    • Chemotherapy and Rituximab retreatment – if Rituximab responsive
    • Autologous stem cell transplant (ASCT) – consider in patients with early relapse
    • PI3K inhibitors (eg. Idelalisib) – relapsed/refractory after 2 prior therapies
    • Lenalidomide +/- Rituximab
    • Rituximab

Useful resources

Key references:

  • Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pilari SA, Stein H, Thiele J, Vardimen JW. WHO classification of tumours of haematopoietic and lymphoid tissues. In: World Health Organization Classification of Tumours. Lyon, France: IARC Press, 2016
  • Solal-Celigny, P., et al. Follicular lymphoma international prognostic index. Blood, 2004. 104(5): p.1258-65.
  • Massimo Federico, Monica Bellei, Luigi Marcheselli, Stefano Luminari, et al. Follicular Lymphoma International Prognostic Index 2: A New Prognostic Index for Follicular Lymphoma Developed by the International Follicular Lymphoma Prognostic Factor Project. Journal of Clinical Oncology 2009 27:27, 4555-4562.
  • McNamara C, Davies J, Dyer M, Hoskin P, Illidge T, Lyttelton M, et al. Haemato-oncology Task Force of the British Committee for Standards in Haematology (BCSH); British Society for Haematology Committee. Guidelines on the investigation and management of follicular lymphoma. Br J Haematol. 2012;156(4):446–67.
  • Brice P, Bastion Y, Lepage E, Brousse N, Haïoun C, Moreau P, et al.Comparison in low-tumor-burden follicular lymphomas between an initial no-treatment policy, prednimustine, or interferon alfa: a randomized study from the Groupe d’Etude des Lymphomes Folliculaires. Groupe d’Etude des Lymphomes de l’Adulte. J Clin Oncol. 1997;15(3):1110–7.
  • Marcus, R. et al. CVP chemotherapy plus Rituximab compared with CVP as first-line treatment for advanced follicular lymphoma. Blood, 2005. 105(4): p.1417-23.
  • Pendlebury, S. et al. Radiotherapy results in early stage low grade nodal non-Hodgkin’s lymphoma. Radiother Oncol, 1995. 36(3):p.167-71.
  • Illidge T et al. Modern radiation therapy for nodal non-hodgkin lymphoma: Targetdefinition and dose guidelines from the International lymphoma radiation oncology group. Int J Radiat Oncol Biol Phys 2014, 89:49-58.
  • Ardeshna KM, Qian W, Smith P, et al. Rituximab versus a watch-and-wait approach in patients with advanced-stage, asymptomatic, non-bulky follicular lymphoma: an open-label randomized phase 3 trial. Lancet Oncol. 2014;15(4):424-35
  • Czuczman MS, Weaver R et al. Prolonged clinical and molecular remisiion in patients with low grade or follicular non-Hodgkin’s lymphoma treated with rituximab plus CHOP chemotherapy: 9-year follow up. J CLin Oncol 2004:22:4711-4716.
  • Salles G, Symour JF, Offner F, et al. Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomized controlled trial. Lancet 2011;377(9759(:42-51.
  • Rummel MJ, Niederle N et al. Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicenter, randomized, phase 3 non-inferiority trial. Lancet. 2013; 381(9873):1203-10.
  • Federico M, Luminari S, et al. R-CVP versus R-CHOP veresus R-FM for the initial treatment of patients with advanced-stage follicular lymphoma: results of the FOLL05 trial conducted by the Fondazione Italiana Linfomi. J Clin Oncol. 2013; 31(12):1506-13.
  • Sehn LH, Chua N, Mayer J, et al. Obinutuzumab plus bendamustine versus bendamustine monotherapy in patients with rituximab-refractory indolent non-Hodgkin lymphoma (GADOLIN): a randomized, controlled, open-label, multicenter, phase 3 trial. Lancet Oncol 2016;17:1081-1093.
  • Cheson BD, Chua N, Mayer J, et al. Overall survival benefit in patients with rituximab-refractory indolent non-Hodgkin lymphoma who received obinutuzumab plus bendamustine induction and obinutuzumab maintenance in the GADOLIN study. J Clin Oncol. 2018 Aug 1;36(22):2259-66.
  • Gopal A, Kahl B, De Vos S, et al. PI3K inhibition by idelalisib in patients with relapsed indolent lymphoma. N Engl J Med 2014;370:1008-1018.
  • Witzig TE et al. Lenalidomide oral monotherapy produces durable responses in relapsed or refractory indolent non-Hodgkin’s Lymphoma. J Clin Oncol 2009;27:5404-5409.
  • Morschhauser F, Fowler NH et al. Rituximab plus lenalidomide in advanced untreated follicular lymphoma. N Engl J Med. 2018; 379(10):934-947.
  • McLaughlin P, et al. Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to four-dose treatment program. J CLin Oncol 1998;16:2825-2833.
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