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

Published:November 26, 2020DOI:https://doi.org/10.1016/j.annonc.2020.11.008

      Highlights

      • This updated ESMO Clinical Practice Guideline provides key recommendations on the management of follicular lymphoma.
      • Authorship includes a multidisciplinary group of experts from different institutions and countries in Europe and abroad, including levels of evidence and grades of recommendation where applicable.
      • In localised stages, combination of radiation and rituximab monotherapy may be considered.
      • In advanced stages, either obinutuzumab or rituximab may be combined with chemotherapy.
      • In early relapses, a switch of chemotherapy and antibody is recommended. In younger patients, an autologous stem-cell transplantation should be discussed.
      • In older patients with either early, first or later relapses, lenalidomide in combination with rituximab may be considered.

      Key words

      Incidence and epidemiology

      Follicular lymphomas (FLs) are the second most frequent subtype of lymphoid malignancies in Western Europe. The annual incidence of this disease has risen from 2-3/100 000 during the 1950s to 5/100 000 recently, without clear explanation.
      • Mounier M.
      • Bossard N.
      • Remontet L.
      • et al.
      Changes in dynamics of excess mortality rates and net survival after diagnosis of follicular lymphoma or diffuse large B-cell lymphoma: comparison between European population-based data (EUROCARE-5).

      Diagnosis and pathology/molecular biology

      Diagnosis should be based on a surgical specimen/excisional lymph node (LN) biopsy. Core biopsies should only be carried out in patients without easily accessible LNs (e.g. retroperitoneal), to evaluate possible transformation at such sites. Keeping in mind the possible heterogeneity of FL, histological grading can be difficult to appreciate on core biopsies and rebiopsy may be required if the material is not adequate. Fine-needle aspirations are insufficient for a reliable primary diagnosis.
      The histological report should give the diagnosis according to the current World Health Organization classification.
      Histological grading of LN biopsies is carried out according to average number of centroblasts/high-power field (Table 1). FL grade IIIb (with sheets of centroblasts) is considered an aggressive lymphoma and treated as such,
      • Tilly H.
      • Gomes da Silva M.
      • Vitolo U.
      • et al.
      Diffuse large B-cell lymphoma (DLBCL): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.
      whereas grades 1, 2 and 3A should be treated as indolent disease.
      • Ott G.
      • Katzenberger T.
      • Lohr A.
      • et al.
      Cytomorphologic, immunohistochemical, and cytogenetic profiles of follicular lymphoma: 2 types of follicular lymphoma grade 3.
      Pathological review, especially of grade 3A or 3B, by an expert hematopathologist is advised.
      Table 1Grading of FL
      Reprinted from Swerdlow et al.
      with permission.
      GradeDescription
      1≤5 blasts/HPF
      26-15 blasts/HPF
      3A>15 blasts/HPF, centroblasts with intermingled centrocytes
      3B>15 blasts/HPF, pure sheets of blasts
      FL, follicular lymphoma; HPF, high-power field.

       Recommendations

      • Diagnosis should be based on a surgical specimen/excisional LN biopsy. Core biopsies should only be carried out in patients without easily accessible LNs.
      • Pathological review by an expert hematopathologist, especially for grade 3A or 3B, is advised.
      • FL grade IIIb should be treated as an aggressive lymphoma, whereas grades 1, 2 and 3A should be treated as indolent disease.

      Staging and risk assessment

      Because treatment largely depends on the stage of the disease, initial staging should be thorough, particularly in the small proportion of patients with apparent early stages I and II (10%-15%) (Table 2). Initial work-up should include a bone marrow (BM) aspirate and biopsy of sufficient size (at least 20 mm), and a computed tomography (CT) scan of the neck, thorax and abdomen (Table 3). Positron emission tomography (PET)–CT improves the accuracy of staging for nodal and extranodal sites and thus is recommended for routine staging in FL [IV, C] (in such instances a separate diagnostic CT scan is not required).
      • Cheson B.D.
      • Fisher R.I.
      • Barrington S.F.
      • et al.
      Recommendations for initial evaluation, staging and response assessment of Hodgkin and non-Hodgkin lymphoma – the Lugano Classification.
      A PET-CT scan is mandatory to confirm localised stage I/II disease before involved-site radiotherapy (ISRT).
      Table 2Ann Arbor classification
      Reprinted from Swerdlow et al.
      with permission.
      StageArea of involvement
      I (IE)One LN region or extralymphatic site (IE)
      II (IIE)Two or more LN regions or at least one LN region plus a localised extralymphatic site (IIE) on the same side of the diaphragm
      III (IIIE, IIIS)LN regions or lymphoid structures (e.g. thymus, Waldeyer's ring) on both sides of the diaphragm with optional localised extranodal site (IIIE) or spleen (IIIS)
      IVDiffuse or disseminated extralymphatic organ involvement
      Ann Arbor staging further classifies patients with lymphoma into A or B categories.
      A: without symptoms.
      B: with symptoms including unexplained fever of >38°C, drenching night sweats or loss of >10% body weight within 6 months.
      E, extranodal; LN, lymph node; S, spleen.
      Table 3Diagnostic work-up
      HistoryB symptoms (see Table 2)
      Physical examinationPeripheral LNs, liver, spleen
      Laboratory work-upBlood and differential count

      Optional: immunophenotyping of peripheral blood

      Coombs test (DAT)
      LDH, uric acid

      Electrophoresis (optional: immune fixation)

      B2M (FLIPI 2)
      SerologyHepatitis B, C and HIV serology
      ImagingCT neck, chest, abdomen

      Optional: PET-CT
      a To confirm localised disease or in case of suspected transformation.


      Optional: abdominal ultrasound
      Bone marrow
      b In advanced stages: if clinically indicated.
      Histology

      Cytology

      Optional: immunophenotyping
      ToxicityCreatinine clearance

      Electrocardiogram, cardiac ultrasound (before anthracyclines), pulmonary function (ASCT)

      Reproductive counselling in young patients
      ASCT, autologous stem cell transplantation; B2M, β2-microglobulin; CT, computed tomography; DAT, direct antiglobulin test or direct Coombs test; FLIPI 2, Follicular Lymphoma International Prognostic Index 2; HIV, human immunodeficiency virus; LDH, lactate dehydrogenase; LN, lymph node; PET-CT, positron emission tomography-computed tomography.
      a To confirm localised disease or in case of suspected transformation.
      b In advanced stages: if clinically indicated.
      A complete blood count, routine blood chemistry including immunoglobulin (Ig) levels, lactate dehydrogenase (LDH), β2-microglobulin (B2M) and uric acid as well as screening tests for human immunodeficiency virus (HIV), hepatitis B virus (HBV) and hepatitis C virus (HCV) are required. Staging is carried out according to the Ann Arbor classification system (Table 2), with mention of bulky disease (>6 cm) when applicable.
      • Federico M.
      • Bellei M.
      • Marcheselli L.
      • et al.
      Follicular lymphoma international prognostic index 2: a new prognostic index for follicular lymphoma developed by the international follicular lymphoma prognostic factor project.
      For prognostic purposes, a ‘Follicular Lymphoma International Prognostic Index’ (FLIPI; Table 4) has been established [I, A].
      • Solal-Céligny P.
      • Roy P.
      • Colombat P.
      • et al.
      Follicular lymphoma international prognostic index.
      A revised FLIPI 2 (incorporating B2M, diameter of largest LN, BM involvement and haemoglobin level) and a simplified PRIMA FLIPI have been suggested for patients requiring treatment.
      • Federico M.
      • Bellei M.
      • Marcheselli L.
      • et al.
      Follicular lymphoma international prognostic index 2: a new prognostic index for follicular lymphoma developed by the international follicular lymphoma prognostic factor project.
      ,
      • Bachy E.
      • Maurer M.J.
      • Habermann T.M.
      • et al.
      A simplified scoring system in de novo follicular lymphoma treated initially with immunochemotherapy.
      Table 4FLIPI and PRIMA-PI risk factors
      ParameterDefinition of risk factors
      FLIPI 1FLIPI 2PRIMA-PI
      Nodal sites>4 LN regions (definition in
      • Federico M.
      • Bellei M.
      • Marcheselli L.
      • et al.
      Follicular lymphoma international prognostic index 2: a new prognostic index for follicular lymphoma developed by the international follicular lymphoma prognostic factor project.
      )
      Long diameter of largest LN >6 cm
      Age>60 years>60 years
      Serum markerElevated LDHElevated B2MElevated B2M
      StageAdvanced stage III-IV (Ann Arbor classification)Bone marrow involvementBone marrow involvement
      Haemoglobin<12 g/dl<12 g/dl
      FLIPI:
      • low risk: 0-1 risk factor.
      • intermediate risk: 2 risk factors.
      • high risk: 3-5 risk factors.
      PRIMA-PI:
      • low risk: B2M normal and bone marrow not involved.
      • intermediate risk: B2M normal and bone marrow involved.
      • high risk: B2M elevated.
      B2M, β2-microglobulin; FLIPI, Follicular Lymphoma International Prognostic Index; LDH, lactate dehydrogenase; LN, lymph node; PRIMA-PI, PRIMA prognostic index.
      Recently, a clinicogenetic risk score (m7-FLIPI) has been proposed based on the FLIPI score and mutation status of seven candidate genes (EZH2, ARID1A, MEF2B, EP300, FOXO1, CREBBP and CARD11)
      • Pastore A.
      • Jurinovic V.
      • Kridel R.
      • et al.
      Integration of gene mutations in risk prognostication for patients receiving first-line immunochemotherapy for follicular lymphoma: a retrospective analysis of a prospective clinical trial and validation in a population-based registry.
      ; similarly, a 23-gene expression panel is also a reliable prognostic predictor.
      • Huet S.
      • Tesson B.
      • Jais J.P.
      • et al.
      A gene-expression profiling score for prediction of outcome in patients with follicular lymphoma: a retrospective training and validation analysis in three international cohorts.
      Nevertheless, none of the techniques are as yet established in routine clinical practice. In addition, several recent immunohistochemical studies have reported conflicting data; hence, these biological parameters are not yet suitable for clinical decision making.
      • Sander B.
      • de Jong D.
      • Rosenwald A.
      • et al.
      The reliability of immunohistochemical analysis of the tumor microenvironment in follicular lymphoma: a validation study from the Lunenburg Lymphoma Biomarker Consortium.
      If possible, additional biopsy material should be stored (fresh frozen and paraffin fixed) to allow for future application of additional molecular analyses.

       Recommendations

      • Initial staging should be carried out according to the Ann Arbor classification system.
      • Initial work-up should include a BM aspirate and biopsy and a CT scan of the neck, thorax and abdomen.
      • A PET-CT scan is recommended for routine staging [IV, C] and is mandatory to confirm localised stage I/II disease before ISRT.
      • A complete blood count, routine blood chemistry including Ig levels, LDH, B2M and uric acid as well as screening tests for HIV, HBV and HCV are required.
      • FLIPI 1/2 and PRIMA prognostic index risk factors can be used for prognostic purposes.

      Treatment of localised FL (stages I-II)

      In the small proportion of patients with limited low tumour burden stages I-II, radiotherapy (RT)-based treatment (ISRT, 24-30 Gy) is the preferred approach with a curative intent, whereas the 2 × 2 Gy schedule is less durably effective but might be used in special situations to minimise side-effects (e.g. lacrimal gland, parotid glands) [II, B].
      • Lowry L.
      • Smith P.
      • Qian W.
      • et al.
      Reduced dose radiotherapy for local control in non-Hodgkin lymphoma: a randomised phase III trial.
      ,
      • Hoskin P.J.
      • Kirkwood A.A.
      • Popova B.
      • et al.
      4 Gy versus 24 Gy radiotherapy for patients with indolent lymphoma (FORT): a randomised phase 3 non-inferiority trial.
      Combination of RT with rituximab chemotherapy (ChT) improved progression-free survival (PFS) compared with RT alone [II, C].
      • MacManus M.P.
      • Fisher R.
      • Roos D.
      • et al.
      Randomized trial of systemic therapy after involved-field radiotherapy in patients with early-stage follicular lymphoma.
      A combination of localised irradiation with single-agent rituximab may potentially provide the best balance between efficacy and side-effects [III, B].
      • Herfarth K.
      • Borchmann P.
      • Schnaidt S.
      • et al.
      Rituximab with involved field irradiation for early stage nodal follicular lymphoma: results of the MIR study.
      In selected cases (e.g. limited life expectancy, large abdominal fields), watch-and-wait or rituximab monotherapy may be considered [IV, B].
      • Solal-Céligny P.
      • Bellei M.
      • Marcheselli L.
      • et al.
      Watchful waiting in low-tumor burden follicular lymphoma in the rituximab era: results of an F2-study database.
      ,
      • Friedberg J.W.
      • Byrtek M.
      • Link B.K.
      • et al.
      Effectiveness of first-line management strategies for stage I follicular lymphoma: analysis of the National LymphoCare Study.
      In stage I-II patients with a high tumour burden, adverse clinical prognostic features or in cases where ISRT is not feasible (e.g. lung, liver), systemic therapy as indicated for advanced stages should be applied [IV, B].
      • Friedberg J.W.
      • Byrtek M.
      • Link B.K.
      • et al.
      Effectiveness of first-line management strategies for stage I follicular lymphoma: analysis of the National LymphoCare Study.

       Recommendations

      • In localised stages, 24-30 Gy ISRT is the preferred approach [II, B] and can be combined with single-agent rituximab [III, B].
      • In selected cases, watch-and-wait or rituximab monotherapy may be considered [IV, B].
      • In stage I-II patients with a high tumour burden, adverse clinical prognostic features or in cases where ISRT is not feasible, systemic therapy as indicated for advanced stages should be applied [IV, B].

      Treatment of advanced FL (stage III-IV)

       First-line treatment

       Induction

      In the majority of patients with advanced stage III and IV disease, no curative therapy is yet established. Because the natural course of the disease is characterised by spontaneous regressions in 10%-20% of cases and varies significantly from case to case, therapy should be initiated only upon the development of symptoms, including B symptoms (unexplained fever >38°C, drenching 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 (Table 5) [I, A].
      Table 5High tumour burden criteria in FL [modified from Groupe d'Etude des Lymphomes Folliculaires (GELF)
      • Brice P.
      • Bastion Y.
      • Lepage E.
      • 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.
      and British National Lymphoma Investigation (BNLI)]
      • Ardeshna K.M.
      • Smith P.
      • Norton A.
      • et al.
      Long-term effect of a watch and wait policy versus immediate systemic treatment for asymptomatic advanced-stage non-Hodgkin lymphoma: a randomised controlled trial.
      ParameterHigh tumour burden criteria
      LNsBulk (>7 cm) or 3 LNs in distinct areas >3 cm
      SpleenSymptomatic splenic enlargement
      (Potential) complicationOrgan compression by tumour, pleural or peritoneal effusion
      Serum markersElevated LDH or elevated B2M
      Blood countLeukaemic phase (>5 × 109/l)

      Cytopaenia (neutrophils <1 × 109/l, platelets <100 × 109/l)
      Clinical presentationB symptoms (see Table 2)
      B2M, β2-microglobulin; FL, follicular lymphoma; LDH, lactate dehydrogenase; LN, lymph node.
      In three randomised trials conducted before the rituximab era, early initiation of therapy in asymptomatic patients did not result in any improvement in disease-specific survival or overall survival (OS) [I, D].
      • Ardeshna K.M.
      • Smith P.
      • Norton A.
      • et al.
      Long-term effect of a watch and wait policy versus immediate systemic treatment for asymptomatic advanced-stage non-Hodgkin lymphoma: a randomised controlled trial.
      In a more recent study, early initiation of rituximab resulted in improved PFS (82% versus 36% at 3 years, P < 0.0001), but no survival benefit has been demonstrated to date,
      • Ardeshna K.M.
      • 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 randomised phase 3 trial.
      and the benefit of rituximab maintenance in this setting appears doubtful.
      • Kahl B.S.
      • Hong F.
      • Williams M.E.
      • et al.
      Rituximab extended schedule or re-treatment trial for low-tumor burden follicular lymphoma: eastern cooperative oncology group protocol e4402.
      Thus, the currently recommended therapeutic approach is based on clinical risk factors, symptoms and patient perspective (Figure 1).
      Figure thumbnail gr1
      Figure 1Therapeutic treatment algorithm for FL.
      B, bendamustine; CHOP, cyclophosphamide, doxorubicin, vincristine, prednisolone; ChT, chemotherapy; CVP, cyclophosphamide, vincristine, prednisolone; FL, follicular lymphoma; FLIPI 1-2, Follicular Lymphoma International Prognostic Index 1-2; G, obinutuzumab; R, rituximab.
      a According to the Ann Arbor classification system ().
      b Off-label.
      Four prospective first-line trials, two salvage trials and a systematic meta-analysis confirmed an improved overall response rate, PFS and OS if rituximab was added to ChT (Table 6) [I, A].
      • Marcus R.
      • Imrie K.
      • Solal-Céligny P.
      • et al.
      Phase III study of R-CVP compared with cyclophosphamide, vincristine, and prednisolone alone in patients with previously untreated advanced follicular lymphoma.
      • Hiddemann W.
      • Kneba M.
      • Dreyling M.
      • et al.
      Frontline therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) significantly improves the outcome of patients with advanced stage follicular lymphoma compared with therapy with CHOP alone: results of a prospective randomized study of the German Low Grade Lymphoma Study Group.
      • Herold M.
      • Haas A.
      • Srock S.
      • et al.
      Rituximab added to first-line mitoxantrone, chlorambucil, and prednisolone chemotherapy followed by interferon maintenance prolongs survival in patients with advanced follicular lymphoma: an East German Study Group Hematology and Oncology Study.
      • Bachy E.
      • Houot R.
      • Morschhauser F.
      • et al.
      Long-term follow up of the FL2000 study comparing CHVP-interferon to CHVP-interferon plus rituximab in follicular lymphoma.
      • Schulz H.
      • Bohlius J.F.
      • Trelle S.
      • et al.
      Immunochemotherapy with rituximab and overall survival in patients with indolent or mantle cell lymphoma: a systematic review and meta-analysis.
      If complete remission and long PFS are the therapeutic goals, rituximab in combination with ChT such as cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) or bendamustine should be used [I, B].
      • Hiddemann W.
      • Kneba M.
      • Dreyling M.
      • et al.
      Frontline therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) significantly improves the outcome of patients with advanced stage follicular lymphoma compared with therapy with CHOP alone: results of a prospective randomized study of the German Low Grade Lymphoma Study Group.
      ,
      • Rummel M.
      • Niederle N.
      • Maschmeyer G.
      • et al.
      Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphoma: an open-label, multicentre, randomised, phase 3 non-inferiority trial.
      Cyclophosphamide, vincristine and prednisone (CVP) is inferior to these two regimens in terms of PFS but similar in OS.
      • Luminari S.
      • Ferrari A.
      • Manni M.
      • et al.
      Long-term results of the FOLL05 trial comparing R-CVP versus R-CHOP versus R-FM for the initial treatment of patients with advanced-stage symptomatic follicular lymphoma.
      If there is evidence (histological grade 3B or clinical signs of transformation) of more aggressive lymphoma, an anthracycline-based regimen (rituximab-CHOP) should be applied.
      Table 6Combined immunochemotherapy in FL (first line)
      StudyTotal number of patientsMedian follow-up (months)Overall response (%)Time to treatment failure (months)Overall survival (%)
      Marcus et al. 2008
      • Marcus R.
      • Imrie K.
      • Solal-Céligny P.
      • et al.
      Phase III study of R-CVP compared with cyclophosphamide, vincristine, and prednisolone alone in patients with previously untreated advanced follicular lymphoma.


      R-CVP


      159


      53


      81

      (P < 0.0001)


      27

      (P < 0.0001)


      83 (4 years)

      (P = 0.029)
      Hiddemann et al. 2005
      • Hiddemann W.
      • Kneba M.
      • Dreyling M.
      • et al.
      Frontline therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) significantly improves the outcome of patients with advanced stage follicular lymphoma compared with therapy with CHOP alone: results of a prospective randomized study of the German Low Grade Lymphoma Study Group.


      R-CHOP


      223


      58


      96


      NR

      (P < 0.001)


      90 (2 years)

      (P = 0.0493)
      Herold et al. 2007
      • Herold M.
      • Haas A.
      • Srock S.
      • et al.
      Rituximab added to first-line mitoxantrone, chlorambucil, and prednisolone chemotherapy followed by interferon maintenance prolongs survival in patients with advanced follicular lymphoma: an East German Study Group Hematology and Oncology Study.


      R-MCP


      105


      48


      92

      (P = 0.0009)


      NR

      (P < 0.0001)


      87 (4 years)

      (P = 0.0096)
      Bachy et al. 2013
      • Bachy E.
      • Houot R.
      • Morschhauser F.
      • et al.
      Long-term follow up of the FL2000 study comparing CHVP-interferon to CHVP-interferon plus rituximab in follicular lymphoma.


      R-CHVP-IFN


      175


      99


      81

      (P = 0.035)


      66

      (P = 0.0004)


      79 (8 years)

      (P = 0.076)
      Rummel et al. 2017
      • Rummel M.
      • Niederle N.
      • Maschmeyer G.
      • et al.
      Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphoma: an open-label, multicentre, randomised, phase 3 non-inferiority trial.
      ,
      • Rummel M.J.
      • Buske C.
      • Hertenstein B.
      • et al.
      Four versus two years of rituximab maintenance (R-maintenance) following bendamustine plus rituximab (B-R): initial results of a prospective, randomized multicenter phase 3 study in first-line follicular lymphoma (the StiL NHL7-2008 MAINTAIN study).


      BR

      BR + R maintenance


      139

      595


      34

      34


      93

      90


      78 (median)

      NR (median)


      NR (median)

      NR (median)
      Luminari et al. 2018
      • Luminari S.
      • Ferrari A.
      • Manni M.
      • et al.
      Long-term results of the FOLL05 trial comparing R-CVP versus R-CHOP versus R-FM for the initial treatment of patients with advanced-stage symptomatic follicular lymphoma.


      R-CVP

      R-CHOP

      R-FM + R maintenance


      178

      178

      178


      84

      84

      84


      88

      93

      91


      38%

      45% (P = 0.033)

      49% (P = 0.016)

      (8 years)


      85%

      83% (n.s.)

      79% (n.s.)

      (8 years)
      Bachy et al. 2019
      • Bachy E.
      • Seymour J.F.
      • Feugier P.
      • et al.
      Sustained progression-free survival benefit of rituximab maintenance in patients with follicular lymphoma: long-term results of the PRIMA study.


      R-CHOP/CVP/FM

      R-CHOP/CVP/FM

      + R maintenance


      1018







      118







      n/a







      35% (10 years)

      51% (10 years)

      (P < 0.001)


      80 (10 years)

      80 (10 years)

      (n.s.)
      Marcus et al. 2017
      • Marcus R.
      • Davies A.
      • Ando K.
      • et al.
      Obinutuzumab for the first-line treatment of follicular lymphoma.


      R-CHOP/CVP/B

      + R maintenance

      G-CHOP/CVP/B

      + G maintenance


      601



      601





      34



      34





      86.9



      88.5





      73.3% (3 years)



      80.0% (3 years)

      (P = 0.001)


      92.1 (3 years)



      94.0 (3 years)

      (n.s.)
      Morschhauser et al. 2018
      • Morschhauser F.
      • Fowler N.H.
      • Feugier P.
      • et al.
      Rituximab plus lenalidomide in advanced untreated follicular lymphoma.


      R-CHOP/BR

      + R maintenance

      R-lenalidomide

      + R maintenance




      517



      513




      38



      38




      84



      89




      78% (3 years)



      77% (3 years)

      (n.s.)




      94 (3 years)



      94 (3 years)

      (n.s.)
      P corresponds to significance levels in comparison to ChT only.
      B, bendamustine; BR, bendamustine-rituximab; CHOP, cyclophosphamide, doxorubicin, vincristine, prednisolone; ChT, chemotherapy; CHVP, cyclophosphamide, doxorubicin, etoposide, prednisone; CVP, cyclophosphamide, vincristine, prednisolone; FL, follicular lymphoma; FM, fludarabine, mitoxantrone; G, obinutuzumab; IFN, interferon; MCP, mitoxantrone, chlorambucil, prednisone; n/a, not applicable; NR, not reached; n.s., not significant; R, rituximab.
      Extended anti-infectious prophylaxis should be considered, especially after bendamustine-containing induction therapy, as long-term CD4-positive T lymphocytopaenia has been observed [IV, B].
      • Hiddemann W.
      • Barbui A.M.
      • Canales M.A.
      • et al.
      Immunochemotherapy with obinutuzumab or rituximab for previously untreated follicular lymphoma in the GALLIUM study: influence of chemotherapy on efficacy and safety.
      Awareness of a potential adverse impact on future cellular immunotherapeutic options, such as chimeric antigen receptor T-cell (CAR-T) treatment (see below), is important.
      In a large randomised trial, the anti-CD20 antibody obinutuzumab (immunochemotherapy and maintenance for 2 years) resulted in significantly prolonged PFS in comparison with rituximab and, therefore, is considered as an additional, potentially more efficacious option, although no OS benefit was observed [I, B].
      • Marcus R.
      • Davies A.
      • Ando K.
      • et al.
      Obinutuzumab for the first-line treatment of follicular lymphoma.
      In another international phase III trial, lenalidomide–rituximab appeared to have a similar efficacy as immunochemotherapy [I, C].
      • Morschhauser F.
      • Fowler N.H.
      • Feugier P.
      • et al.
      Rituximab plus lenalidomide in advanced untreated follicular lymphoma.
      Similarly, lenalidomide–rituximab achieve a longer PFS in comparison to rituximab monotherapy.
      • Zucca E.
      • Rondeau S.
      • Vanazzi A.
      • et al.
      Short regimen of rituximab plus lenalidomide in follicular lymphoma patients in need of first-line therapy.
      Antibody monotherapy (rituximab, radioimmunotherapy) or chlorambucil plus rituximab remain alternatives for patients with a low-risk profile or when conventional ChT is contraindicated [III, C].
      • Martinelli G.
      • Schmitz S.F.
      • Utiger U.
      • et al.
      Long-term follow-up of patients with follicular lymphoma receiving single-agent rituximab at two different schedules in trial SAKK 35/98.
      ,
      • Taverna C.J.
      • Martinell G.
      • Hitz F.
      • et al.
      Rituximab maintenance for a maximum of 5 years after single-agent rituximab induction in follicular lymphoma: results of the randomized controlled phase III trial SAKK 35/03.
      In patients with positive hepatitis B serology including occult carrier (hepatitis B surface antigen negative and anti-core antibody positive), prophylactic antiviral medication up to 2 years beyond the last rituximab exposure is strongly recommended, although strict monitoring of HBV, DNA and liver enzymes represents another option in regions where HBV infection is endemic [I, A].
      • Huang Y.H.
      • Hsiao L.T.
      • Hong Y.C.
      • et al.
      Randomized controlled trial of entecavir prophylaxis for rituximab-associated hepatitis B virus reactivation in patients with lymphoma and resolved hepatitis B.

       Consolidation/maintenance

      Rituximab maintenance every 2 months for 2 years improves PFS after various induction regimens (median PFS 10.5 years versus 4.1, P < 0.0001), but there is no impact on OS [I, B],
      • Bachy E.
      • Seymour J.F.
      • Feugier P.
      • et al.
      Sustained progression-free survival benefit of rituximab maintenance in patients with follicular lymphoma: long-term results of the PRIMA study.
      • Hoster E.
      • Unterhalt M.
      • Hänel M.
      • et al.
      Rituximab maintenance versus observation after immunochemotherapy (R-CHOP, R-MCP, R-FCM) in previously untreated follicular lymphoma: a randomised trial of GLSG and OSHO.
      • Rummel M.J.
      • Buske C.
      • Hertenstein B.
      • et al.
      Four versus two years of rituximab maintenance (R-maintenance) following bendamustine plus rituximab (B-R): initial results of a prospective, randomized multicenter phase 3 study in first-line follicular lymphoma (the StiL NHL7-2008 MAINTAIN study).
      whereas a shorter maintenance period results in inferior benefit.
      • Martinelli G.
      • Schmitz S.F.
      • Utiger U.
      • et al.
      Long-term follow-up of patients with follicular lymphoma receiving single-agent rituximab at two different schedules in trial SAKK 35/98.
      Radioimmunotherapy consolidation also prolongs PFS after ChT, but its benefit seems to be inferior in comparison to rituximab maintenance for 2 years [II, B].
      • Morschhauser F.
      • Radford J.
      • Van Hoof A.
      • et al.
      90Yttrium-ibritumomab-tiuxetan consolidation of first remission in advanced-stage follicular non-Hodgkin lymphoma: updated results after a median follow up of 7.3 years from the international, randomized, phase III first-line indolent trial.
      ,
      • Lopez-Guillermo A.
      • Canales M.A.
      • Dlouhy I.
      • et al.
      A randomized phase II study comparing consolidation with a single dose of 90Y ibritumomab tiuxetan (Zevalin) (Z) vs. maintenance with rituximab (R) for two years in patients with newly diagnosed follicular lymphoma (FL) responding to R-CHOP. Preliminary results at 36 months from randomization.
      However, a recent study showed an improved PFS but no difference in OS and an increased cumulative risk of myeloid malignancies after iodine-131 (131I)–tositumomab radioimmunotherapy consolidation in comparison to rituximab in combination with ChT.
      • Shadman M.
      • Li H.1
      • Rimsza L.
      • et al.
      Continued excellent outcomes in previously untreated patients with follicular lymphoma after treatment with CHOP plus rituximab or CHOP plus 131I-tositumomab: long-term follow-up of phase III randomized study SWOG-S0016.
      Myeloablative consolidation followed by autologous stem-cell transplantation (ASCT) prolongs PFS after ChT, but its benefit after a rituximab-containing induction is minor and no OS advantage has been observed.
      • Schaaf M.
      • Reiser M.
      • Borchmann P.
      • et al.
      High-dose therapy with autologous stem cell transplantation versus chemotherapy or immuno-chemotherapy for follicular lymphoma in adults.
      Therefore, such an approach is not recommended in first-line therapy of responding patients [I, D].

       Relapsed disease

      At suspected disease relapse or progression, it is strongly recommended to obtain a new confirmatory biopsy in order to exclude transformation to an aggressive lymphoma. It may be useful to perform a PET-guided biopsy of the site with highest tracer intensity uptake (maximum standardised uptake value).
      Observation is an accepted approach in asymptomatic patients with low tumour burden and confirmed follicular histology at relapse or progression.

       Induction

      Selection of the salvage treatment regimen depends on efficacy and duration of response of prior regimens and stage at relapse. Localised symptomatic disease may be managed with low-dose ISRT (2 × 2 Gy). In early systemic relapses (<12-24 months), a noncross-resistant regimen is preferred (e.g. bendamustine after CHOP or vice versa). Other options, including fludarabine-based, platinum-based or alkylating agents-based regimens, could also be useful. Rituximab should be added if the previous antibody-containing scheme achieved >6-12-month duration of remission [IV, B]. In rituximab-refractory cases or remissions lasting <6 months, obinutuzumab–bendamustine (plus obinutuzumab maintenance) has been shown to improve both PFS and OS in comparison with bendamustine only [I, B].
      • Cheson B.D.
      • 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.
      In symptomatic cases with low tumour burden, rituximab monotherapy may be applied.
      In relapsed FL, lenalidomide plus rituximab was superior to rituximab monotherapy in terms of response rates and PFS with a trend towards improved OS
      • Leonard J.P.
      • Trneny M.
      • Izutsu K.
      • et al.
      AUGMENT: a phase III study of lenalidomide plus rituximab versus placebo plus rituximab in relapsed or refractory indolent lymphoma.
      ; thus, lenalidomide–rituximab may be considered, especially for those patients with short remissions after ChT [II, B].
      Radioimmunotherapy [yyttrium-90 (90Y) ibritumomab-tiuxetan] may represent an effective therapeutic approach in elderly patients with comorbidities not appropriate for ChT [IV, B].
      In later relapses, monotherapy is an established option with palliative intent, but long-term survival can be achieved [III, C]. The phosphoinositide 3-kinase (PI3K) inhibitor idelalisib has been registered in double-refractory FL, based on a phase II study,
      • Gopal A.K.
      • Kahl B.S.
      • de Vos S.
      • et al.
      PI3Kδ inhibition by idelalisib in patients with relapsed indolent lymphoma.
      but is hampered by infections, late-onset colitis and pulmonary toxicity (atypical pneumonias/pneumonitis); therefore, anti-infectious prophylaxis (co-trimoxazole/acyclovir) and cytomegalovirus (CMV) monitoring are strongly recommended [II, B]. Recent data suggest that other PI3K inhibitors display a more favourable toxicity profile [IV, B].
      • Dreyling M.
      • Santoro A.
      • Mollica L.
      • et al.
      Phosphatidylinositol 3-kinase inhibition by copanlisib in relapsed or refractory indolent lymphoma.

       Consolidation/maintenance

      Rituximab maintenance every 3 months for up to 2 years has a favourable side-effect profile and, based on a systematic meta-analysis, substantially prolongs PFS and OS in relapsed disease, even after antibody-containing salvage [I, A].
      • Vidal L.
      • Gafter-Gvili A.
      • Salles G.
      • et al.
      Rituximab maintenance for the treatment of patients with follicular lymphoma: an updated systematic review and meta-analysis of randomized trials.
      Nevertheless, second-line maintenance treatment has not been investigated in patients who have received antibody maintenance as part of their first-line therapy and probably should not be used for those patients who have relapsed during their first maintenance period, but is reasonable for other patient subsets [IV, D].
      Based on the results of phase II or observational studies, high-dose ChT with ASCT prolongs PFS and potentially OS and should be considered, especially in patients who experience brief first remissions (<2-3 years) after rituximab-containing regimens, which usually have a much worse long-term outcome [II, B].
      • Schouten H.C.
      • Qian W.
      • Kvaloy S.
      • et al.
      High-dose therapy improves progression-free survival and survival in relapsed follicular non-Hodgkin's lymphoma: results from the randomized European CUP trial.
      • Jurinovic V.
      • Metzner B.
      • Pfreundschuh M.
      • et al.
      Autologous stem cell transplantation for patients with early progression of follicular lymphoma: a follow-up study of 2 randomized trials from the German Low Grade Lymphoma Study Group.
      • Casulo C.
      • Friedberg J.W.
      • Ahn K.W.
      • et al.
      Autologous transplantation in follicular lymphoma with early therapy failure: a national LymphoCare study and Center for International Blood and Marrow Transplant Research analysis.
      • Casulo C.
      • Byrtek M.
      • Dawson K.L.
      • et al.
      Early relapse of follicular lymphoma after rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone defines patients at high risk for death: an analysis from the national LymphoCare study.
      Subsequent rituximab maintenance achieves some improvement in PFS [II, B].
      • Pettengell R.
      • Schmitz N.
      • Gisselbrecht C.
      • et al.
      Rituximab purging and/or maintenance in patients undergoing autologous transplantation for relapsed follicular lymphoma: a prospective randomized trial from the Lymphoma Working Party of the European Group for Blood and Marrow Transplantation.
      In selected younger patients with later relapses with a high-risk profile or relapse after ASCT, a potentially curative allogeneic stem cell transplantation (alloSCT) (preferably with dose-reduced conditioning) may be considered, especially in patients with early relapse and refractory disease, whereas alloSCT in first relapse may worsen OS [IV, B].
      • Montoto S.
      • Corradini P.
      • Dreyling M.
      • et al.
      Indications for hematopoietic stem cell transplantation in patients with follicular lymphoma: a consensus project of the EBMT-Lymphoma Working Party.

       Innovative approaches

      In recent years, new approaches, including inhibitors of the B-cell signalling pathway and other targeted agents, have shown activity in phase II studies, but to date their benefit has yet to be confirmed in randomised phase III studies. The combination of bortezomib–rituximab has shown only a minor benefit compared with antibody monotherapy and is therefore not recommended [I, D].
      • Coiffier B.
      • Osmanov E.A.
      • Hong X.
      • et al.
      Bortezomib plus rituximab versus rituximab alone in patients with relapsed, rituximab-naive or rituximab-sensitive, follicular lymphoma: a randomised phase 3 trial.
      Treatment with CD19-specific CAR-T can lead to long-term remissions in relapsed FL but this approach currently remains reserved for transformed FL due to toxicities (registered indication), and its use in indolent lymphoma is limited to clinical trials for refractory disease or relapsing patients with poor prognostic features [IV, B].
      • Schuster S.J.
      • Svoboda J.
      • Chong E.A.
      • et al.
      Chimeric antigen receptor T cells in refractory B-cell lymphomas.

       Response evaluation

      Appropriate structural imaging evaluation should be carried out mid-treatment and after completion of ChT. Patients with an inadequate response (less than partial response) should be evaluated for early salvage regimens. Patients with a partial response may convert to complete response under rituximab maintenance.
      PET-CT after completion of induction ChT has been recommended for prognostic reasons, as persistent PET positivity (using appropriate Deauville assessment scale) identified a small group (20%-25%) of patients with an adverse prognosis,
      • Trotman J.
      • Luminari S.
      • Boussetta S.
      • et al.
      Prognostic value of PET-CT after first-line therapy in patients with follicular lymphoma: a pooled analysis of central scan review in three multicentre studies.
      but therapeutic consequences remain undefined [II, B]. There is no established role for interim PET-CT scan.
      Minimal residual disease (MRD) analysis by polymerase chain reaction (PCR) at the end of the treatment and during follow-up is an independent predictor of long-term outcome but should not guide therapeutic strategies outside of clinical studies. Thus far, few data are available on the use of circulating tumour DNA in FL.

       Recommendations

      • In asymptomatic advanced cases, watch-and-wait is the standard approach [I, A].
      • Therapy should be initiated only upon the development of symptoms, including B symptoms, hematopoietic impairment, bulky disease, vital organ compression, ascites, pleural effusion or rapid lymphoma progression [I, A].
      • Obinutuzumab or rituximab in combination with CHOP or bendamustine should be used if complete remission and long PFS are the therapeutic goals [I, B]. If there is evidence of more aggressive clinical course, obinutuzumab/rituximab-CHOP should be applied. Extended anti-infectious prophylaxis should be considered after bendamustine-containing induction therapy [IV, B].
      • Antibody monotherapy (rituximab, radioimmunotherapy) or chlorambucil plus rituximab remain alternatives for patients with a low-risk profile or when conventional ChT is contraindicated [III, C].
      • Rituximab maintenance every 2 months for 2 years is recommended after immunochemotherapy [I, B].
      • Alternatively, radioimmunotherapy consolidation may be considered after ChT [II, B].
      • Myeloablative consolidation followed by ASCT after ChT is not recommended in first-line therapy of responding patients [I, D].
      • In patients with positive hepatitis B serology including occult carrier, prophylactic antiviral medication up to 2 years beyond the last rituximab exposure is strongly recommended [I, A].
      • At suspected disease relapse or progression, it is strongly recommended to obtain a new confirmatory biopsy.
      • Localised symptomatic disease may be managed with low-dose ISRT (2 × 2 Gy).
      • In early systemic relapses (<12-24 months), a noncross-resistant regimen is preferred.
      • Rituximab should be added if the previous antibody-containing scheme achieved >6-12-month duration of remission [IV, B]. In rituximab-refractory cases or remissions lasting <6 months, obinutuzumab–bendamustine (or other ChT regimen) plus obinutuzumab maintenance is recommended [I, B].
      • Rituximab maintenance every 3 months for up to 2 years is recommended [I, A].
      • High-dose ChT with ASCT should be considered in patients who experience brief first remissions after rituximab-containing regimens [II, B].
      • In relapsed FL, lenalidomide plus rituximab may be considered for patients with short remissions after ChT [II, B].
      • In symptomatic cases with low tumour burden, rituximab monotherapy may be applied.
      • Radioimmunotherapy may be considered in elderly patients with comorbidities [IV, B].
      • In later relapses, a non-ChT approach is recommended [III, C]: lenalidomide plus rituximab [II, B]; idelalisib in double-refractory cases only with anti-infectious prophylaxis (co-trimoxazole/acyclovir) and CMV monitoring.
      • In selected younger patients with later relapses with a high-risk profile or relapse after ASCT, alloSCT may be considered [IV, B].

      Personalised medicine

      As various therapeutic approaches may achieve durable responses in the vast majority of patients, the selection of optimal treatment is mainly based on clinical risk factors, symptoms and individual patient priorities (Figure 1). PET- and MRD-based tailored treatments are currently being evaluated in ongoing studies but are not yet routine clinical practice.
      Paediatric FL is an FL variant originally described in children, but rarely occurs in adults. It is characterised by typically localised disease, the absence of BCL2 aberrations, lack of t(14;18), grade III histology and a high proliferation rate. It shows a much more indolent disease course and can be managed with local therapy only, despite displaying histologically more aggressive features.
      • Louissaint Jr., A.
      • Ackerman A.M.
      • Dias-Santagata D.
      • et al.
      Pediatric-type nodal follicular lymphoma: an indolent clonal proliferation in children and adults with high proliferation index and no BCL2 rearrangement.
      Similarly, duodenal-type FL should be followed with observation only as long as asymptomatic [IV, B].
      • Schmatz A.I.1
      • Streubel B.
      • Kretschmer-Chott E.
      • et al.
      Primary follicular lymphoma of the duodenum is a distinct mucosal/submucosal variant of follicular lymphoma: a retrospective study of 63 cases.

      Follow-up, long-term implications and survivorship

      The following minimal recommendations are based on consensus rather than on evidence (Table 7):
      • After local RT: history and physical examination every 6 months for 2 years, subsequently once a year if clinically indicated.
      • Evaluation of thyroid function in patients with irradiation of the neck at 1, 2 and 5 years.
      • After (during continuous) systemic treatment: history and physical examination every 3-6 months for 2 years, and every 6-12 months subsequently [V, C].
      • Blood count and routine chemistry including IgG levels every 6 months for 2 years, then only as needed for evaluation of suspicious symptoms.
      • Minimal adequate radiological or other examinations every 6 months for 2 years and optionally annually up to 5 years. Regular CT scans are not mandatory outside of clinical trials, and PET-CT should not be used for surveillance [V, D].
      • MRD screening may be carried out in clinical studies but should not guide therapeutic strategies in clinical practise.
      • Adequate prophylaxis (antibiotics and/or IgG supplementation) in patients with symptomatic recurrent infections and based on prior treatment (e.g. with fludarabine or bendamustine). Yearly seasonal flu vaccination may be considered.
      Table 7Recommended follow-up after end of therapy
      ExaminationDetailsYear 1-2Year 3-5Year >5
      HistoryB symptoms (see Table 2)Every 3-6 monthsEvery 6-12 monthsAnnually
      Physical examinationParticular: peripheral LNs, liver, spleenEvery 3-6 monthsEvery 6-12 monthsAnnually
      Laboratory work-upBlood and differential countEvery 3-6 monthsEvery 6-12 monthsAnnually
      LDH, IgG levelsEvery 3-6 monthsEvery 6-12 monthsIf progression suspected
      Imaging (optional)Abdominal ultrasoundEvery 6 monthsEvery 12 monthsIf progression suspected
      CT neck, chest, abdomenEvery 6-12 monthsEvery 12-24 monthsIf progression suspected
      CT, computed tomography; IgG, immunoglobulin G; LDH, lactate dehydrogenase; LN, lymph node.

      Methodology

      These Clinical Practice Guidelines were developed in accordance with the ESMO standard operating procedures for Clinical Practice Guidelines development (http://www.esmo.org/Guidelines/ESMO-Guidelines-Methodology). The relevant literature has been selected by the expert authors. A summary of recommended treatment strategies outside of clinical studies is provided in Figures 2 and 3. Levels of evidence and grades of recommendation have been applied using the system shown in Supplementary Table S1, available at https://doi.org/10.1016/j.annonc.2020.11.008.
      • Dykewicz C.A.
      Summary of the guidelines for preventing opportunistic infections among hematopoietic stem cell transplant recipients.
      Statements without grading were considered justified standard clinical practice by the experts and the ESMO faculty. This manuscript has been subjected to an anonymous peer review process.
      Figure thumbnail gr2
      Figure 2Consensus-driven recommendations—low tumour burden FL.
      ChT, chemotherapy; FL, follicular lymphoma; INRT, involved-node radiotherapy; ISRT, involved-site radiotherapy.
      Figure thumbnail gr3
      Figure 3Consensus-driven recommendations—high tumour burden FL.
      alloSCT, allogeneic stem cell transplantation; ASCT, autologous stem cell transplantation; B, bendamustine; CHOP, cyclophosphamide, doxorubicin, vincristine, prednisolone; ChT, chemotherapy; CR, complete response; CVP, cyclophosphamide, vincristine, prednisolone; FL, follicular lymphoma; G, obinutuzumab; PR, partial response; R, rituximab.
      a Biological age (years).
      b Off-label.
      c Preferred in rituximab-refractory cases.

      Acknowledgements

      The ESMO Guidelines Committee thank the ESMO Faculty and other experts who provided critical reviews of these ESMO Clinical Practice Guidelines. They also thank the European Cancer Patient Coalition and the following patient organisation for their review: the Polish Lymphoma Association Owl Eyes.

      Funding

      No external funding has been received for the preparation of these guidelines. Production costs have been covered by ESMO from central funds.

      Disclosure

      MD has reported scientific advisory boards for Accerta, Bayer, Celgene, Gilead, Janssen, Novartis, Roche and Sandoz, speaker's honoraria from Bayer, Celgene, Gilead, Janssen and Roche and research support from Celgene, Janssen, Mundipharma and Roche; GS has reported advisory boards or consulting for AbbVie, Autolus, Celgene, Genmab, Gilead, Epizyme, Janssen, Karyopharm, Kite, Merck, MorphoSys, Novartis, Roche, Servier and Takeda and educational events with AbbVie, Amgen, Celgene, Gilead, Janssen, Kite, MorphoSys, Novartis, Roche, Servier and Takeda; ML has reported consultancy, advisory boards, scientific meetings, institutional research support and contracts from AbbVie, Acerta, Amgen, Archigen, ADC Therapeutics, BeiGene, Celgene, Gilead, J&J, Jazz, Roche, Sandoz and Takeda and has received research grants from Celgene, J&J and BeiGene; KH has received research support from Roche; JFS has reported advisory boards for AbbVie, Celgene, Janssen, Roche, Acerta, Genentech, Gilead, Mei Pharma, MorphoSys, Sunesis and Takeda, speaker's bureau for AbbVie, Celgene and Roche and has received research funding from AbbVie, Celgene, Roche and Janssen; MJ has received research funding from Celgene, Roche, Gilead, AbbVie and Janssen and honoraria from Kite, Kyowa-Kirin and Acerta; MG, SR and SHT have declared no conflicts of interest.

      Supplementary data

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