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

Abstract

Follicular lymphomas (FLs) are the second most frequent subtype of nodal lymphoid malignancies in Western Europe. The annual incidence of this disease has rapidly increased during recent decades and has risen from 2–3/100 000 during the 1950s to 5/100 000 recently [1.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).Lancet Haematol. 2015; 2: e481-e491Google Scholar]. Diagnosis should be based on a surgical specimen/excisional lymph node biopsy. Core biopsies should only be carried out in patients without easily accessible lymph nodes (e.g. retroperitoneal bulk), keeping in mind the possible heterogeneity of FL grading can be difficult to appreciate on core biopsies and re-biopsy may be required if the material is not adequate. Fine needle aspirations are inappropriate for a reliable diagnosis. The histological report should give the diagnosis according to the World Health Organization (WHO) classification. Grading of lymph node biopsies is carried out according to the number of blasts/high-power field (Table 1). FL grade 3A (with sheets of blasts) is considered an aggressive lymphoma and treated as such [2.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.Ann Oncol. 2015; 26: v116-v125Google Scholar], whereas grade 1, 2 and 3A should be treated as indolent disease [3.Ott G. Katzenberger T. Lohr A. et al.Cytomorphologic, immunohistochemical, and cytogenetic profiles of follicular lymphoma: 2 types of follicular lymphoma grade 3.Blood. 2002; 99: 3806-3812Google Scholar]. Review, especially of grade 3A or 3B, by an expert haematopathologist is advised if the infiltration pattern is atypical (diffuse areas, even with small cells).Table 1Grading of follicular lymphoma (FL)GradeDescription1≤5 blasts/high-power field26–15 blasts/high-power field3A>15 blasts/high-power field, centroblasts with intermingled centrocytes3B>15 blasts/high-power field, pure sheets of blasts Open table in a new tab Since treatment largely depends on the stage of the disease, initial staging should be thorough, particularly in the small proportion of patients with early stages I and II (10%–15%) (Table 2). Initial work-up should include a computed tomography (CT) scan of the neck, thorax, abdomen and pelvis, and a bone marrow aspirate and biopsy (Table 3). Positron emission tomography (PET)–CT improves the accuracy of staging for nodal and extranodal sites and thus should be recommended for routine staging in FL [IV, C] [4.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.J Clin Oncol. 2014; 32: 3059-3068Google Scholar]. This is particularly important to confirm localised stage I/II before involved-field radiotherapy.Table 2Ann Arbor classificationStageArea of involvementI (IE)One lymph node region or extralymphatic site (IE)II (IIE)Two or more lymph node regions or at least one lymph node region plus a localised extralymphatic site(IIE) on the same side of the diaphragmIII (IIIE, IIIS)Lymph node 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 involvementA: no symptoms.B: unexplained fever of >38°C, drenching night sweats; or loss of >10% body weight within 6 months. Open table in a new tab Table 3Diagnostic work-upHistoryB symptomsPhysical examinationPeripheral lymph nodes, liver, spleenLaboratory work-upBlood and differential countOptional: FACS on peripheral blood, PCR for BCL2 rearrangementLDH, uric acidElectrophoresis (optional: immune fixation)&bgr;2 microglobulin (FLIPI 2)SerologyHepatitis B, C and HIV serologyImagingCT neck, chest, abdomen, pelvisRecommended: PET–CTaTo confirm localised disease or in the case of suspected transformation.Optional: abdominal ultrasoundBone marrowbIf clinically indicated.HistologyCytologyOptional: FACS, PCR for BCL2 rearrangementToxicityElectrocardiogram, cardiac ultrasound (before anthracyclines, ASCT)Creatinine clearanceReproductive counselling in young patientsFACS, fluorescence-activated cell sorting; PCR, polymerase chain reaction; LDH, lactate dehydrogenase; FLIPI 2, Follicular Lymphoma International Prognostic Index 2; HIV, human immunodeficiency virus; CT, computed tomography; PET–CT, positron emission tomography–computed tomography; ASCT, autologous stem cell transplantation.a To confirm localised disease or in the case of suspected transformation.b If clinically indicated. Open table in a new tab A: no symptoms. B: unexplained fever of >38°C, drenching night sweats; or loss of >10% body weight within 6 months. FACS, fluorescence-activated cell sorting; PCR, polymerase chain reaction; LDH, lactate dehydrogenase; FLIPI 2, Follicular Lymphoma International Prognostic Index 2; HIV, human immunodeficiency virus; CT, computed tomography; PET–CT, positron emission tomography–computed tomography; ASCT, autologous stem cell transplantation. A complete blood count, routine blood chemistry including lactate dehydrogenase (LDH), &bgr;2 microglobulin and uric acid as well as screening tests for human immunodeficiency virus (HIV), hepatitis B virus (HBV) and hepatitis C are required. The staging is carried out according to the Ann Arbor classification system (Table 2), with mention of bulky disease (>7 cm) when appropriate. For prognostic purposes, a ‘Follicular Lymphoma-specific International Prognostic Index’ (FLIPI, Table 4) has been established [I, A] [6.Solal-Céligny P. Roy P. Colombat P. et al.Follicular lymphoma international prognostic index.Blood. 2004; 104: 1258-1265Google Scholar]. A revised FLIPI 2 (incorporating &bgr;2 microglobulin, diameter of largest lymph node, bone marrow involvement and haemoglobin level) has been suggested for patients requiring treatment which may be more informative on progression-free survival (PFS) [7.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.J Clin Oncol. 2009; 27: 4555-4562Google Scholar].Table 4‘Follicular Lymphoma-specific International Prognostic Index’ (FLIPI) risk factorsParameterDefinition of risk factorsFLIPI 1FLIPI 2Nodal sites>4 lymph node regions (definition in [5.Dave S.S. Wright G. Tan B. et al.Prediction of survival in follicular lymphoma based on molecular features of tumor-infiltrating immune cells.N Engl J Med. 2004; 351: 2159-2169Google Scholar])Long diameter of largest lymph node >6 cmAge>60 years>60 yearsSerum markerElevated LDHElevated &bgr;2 microglobulinStageAdvanced (III–IV according to Ann Arbor classification)Bone marrow involvementHaemoglobin<12 g/dl<12 g/dl0–1 risk factors, low risk; 2 risk factors, intermediate risk; 3–5 risk factors, high risk.LDH, lactate dehydrogenase. Open table in a new tab 0–1 risk factors, low risk; 2 risk factors, intermediate risk; 3–5 risk factors, high risk. LDH, lactate dehydrogenase. Extended gene-expression profiling of tumour biopsy suggests a more favourable clinical course in cases with infiltrating T cells, in comparison with cases with non-specific macrophage bystander cells [5.Dave S.S. Wright G. Tan B. et al.Prediction of survival in follicular lymphoma based on molecular features of tumor-infiltrating immune cells.N Engl J Med. 2004; 351: 2159-2169Google Scholar]. Recently, a clinicogenetic risk score (m7-FLIPI) has been proposed based on mutation status of seven candidate genes (EZH2, ARID1A, MEF2B, EP300, FOXO1, CREBBP and CARD11) [8.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.Lancet Oncol. 2015; 16: 1111-1122Google Scholar]; however, none of the techniques are yet established in clinical routine practice. In addition, several recent immunohistochemistry studies have reported conflicting data; hence, biological parameters are still investigational for prognostic assessment and are not yet suitable for clinical decision-making [9.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.Haematologica. 2014; 99: 715-725Google Scholar]. If possible, additional biopsy material should be stored fresh frozen to allow for the possible future application of additional molecular analyses. In the small proportion of patients with limited non-bulky stages I–II, radiotherapy (involved field, 24 Gy) is the preferred treatment with a potentially curative potential, whereas the 2 × 2 Gy schedule is inferior and is merely palliative [II, B] [10.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.Lancet Oncol. 2014; 15: 457-463Google Scholar]. In selected cases, watchful waiting or rituximab monotherapy may be considered to avoid the side-effects of radiation (e.g. cervical: sicca syndrome, hypothyroidism; abdominal: mucositis, myeloablative suppression) [11.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.J Clin Oncol. 2012; 30: 3848-3853Google Scholar, 12.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.J Clin Oncol. 2012; 30: 3368-3375Google Scholar]. In stage I–II patients with large tumour burden, adverse clinical or biological prognostic features or when local radiotherapy is not applicable (e.g. lung, liver), systemic therapy as indicated for advanced stages should be applied [IV, B] [12.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.J Clin Oncol. 2012; 30: 3368-3375Google Scholar]. In the majority of patients with advanced stage III and IV disease, no curative therapy is yet established. Since 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 occurrence of symptoms, including B symptoms, haematopoietic impairment, bulky disease, vital organ compression, ascites, pleural effusion or rapid lymphoma progression (Table 5) [I, A].Table 5High tumour burden criteria in FL [Groupe d'Etude des Lymphomes Folliculaires (GELF)ParameterHigh tumour burden criteriaLymph nodesBulk (>7 cm) or 3 lymph nodes in distinct areas >3 cmSpleenSymptomatic splenic enlargement(Potential) complicationOrgan compression by tumour, pleural or peritoneal effusionSerum markersElevated LDH or elevated &bgr;2-microglobulineClinical presentationB symptoms (see Table 2)LDH, lactate dehydrogenase. Open table in a new tab LDH, lactate dehydrogenase. In three randomised trials before the rituximab era, an early initiation of therapy in asymptomatic patients did not result in any improvement of disease-specific survival or overall survival (OS) [13.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.Lancet. 2003; 362: 516-522Google Scholar]. In a more recent study, early initiation of rituximab resulted in improved PFS (80% versus 48%, P <0.001), but no survival benefit has been determined so far [14.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.Lancet Oncol. 2014; 15: 424-435Google Scholar], and the benefit of rituximab maintenance in this setting appears doubtful [15.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.J Clin Oncol. 2014; 32: 3096-3102Google Scholar]. Thus, the current therapeutic approach is based on clinical risk factors, symptoms and patient perspective (Figure 1). Four prospective first-line trials, two salvage trials and a systematic meta-analysis confirmed an improved overall response, PFS and OS if rituximab was added to chemotherapy (Table 6) [16.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.J Clin Oncol. 2008; 26: 4579-4586Google Scholar, 17.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.Blood. 2005; 106: 3725-3732Google Scholar, 18.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.J Clin Oncol. 2007; 25: 1986-1992Google Scholar, 19.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.Haematologica. 2013; 98: 1107-1114Google Scholar, 20.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.J Natl Cancer Inst. 2007; 99: 706-714Google Scholar]. If complete remission and long PFS is to be achieved, rituximab in combination with chemotherapy such as CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) or bendamustine should be used [I, B] [17.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.Blood. 2005; 106: 3725-3732Google Scholar, 21.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 lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial.Lancet. 2013; 381: 1203-1210Google Scholar]. CVP (cyclophosphamide, vincristine and prednisone) is not as effective as these two regimens with respect to PFS but not OS [22.Federico M. Luminari S. Dondi A. et al.R-CVP versus R-CHOP versus 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: 1506-1513Google Scholar]. Full courses of purine analogue-based schemes [FC (fludarabine and cyclophosphamide) or FM (fludarabine and mitoxantrone)] are not recommended due to higher haematological toxicities, but a brief course of chemoimmunotherapy with full rituximab course is an alternative in elderly patients, with good efficacy and low toxicity [II, B] [22.Federico M. Luminari S. Dondi A. et al.R-CVP versus R-CHOP versus 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: 1506-1513Google Scholar, 23.Vitolo U. Ladetto M. Boccomini C. et al.Rituximab maintenance compared with observation after brief first-line R-FND chemoimmunotherapy with rituximab consolidation in patients age older than 60 years with advanced follicular lymphoma: a phase III randomized study by the Fondazione Italiana Linfomi.J Clin Oncol. 2013; 31: 3351-3359Google Scholar]. If there is evidence (histological grade 3B or clinical signs of transformation) of more aggressive lymphoma, an anthracycline-based regimen [rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP)] should be applied.Table 6Combined chemoimmunotherapy in FL (first line)StudyTotal no. of patientsMedian follow-upOverall responseTime to treatment failure (months)Overall survivalMarcus et al. [16.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.J Clin Oncol. 2008; 26: 4579-4586Google Scholar]15953 months81%2783% (4 years) R-CVP(P < 0.0001)(P < 0.0001)(P = 0.029)Hiddemann et al. [17.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.Blood. 2005; 106: 3725-3732Google Scholar]22358 months96%NR90% (2 years) R-CHOP(P < 0.001)(P = 0.0493)Herold et al. [18.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.J Clin Oncol. 2007; 25: 1986-1992Google Scholar]10548 months92%NR87% (4 years) R-MCP(P = 0.0009)(P < 0.0001)(P = 0.0096)Bachy et al. [19.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.Haematologica. 2013; 98: 1107-1114Google Scholar]17599 months81%6679% (8 years) R-CHVP-IFN(P = 0.035)(P = 0.0004)(P = 0.076)Rummel et al. [21.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 lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial.Lancet. 2013; 381: 1203-1210Google Scholar]13934 months93%NR84% (4 years) BRFederico et al. [22.Federico M. Luminari S. Dondi A. et al.R-CVP versus R-CHOP versus 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: 1506-1513Google Scholar]34 months95% (3 years) R-CVP17888%46% (3 years) R-CHOP17893%62% (3 years) R-FM17891%59% (3 years) + R maintenanceVitolo et al. [23.Vitolo U. Ladetto M. Boccomini C. et al.Rituximab maintenance compared with observation after brief first-line R-FND chemoimmunotherapy with rituximab consolidation in patients age older than 60 years with advanced follicular lymphoma: a phase III randomized study by the Fondazione Italiana Linfomi.J Clin Oncol. 2013; 31: 3351-3359Google Scholar]23442 months86%NR89% (3 years) 4× R-FND + 4× R ± R maintenanceP, significance levels in comparison with chemotherapy only.FL, follicular lymphoma; R-CVP, cyclophosphamide, vincristine and prednisolone; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone; R-MCP: mitoxantrone, chlorambucil, prednisone; R-CHVP-IFN, rituximab, cyclophosphamide, doxorubicin, etoposide, prednisone, interferon; BR, bendamustine–rituximab; R-FM, rituximab, fludarabine and mitoxantrone; R-FND, cyclophosphamide, vincristine and prednisolone; NR, not reached. Open table in a new tab P, significance levels in comparison with chemotherapy only. FL, follicular lymphoma; R-CVP, cyclophosphamide, vincristine and prednisolone; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone; R-MCP: mitoxantrone, chlorambucil, prednisone; R-CHVP-IFN, rituximab, cyclophosphamide, doxorubicin, etoposide, prednisone, interferon; BR, bendamustine–rituximab; R-FM, rituximab, fludarabine and mitoxantrone; R-FND, cyclophosphamide, vincristine and prednisolone; NR, not reached. Antibody monotherapy (rituximab, radioimmunotherapy) or chlorambucil plus rituximab remain alternatives for patients with a low-risk profile or when conventional chemotherapy is contraindicated [III, B] [24.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.J Clin Oncol. 2010; 28: 4480-4484Google Scholar, 25.Scholz C.W. Pinto A. Linkesch W. et al.(90)Yttrium-ibritumomab-tiuxetan as first-line treatment for follicular lymphoma: 30 months of follow-up data from an international multicenter phase II clinical trial.J Clin Oncol. 2013; 31: 308-313Google Scholar]. In patients with positive hepatitis B serology including occult carrier (HBS Ag negative and anti-core positive), prophylactic antiviral medication and regular monitoring of HBV DNA are strongly recommended [I, A] [26.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.J Clin Oncol. 2013; 31: 2765-2772Google Scholar]. Rituximab maintenance for 2 years improves PFS (59% versus 43% after 6 years, P < 0.0001) [I, B] [27.Salles G. Seymour J.F. Feugier P. et al.Updated 6 year follow-up of the PRIMA study confirms the benefit of 2-year rituximab maintenance in follicular lymphoma patients responding to frontline immunochemotherapy.Blood. 2013; 122 (abstr. 509)Google Scholar], whereas a shorter maintenance period results in inferior benefit [28.Taverna C.J. Martinell G. Hitz F. et al.Rituximab maintenance treatment for a maximum of 5 years in follicular lymphoma: results of the randomized phase III trial SAKK 35/03.Blood. 2013; 122 (abstr. 508)Google Scholar]. Radioimmunotherapy consolidation also prolongs PFS after chemotherapy, but its benefit seems to be inferior in comparison with rituximab maintenance for 2 years [II, B] [29.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.J Clin Oncol. 2013; 31: 1977-1983Google Scholar, 30.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.Blood. 2013; 122 (abstr. 369)Google Scholar]. Myeloablative consolidation followed by autologous stem cell transplantation (ASCT) prolongs PFS after chemotherapy, but its benefit after a rituximab-containing induction is minor and no OS has been observed [31.Hiddemann W. Dreyling M.H. Metzner B. et al.Evaluation of myeloablative therapy followed by autologous stem cell transplantation in first remission in patients with advanced stage follicular lymphoma after initial immuno-chemotherapy (R-CHOP) or chemotherapy alone: analysis of 940 patients treated in prospective randomized trials of the German Low Grade Lymphoma Study Group (GLSG).Blood. 2013; 122 (abstr. 419)Google Scholar]. Therefore, such an approach is not recommended in first-line therapy of responding patients [I, D]. At relapse, it is strongly recommended to obtain a new biopsy in order to exclude transformation into an aggressive lymphoma. It may be useful to target the biopsy based on PET scanning. As at first presentation, observation is an accepted approach in asymptomatic patients with low tumour burden. Selection of salvage treatment depends on efficacy of prior regimens. In early relapses (<12–24 months), a non-cross-resistant scheme should be preferred (e.g. bendamustine after CHOP or vice versa). Other options, including fludarabine-based, platinum salts-based or alkylating agents-based regimens, could also be useful. Rituximab should be added if the previous antibody-containing scheme achieved >6- to 12-month duration of remission [IV, B]. On the other hand, obinutuzumab has recently received a positive recommendation for approval by the European Medicines Agency for rituximab-refractory cases based on an improved PFS in comparison with bendamustine only [I, B] [32.Sehn L.H. Chua N. Mayer J. et al.Obinutuzumab plus bendamustine versus bendamustine monotherapy in patients with rituximab-refractory indolent non-Hodgkin lymphoma (GADOLIN): a randomised, controlled, open-label, multicentre, phase 3 trial.Lancet Oncol. 2016; 17: 1081-1093Google Scholar]. In symptomatic cases with low tumour burden, rituximab monotherapy may be applied. Radioimmunotherapy (90yttrium–ibritumomab–tiuxetan) may represent an effective therapeutic approach in elderly patients with comorbidities not appropriate for chemotherapy [IV, B]. Rituximab maintenance 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 induction in patients who have not received antibody as first-line therapy [I, A] [33.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.J Natl Cancer Inst. 2011; 103: 1799-1806Google Scholar]. A second-line maintenance treatment has not been investigated in the setting of maintenance use in first line and probably should not be used for those patients who had relapsed during their first maintenance period [IV, D]. High-dose chemotherapy with ASCT prolongs PFS and OS and should be considered, especially in patients who experience short-lived first remissions (<2–3 years) after rituximab-containing regimens, which usually have a much worse long-term outcome, but its general role in the rituximab era has to be redefined [I, B] [34.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.J Clin Oncol. 2003; 21: 3918-3927Google Scholar, 35.Le Gouill S. De Guibert S. Planche L. et al.Impact of the use of autologous stem cell transplantation at first relapse both in naive and previously rituximab exposed follicular lymphoma patients treated in the GELA/GOELAMS FL2000 study.Haematologica. 2011; 96: 1128-1135Google Scholar, 36.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.Haematologica. 2013; 98: 1014-1021Google Scholar, 37.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.J Clin Oncol. 2015; 33: 2516-2522Google Scholar]. A subsequent rituximab maintenance may achieve some improvement in PFS [II, B] [38.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.J Clin Oncol. 2013; 31: 1624-1630Google Scholar]. In later relapses, monotherapy is an established option with palliative intent [II, B]. The PI3K inhibitor idelalisib has been registered in double-refractory FL, based on a phase II study [39.Gopal A.K. Kahl B.S. de Vos S. et al.PI3K&dgr; inhibition by idelalisib in patients with relapsed indolent lymphoma.N Engl J Med. 2014; 370: 1008-1018Google Scholar]. Recent analyses suggest an increased mortality risk as a consequence of pulmonary morbidity (atypical pneumonias/pneumonitis), so appropriate prophylaxis (cotrimoxazole/acyclovir) is strongly recommended. Cytomegalovirus monitoring may be also advised. In selected younger patients with later relapses of high-risk profile or relapse after ASCT, a potentially curative allogeneic stem cell transplantation (preferably with dose-reduced conditioning) may be considered, especially in patients with early relapse and refractory disease [IV, B] [36.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.Haematologica. 2013; 98: 1014-1021Google Scholar]. In recent years, new approaches, including lenalidomide–rituximab and additional inhibitors of the B-cell signalling pathway, have proved active 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 [I, D]. Appropriate imaging evaluation should be carried out midterm and after completion of chemotherapy. Patients with an inadequate response [less than partial response (PR)] should be evaluated for early salvage regimens. PR patients may convert to complete response (CR) under rituximab maintenance. PET–CT after completion of chemotherapy induction has been recommended for prognostic reasons as persistent PET-positivity (using appropriate Deauville scales) identifies a small group (20%–25%) of patients with a worse prognosis [40.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.Lancet Haematol. 2014; 1: e17-e27Google Scholar], but therapeutic consequences remain undefined [II, B]. Minimal residual disease (MRD) analysis by polymerase chain reaction at the end of the treatment is an independent predictor of long-term outcome, but should not guide therapeutic strategies outside of clinical studies. 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 patient perspective (Figure 1). PET- and MRD-based tailored treatments are currently evaluated in studies but are not yet routine clinical practice. Paediatric FL is an FL variant originally described in children, but occurs in adults as well. It is characterised by a localised disease, the absence of bcl-2 aberrations, lack of t(14;18), grade III and a high proliferation rate. It shows a much more indolent course and should be managed with local therapy only, despite displaying histologically more aggressive features [41.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.Blood. 2012; 120: 2395-2404Google Scholar]. The following minimal recommendations are based on consensus rather than on evidence (Table 7):•After local radiotherapy: history and physical examination every 6 months for 2 years, subsequently once a year if clinically indicated.•After (during continuous) systemic treatment: history and physical examination every 3–4 months for 2 years, every 6 months for 3 additional years, and subsequently once a year [V, D].•Blood count and routine chemistry every 6 months for 2 years, then only as needed for evaluation of suspicious symptoms.•Evaluation of thyroid function in patients with irradiation of the neck at 1, 2 and 5 years.•Minimal adequate radiological or ultrasound examinations every 6 months for 2 years and optionally annually up to 5 years. Regular CT scans are not mandatory outside of clinical trials, especially if abdominal ultrasound is applicable. PET–CT should be not used for surveillance.•MRD screening may be carried out in clinical studies but should not guide therapeutic strategies.Table 7Recommended follow-up after end of therapyExaminationDetailsYear 1–2Year 3–5Year >5HistoryB symptomsEvery 3–4 monthsTwice annuallyAnnuallyPhysical examinationParticular: peripheral lymph nodes, liver, spleenEvery 3–4 monthsTwice annuallyAnnuallyLaboratory work-upBlood and differential countEvery 3–4 monthsTwice annuallyAnnuallyLDHEvery 3–4 monthsTwice annuallyIf progress suspectedImagingAbdominal ultrasoundTwice annuallyEvery 12 monthsIf progress suspectedCT neck, chest, abdomen, pelvisOptional: 6–12 monthsOptional: 12–24 monthsIf progress suspectedLDH, lactate dehydrogenase; CT, computed tomography. Open table in a new tab LDH, lactate dehydrogenase; CT, computed tomography. 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, and a summary of recommendations is provided in Table 8. Levels of evidence and grades of recommendation have been applied using the system shown in Table 9. 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 3Consensus-driven recommendations outside of clinical studies—high tumour burden. R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone; R-CVP, cyclophosphamide, vincristine and prednisolone; BR, bendamustine–rituximab; CR, complete response; PR, partial response; ASCT, autologous stem cell transplantation. aAccording to biological age; bespecially if transformation is suspected; c70–90 mg/m2, 4–6 cycles [42.Cheson B.D. Brugger W. Damaj G. et al.Optimal use of bendamustine in hematologic disorders: treatment recommendations from an international consensus panel—an update.Leuk Lymphoma. 2016; 57: 766-782Google Scholar].View Large Image Figure ViewerDownload (PPT)Table 8Summary of recommendationsIn localised stages: radiation (24 Gy)In advanced stages: treatment depends on clinical risk factors, symptoms and patient perspectiveStandard approach in asymptomatic advanced cases: watch and waitIn advanced symptomatic cases Combined chemoimmunotherapy for long-term remissions Recommend rituximab maintenance for consolidationRelapse is frequently sensitive to conventional approachesAutologous (and allogeneic) transplantation should be only discussed in relapseMonotherapy (antibodies, idelalisib) is appropriate, especially in later relapses Open table in a new tab Table 9Levels of evidence and grades of recommendation (adapted from the Infectious Diseases Society of America-United States Public Health Service Grading SystemaBy permission of the Infectious Diseases Society of America [43].)Levels of evidence IEvidence from at least one large randomised, controlled trial of good methodological quality (low potential for bias) or meta-analyses of well-conducted randomised trials without heterogeneity IISmall randomised trials or large randomised trials with a suspicion of bias (lower methodological quality) or meta-analyses of such trials or of trials with demonstrated heterogeneity IIIProspective cohort studies IVRetrospective cohort studies or case–control studies VStudies without control group, case reports, experts opinionsGrades of recommendation AStrong evidence for efficacy with a substantial clinical benefit, strongly recommended BStrong or moderate evidence for efficacy but with a limited clinical benefit, generally recommended CInsufficient evidence for efficacy or benefit does not outweigh the risk or the disadvantages (adverse events, costs, …), optional DModerate evidence against efficacy or for adverse outcome, generally not recommended EStrong evidence against efficacy or for adverse outcome, never recommendeda By permission of the Infectious Diseases Society of America [43.Dykewicz C.A. Summary of the guidelines for preventing opportunistic infections among hematopoietic stem cell transplant recipients.Clin Infect Dis. 2001; 33: 139-144Google Scholar]. Open table in a new tab MD has reported institutional research support from Celgene, Janssen, Mundipharma, Pfizer and Roche; speaker's honoraria from Bayer, Celgene, Gilead, Janssen and Roche; advisory boards for Bayer, Celgene, Gilead, Janssen, Pfizer and Roche. MG has reported honoraria from Roche, Mundipharma, Gilead and Janssen. SR has reported research support from Janssen, Roche and Celgene; advisory boards for Janssen, Gilead, Roche, AstraZeneca and Celgene; speaker's honoraria from Janssen, Celgene and Roche. GS has reported personal fees for advisory boards or participation in meetings from Amgen, Celgene, Gilead, Janssen, Mundipharma, Novartis and Roche; grant support from Roche. UV has reported advisory boards for Roche and Janssen; honoraria for lectures from Roche, Janssen, Celgene, Takeda; conducting research as a global PI in multicentre studies sponsored by Roche and Celgene. ML has reported institutional research support from Celgene, Janssen, Mundipharma, Pfizer and Roche; speaker's honoraria from Bayer, Celgene, Gilead, Janssen and Roche; advisory boards for Bayer, Celgene, Gilead, Janssen, Pfizer and Roche. Correction to: Newly diagnosed and relapsed follicular lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-upAnnals of OncologyVol. 28Issue 12PreviewAnn Oncol 2016; 27(Suppl 5): v83–v90 (doi: ) Full-Text PDF Open Archive