DÄ internationalArchive18/2021Follicular Lymphoma—Diagnosis, Treatment, and Follow-Up

Clinical Practice Guideline

Follicular Lymphoma—Diagnosis, Treatment, and Follow-Up

Diagnosis, treatment, and follow-up

Dtsch Arztebl Int 2021; 118: 320-5. DOI: 10.3238/arztebl.m2021.0022

Zoellner, A; Herfarth, K; Herold, M; Klapper, W; Skoetz, N; Hiddemann, W

Background: Follicular lymphoma (FL) occurs predominantly at advanced age, with an annual incidence of 3–5 cases per 100 000 inhabitants in Western countries. The clinical course is heterogeneous.

Methods: For this new guideline, systematic literature searches were conducted in medical databases (MEDLINE, PubMed Central) (up to November 2017) and in the Guidelines International Network (G-I-N), and recent publications were added.

Results: The results of 21 systematic reviews with meta-analyses, 75 randomized controlled trials, and 58 prospective and retrospective studies were evaluated. Lymph-node biopsy is necessary for initial diagnosis of FL. CT scanning of the neck, thorax, and abdomen should be performed to assess how far the disease has spread, together with bone marrow biopsy and, if required, PET/CT. In early FL (stages I and II; 10–15 %), potentially curative radiotherapy combined with an anti-CD 20 antibody is recommended. In advanced disease (stages III and IV), watchful waiting is indicated for patients who have no clinical symptoms and a low tumor burden. Patients with clinical symptoms and/or high tumor burden should receive chemotherapy in combination with an anti-CD 20 antibody, followed by 2 years’ maintenance treatment with an anti-CD 20 antibody.

Conclusion: Given the good long-term prognosis of FL, the treatment must be chosen with care and thorough follow-up is necessary to ensure detection of late sequelae such as second malignancies or organ damage.

LNSLNS

Follicular lymphoma (FL) is a malignancy that develops from the B-cell lineage in the lymphatic system. After diffuse large-cell B-cell lymphoma, FL is the second most common malignant lymphoma in Western countries. The incidence is between three and five cases per 100 000 inhabitants per year and has risen in recent years (1). FL affects particularly the older age groups (mean age at diagnosis >60 years) and is characterized by a heterogeneous clinical presentation and a very variable prognosis. Some patients have no or only minor symptoms for years and initially do not require treatment. Others, however, present with symptoms at diagnosis or shortly after and will have to undergo treatment (2, 3, 4). The S3 clinical practice guideline that has been developed for Germany for the first time provides an overview of the current recommendations for the diagnosis, therapy, and follow-up of follicular lymphoma.

Methods

Guideline conceptualization and development

The German clinical practice guideline for follicular lymphoma was developed by an interdisciplinary group of clinicians, methodologists, patient representatives, and representatives from 24 scientific medical societies (see eMethods), the Deutsche Studiengruppe niedrig-maligne Lymphome (GLSG, German Low Grade Lymphoma Study Group), and the German Lymphoma Alliance (GLA). The scientific medical society in charge was the German Society of Hematology and Medical Oncology (DGHO); the guideline was published by the guideline program oncology of the Association of the Scientific Medical Societies in Germany (AWMF), the German Cancer Society (DKG), and the German Cancer Aid (DKH). The latter provided the funding for the guideline project. The guideline program oncology accompanied the development of the guideline methodologically and provided AWMF certified guideline advisers as moderators.

After key questions and patient relevant endpoints had been defined, the methodological process was set out. The quality of the evidence (confidence in the effect estimates) was evaluated by using the GRADE approach—depending on the endpoint prioritized beforehand (eTable). For the remaining statements/recommendations, the development process was decided on the basis of expert consensus of the guideline group.

Recommendation grades and confidence in the evidence by endpoint according to GRADE
eTable
Recommendation grades and confidence in the evidence by endpoint according to GRADE

A detailed description of the methods including the management of conflicts of interests can be found in the guideline report (https://www.awmf.org/uploads/tx_szleitlinien/018–033OLk_S3_Follikulaeres_Lymphom_/>2020–06.pdf).

Results

A systematic literature search identified a total of 8508 potentially relevant publications. Of these, 21 (23 publications) systematic reviews with meta-analyses, 75 (97 publications) randomized controlled trials, and 58 (68 publications) prospective or retrospective studies were included to address the defined key questions. The eFigure shows as an example the specific literature search strategy for randomized controlled trials that were evaluated for the guideline.

Flow chart showing the specific literature search for randomized controlled trials
eFigure
Flow chart showing the specific literature search for randomized controlled trials

The extended version and the abbreviated version as well as the guideline reports can be found at www.awmf.org and www.leitlinienprogramm-onkologie.de/leitlinien/follikulaeres-lymphom/. The guideline is also available digitally in the app for the guideline program oncology (www.leitlinienprogramm-onkologie.de/app/).

Diagnosis and staging

Follicular lymphomas are usually characterized by slowly progressive growth. Accordingly, many patients remain asymptomatic for a long time, particularly in the early stages. Characteristic symptoms are mostly painless swollen lymph nodes on the neck or axilla, also in the abdomen, more rarely in the inguinal region. Additionally, some patients experience non-specific losses in performance (38%) and fatigue (34%) (2). B-symptoms (fevers, night sweats, weight loss) are found in less than a quarter of patients, with night sweats being the most common of the three B-symptoms, followed by weight loss in 19% and a fever in 8% of patients (2).

Swollen lymph nodes that last for several weeks or increase should prompt a histological investigation. As large a tissue specimen as possible should be harvested, and a completely excised lymph node is preferable to a punch biopsy (expert consensus [EC]). A cytological aspirate is not sufficient for diagnosis (EC). Histology should be complemented by immunohistochemistry in order to confirm the B-cell nature of the lymphoma (CD20, CD79a), the germinal center phenotype (CD10, BCL6), and criteria of malignancy (for example, lowered intrafollicular proliferation, BCL2-expression). The histological diagnosis should be made by a pathologist with extensive hemopathological experience (EC).

After confirming a diagnosis of follicular lymphoma, the stage and therapeutic requirement are determined by appropriate investigations. Since most patients do not have clinical symptoms that necessitate immediate therapy, the following investigations should be undertaken within 4–6 weeks (EC) (Box 1).

Diagnostic investigations*
Box 1
Diagnostic investigations*

If the physical examination, bone marrow biopsy, and existing imaging findings including computed tomography (CT) or alternatively, magnetic resonance imaging (MRI), do not provide any indications of stage III or IV, any planned curative radiotherapy should be preceded by positron emission tomography (PET/CT) to determine the spread of the lymphoma and to define the size of the area to be irradiated (EC) (5, 6). Since PET/CT is not covered by the statutory health insurance system, cost reimbursement may not be granted.

Primary treatment

The treatment of follicular lymphoma should be guided by the stage according to the Ann Arbor classification (Table 1) and in advanced stages III and IV also by the clinical symptoms (7).

Spread of malignant lymphomas according to the Ann Arbor staging system
Table 1
Spread of malignant lymphomas according to the Ann Arbor staging system

Treatment in the early stages

Radiotherapy is an effective method for achieving local remission (8, 9). But when using radiotherapy as the sole treatment modality in the early stages I and II, recurrences outside the radiation field are frequently observed (10, 11), which suggests that a proportion of patients has a more extensive lymphoma spread than the initial staging may indicate. For this reason, several studies have investigated the combination of radiotherapy with systemic therapy—such as chemotherapy or antibody therapy. Both additional therapeutic modalities were found to be beneficial (12, 13, 14), with antibody therapy being the preferred method because of its lower toxicity. For this reason, therapy with curative intent in stages I and II should be given as radiotherapy in combination with rituximab (recommendation grade B; caution: off-label use of rituximab). Radiotherapy should comprise “involved site” radiotherapy (EC). A recently published study reported for this approach a plateauing of progression free survival after five years in 75% for a follow-up period of more than five years (14).

Treatment in the advanced stages

In the advances stages III and IV therapy does not aim to cure but to alleviate disease-related symptoms and prolong progression free survival and as far as is possible overall survival. The timing and choice of first-line therapy depend on clinical symptoms, clinical course, and the tumor burden. The latter is defined according to the modified GELF (Groupe d’Étude des Lymphomes Folliculaires) criteria (Box 2), 15, 16).

Modified GELF criteria for determining tumor burden
Box 2
Modified GELF criteria for determining tumor burden

Strategy in case of low tumor burden without clinical symptoms

Because of the indolent course of follicular lymphomas, watchful waiting is the approach of choice in patients at the advanced stages III and IV without clinical symptoms and a low tumor burden. A prospective randomized trials compared such a “watch and wait” approach with a short course of rituximab (given as four applications) and a third arm, in which rituximab was applied for a total of two years (17). Initial results from this study show a significantly prolonged time to progression in patients in both rituximab arms. But the follow-up periods were short, and overall survival after three years did not differ. The question that also remains unanswered is whether the early administration of rituximab in asymptomatic patients may have a negative effect on treatment required at a later stage.

An analysis of the National LymphoCare Study, reflecting real life healthcare conditions, confirmed that the “watch and wait” strategy does not put affected patients at any disadvantage (18). Because of these data, early initiation of therapy of asymptomatic patients with a low tumor burden is not indicated outside clinical trials, and for this group of patients, a “watch and wait” strategy continues to be the recommended approach (recommendation grade A).

Treatment in patients with a high tumor burden and/or clinical symptoms

In patients with a high tumor burden and/or clinical symptoms, therapy should be initiated (EC). In accordance with the encouraging results of four large prospectively randomized trials, such patients should initially be treated with a combination of an anti-CD20-antibody plus chemotherapy as long as no contraindications exist to such a therapy (recommendation grade A) (Table 2) (19, 20, 21, 22).

Comparison of chemotherapy versus chemotherapy plus rituximab in RCTs
Table 2
Comparison of chemotherapy versus chemotherapy plus rituximab in RCTs

The chemotherapeutic options should include bendamustine and CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone (recommendation grade B) (Caution: off-label use of bendamustine). The selection should be guided by the patient’s individual risk profile—for example, a cardiac comorbidity—and/or the patient’s wishes. It should be borne in mind that CHOP has a higher acute toxicity especially in the form of neutropenia (55–74%) and neutropenic fevers (7–11%), whereas bendamustine leads to long-term immunosuppression and is therefore associated with infectious complications (20–26%) (23), and prophylaxis for Pneumocystis carinii pneumonia and viral infections should be given longer-term, at least to the end of maintenance treatment.

The anti-CD20-antibodies of choice are rituximab or obinutuzumab (EC). In a prospective randomized study, a combination of obinutuzumab plus chemotherapy led for the primary endpoint progression free survival (PFS) to an extended PFS (after three years: 76% versus 69%, p=0.0012) compared with a combination containing rituximab, and was also found to be superior in certain subgroups. The obinutuzumab combination did, however, have a higher rate of adverse effects. Differences in overall survival were not observed (23,24).

After complete or partial remission has been achieved, the initial treatment should be followed by two years of maintenance treatment with an anti-CD20-antibody (recommendation grade A). This recommendation is supported by several prospective randomized trials that consistently showed a statistically significantly prolonged progression free survival (PFS after 3 years: 75% versus 58%, p<0.0001 [25); median PFS: 10.5 years versus 4.1 years, p<0.001 [26]) but not overall survival (>12 years) (25, 26, 27).

Therapy in the setting of tumor recurrence

To date one has to continue to assume that follicular lymphomas at advanced stages (III and IV) cannot be cured and recurrences occur regularly. In case of a recurrence, repeated lymph node biopsy should be undertaken in order to detect a possible transformation into a high malignant lymphoma or exclude such a transformation (EC). The further diagnostic evaluation resembles the approach taken in primary therapy (EC). The indication for initiating recurrence treatment also follows the recommendations for primary treatment.

The selection of therapy for the recurrence takes into account the type of previous therapy and maintenance therapy, the quality of the response to prior therapy, the time to recurrence, the clinical symptoms associated with the recurrence, the patient’s age and comorbidities, and the patient’s own wishes. In case of recurrence or progression after more than two years after chemo-immunotherapy, the identical chemo-immunotherapy can be used again (EC) (28, 29). If the lymphoma has become refractory to rituximab, an antibody switch to obinutuzumab is beneficial (30). In case of recurrence or progression after less than two years after chemo-immunotherapy, other therapeutic options (for example, high-dose therapy followed by autologous stem cell transplantation) can be deployed in suitable patients (EC) (31, 32).

New substances

In recent years, numerous new agents for the therapy of malignant lymphomas have been developed, some of which interfere with specific signaling pathways, attach defined surface structures, or have an immunomodulatory effect. We cannot go into more detail here. Results from clinical trials, however, indicate that chemotherapy-free therapeutic approaches may become a possibility with such agents, which have a higher specificity and efficacy while also having reduced toxicity (33, 34, 35).

Follow-up

Follow-up aims to monitor the overall condition of the patient and the remission status of the lymphoma, but also to detect potential long term effects of the treatment.

In order to identify unfavorable early recurrences in a timely manner, control examinations should be undertaken every three months in the first two years after the end of therapy, and every six months from the third year onward (EC). To check the remission status after achieving complete or partial remission, CT scanning and where required PET/CT are the basis, which in case of symptoms or existing residual manifestations can be extended by using suitable additional investigations (EC). In the follow-up of asymptomatic patients, outside clinical trials, routine imaging using CT or PET/CT should not be undertaken after a progression free interval of more than two years.

The potential long term sequelae of the therapy include the development of secondary malignancies. This depends mainly on the treatment given previously. After a combination of mitoxantrone, cyclophosphamide, and predniso[lo]ne, the risk of secondary hematological neoplasms was notably higher than for CHOP (5% versus 1%) (36), whereas a Cochrane analysis founds no difference in the rate of secondary leukemias after autologous stem cell transplantation compared with conventional chemotherapy (37). On the basis of such uncertain data, patients with follicular lymphoma should be urgently advised to attend the generally recommended cancer screenings (EC).

No reliable data for follicular lymphoma exist regarding the long term injury to organs. Anthracycline induced cardiomyopathies are the exception; these occur at higher rates, with the risk of cardiac dysfunction being increased by a factor of 2.6–7 (38, 39). Because of the lack of data, the recommendation for late sequelae and organ toxicities was kept general and their evaluation recommended for the follow-up examinations.

Conclusions

The new S3 clinical practice guideline provides evidence based recommendations for the diagnosis, therapy, and follow-up of patients with follicular lymphoma. Recent studies, whose results were not yet available when the guideline was developed, are highly likely to necessitate updates and revisions to the guideline in the near future.

Conflict of interest statement
Dr Zoellner received consultancy fees from Abbvie und Hexal. She was reimbursed for travel expenses by Abbvie. She has been an employee of Janssen-Cilag since August 2019.

Prof Herfahrt has received funding from Roche Pharma for a research project he initiated.

Prof Herold has received third party funding from Roche Pharma for conducting commissioned clinical studies.

Prof Klapper received third party funding from Roche and Bayer for conducting commissioned clinical studies.

Prof Hiddeman received consultancy fees from Roche Pharma, Janssen-Cilag, and Gilead. He was reimbursed for travel expenses from Roche Pharma. He received speaker honoraria from Janssen-Cilag and Roche Pharma. He received third party funding from Roche Pharma, Janssen-Cilag, and Gilead for conducting commissioned clinical studies.

Dr Skoetz declares that no conflict of interest exists.

Manuscript received on 29 June 2020, revised version accepted on
9 November 2020.

Translated from the original German by Birte Twisselmann, PhD.

Clinical guidelines published in Deutsches Ärzteblatt are not subject to peer review—just as in many other specialist journals—because S3 clinical practice guidelines are texts that have in many cases been assessed, discussed, and broadly consented by experts (peers).

Corresponding author
Prof. Dr. med. Wolfgang Hiddemann
Medizinische Klinik III
LMU Klinikum Großhadern
Marchioninistr. 15, 81377 München
Wolfgang.Hiddemann@med.uni-muenchen.de

Cite this as:
Zoellner A, Herfarth K, Herold M, Klapper W, Skoetz N, Hiddemann W:
Clinical practice guideline: Follicular lymphoma—diagnosis, treatment, and follow-up. Dtsch Arztebl Int 2021; 118: 320–5. DOI: 10.3238/arztebl.m2021.0022

Supplementary material

eMethods, eFigure, eTable:
www.aerzteblatt-international.de/m2021.0022

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Engelhard M, Unterhalt M, Hansmann ML, Stuschke M: Follicular lymphoma: final results of the randomized evaluation of curative radiotherapy in limited stage nodal disease. Strahlenther Onkol 2013; 189 (Suppl 1): 36.
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Department of Medicine III, Hospital of the Ludwig-Maximilians-University (LMU), Munich, Germany: Dr. med. Anna Zoellner, Prof. Dr. med. Wolfgang Hiddemann
Department of Radiation Oncology, Heidelberg University Hospital, Heidelberg, Germany:
Prof. Dr. med. Klaus Herfarth
Helios-Klinikum Erfurt, Erfurt, Germany: Prof. Dr. med. Michael Herold
Department of Pathology, Lymph Node Registry, Hematopathology Section, University Hospital Schleswig-Holstein, Kiel, Germany: Prof. Dr. med. Wolfram Klapper
Evidence-based Oncology Research Group, Department of Medicine I, University of Cologne, Cologne, Germany: PD Dr. med. Nicole Skoetz
Diagnostic investigations*
Box 1
Diagnostic investigations*
Modified GELF criteria for determining tumor burden
Box 2
Modified GELF criteria for determining tumor burden
Spread of malignant lymphomas according to the Ann Arbor staging system
Table 1
Spread of malignant lymphomas according to the Ann Arbor staging system
Comparison of chemotherapy versus chemotherapy plus rituximab in RCTs
Table 2
Comparison of chemotherapy versus chemotherapy plus rituximab in RCTs
Flow chart showing the specific literature search for randomized controlled trials
eFigure
Flow chart showing the specific literature search for randomized controlled trials
Recommendation grades and confidence in the evidence by endpoint according to GRADE
eTable
Recommendation grades and confidence in the evidence by endpoint according to GRADE
1.Zentrum für Krebsregisterdaten und Gesellschaft der epidemiologischen Krebsregister in Deutschland: Krebs in Deutschland für 2015/2016. Robert Koch-Institut, Berlin 2019.
2.Schmidt C, Fingerle-Rowson G, Boehme A, et al.: Changes in the diagnosis and treatment of patients with low grade lymphoma in Germany: years 2006–2009. Leuk Lymphoma 2015; 56: 694–702 CrossRef MEDLINE
3. Hiddemann W, Cheson BC: How we manage follicular lymphoma. Leukemia 2014; 28:1388–95 CrossRef MEDLINE
4.Wohrer S, Jaeger U, Kletter K, et al.: 18F-fluoro-deoxy-glucose positron emissiontomography (18F-FDG-PET) visualizes follicular lymphoma irrespective of grading. Ann Oncol 2006; 17: 780–4 CrossRef MEDLINE
5.Wirth A, Foo M, Seymour JF, Macmanus MP, Hicks JR: Impact of [18f] fluorodeoxyglucose positron emission tomography on staging and management of early-stage follicular non-hodgkin lymphoma. Int J Radiat Oncol Biol Phys 2008; 71: 213–9 CrossRef MEDLINE
6.Metser U, Dudebout J, Baetz T, et al.: [(18) F]-FDG PET/CT in the staging and management of indolent lymphoma: a prospective multicenter PET registry study. Cancer 2017; 123: 2860–6 CrossRef MEDLINE
7.Carbone PP, Kaplan HS, Musshoff K, Smithers DW, Tubiana M: Report of the committee on Hodgkin‘s disease staging classification. Cancer Res 1971; 31: 1860–1.
8.Lowry L, Smith P, Qian W, et al.: Reduced dose radiotherapy for local control in non-Hodgkin lymphoma: a randomised phase III trial. Radiother Oncol 2011; 100: 86–92 CrossRef MEDLINE
9.Stuschke M, Hoederath A, Sack H, et al.: Extended field and total central lymphatic radiotherapy in the treatment of early stage lymph node centroblastic-centrocytic lymphomas: results of a prospective multicenter study. Study Group NHL-frühe Stadien. Cancer 1997; 80: 2273–84 CrossRef
10.Mac Manus MP, Hoppe RT: Is radiotherapy curative for stage I and II low-grade follicular lymphoma? Results of a long-term follow-up study of patients treated at Stanford University. J Clin Oncol 1996; 14: 1282–90 CrossRef MEDLINE
11. Engelhard M, Unterhalt M, Hansmann ML, Stuschke M: Follicular lymphoma: final results of the randomized evaluation of curative radiotherapy in limited stage nodal disease. Strahlenther Onkol 2013; 189 (Suppl 1): 36.
12.Friedberg JW, Byrtek M, Link BK, et al.: Effectiveness of first-line management strategies for stage I follicular lymphoma: analysis of the National LymphoCare Study. J Clin Oncol 2012; 30: 3368–75 CrossRef MEDLINE PubMed Central
13.MacManus M, Fisher R, Roos D, et al.: Randomized trial of systemic therapy after involved-field radiotherapy in patients with early-stage follicular lymphoma: TROG 99.03. J Clin Oncol 2018; 36: 2918–25 CrossRef MEDLINE
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