Follicular lymphoma is a subtype of non-Hodgkin lymphoma and it represents easy-to-diagnose and incurable lymphomas
Tijana Kovačević MRPharmS
University Hospital Clinical Centre Banja Luka, Republic of Srpska, Bosnia and Herzegovina
Pedja Kovačević MD PhD
Medical Intensive Care Unit,
University Hospital Clinical Centre Banja Luka,
Republic of Srpska, Bosnia and Herzegovina; Physiology department, Faculty of Medicine, University of Banja Luka, Republic of Srpska, Bosnia and Herzegovina
Follicular lymphoma (FL) is the most common of the clinically indolent non-Hodgkin lymphomas (NHLs): it represents easy-to-diagnose and incurable lymphomas. Histologically, it is composed of centrocytes (small cleaved follicular centre cells) and centroblasts (large noncleaved follicular centre cells), and virtually always demonstrates a growth pattern that is partially follicular. FL is the second most common subtype of NHL. The estimated incidence of FL in the US is 3.18 cases per 100,000 people, whereas the estimated incidence in Europe is 2.18 cases per 100,000 people per year. FL appears to be more common in White populations compared with Black and Asian populations, and its incidence increases with age, so FL is most commonly diagnosed in middle-aged and elderly individuals, while it is quite rare in children and adolescents.1
FL is defined as those lymphomas in which survival of the untreated patient is measured in years. Its median survival was for decades evaluated to be approximately nine to ten years, but with the advent of new treatment modalities and better supportive care it has increased to 14 years. The survival curve of these patients is characterised by a continuously descending straight line never reaching a plateau.2
Patients with FL generally present with asymptomatic peripheral lymphadenopathy in the cervical, axillary, inguinal, and/or femoral regions with waxing and waning present for years. Involvement of bone marrow is present in 70% of patients, whereas involvement of other normal organs is uncommon. Some patients present with relatively asymptomatic large abdominal masses with or without evidence of gastrointestinal and/or urinary tract obstruction. Staging studies usually demonstrate widely disseminated disease with overt involvement of the spleen, liver, and/or bone marrow in approximately 40, 50, and 60–80% of cases, respectively.
Most patients are asymptomatic at diagnosis except for lymph node enlargement, despite the presence of widespread disease. Less than 20% present with B symptoms (that is, fevers, night sweats, or unintentional weight loss). There are no characteristic laboratory abnormalities specifically associated with FL and, despite the large tumour burden, fewer than 25% of patients present with an increased serum lactate dehydrogenase (LDH) or cytopenias in the peripheral blood.3
The prognosis is determined by several clinical and biological factors, the most commonly used being the follicular lymphoma international prognostic index (FLIPI) as presented in Table 1. The FLIPI was created out of survival data of 4167 patients in a seven-year international study and includes five prognostic factors: serum LDH, involved nodal areas, patient age, stage and haemoglobin.4
The diagnosis of FL is best made by excisional tissue biopsy, most commonly a lymph node. The histologic examination is essential, while immunophenotypic and molecular genetic studies can help to support a suspected diagnosis. Most patients will have systemic follicular lymphoma. The 2008 World Health Organization (WHO) classification of tumours of haematopoietic and lymphoid tissues recognises three additional clinical variants of FL:
- Paediatric follicular lymphoma
- Intrafollicular neoplasia/’in situ’ follicular lymphoma
- Primary intestinal follicular lymphoma.
Involvement of bone marrow is very common with paratrabecular lymphoid aggregates. FL cells express monoclonal immunoglobulin light chain CD19, CD20, CD10, and BCL-6 and are negative for CD5 and CD23. Clonal immunoglobulin gene rearrangements are also present and most cases have extensive somatic mutations.5
The patient’s stage of the disease at presentation should be evaluated before the start of the treatment. Evaluation is performed using Ann Arbor Staging system, as shown in Table 2.6
Treatment of limited stage (I/II) FL
Less than 10% of patients with FL will present with pathological stage I/II disease. There are three treatment options for this group of patients: radiotherapy, chemoimmunotherapy and observation, with radiotherapy being the treatment of choice for most. Radiotherapy (RT) in a dose of 24 Gy appears to be highly effective and results in ten-year overall survival rates of 60–80%, with a median survival of approximately 19 years. Adjuvant chemotherapy does not appear to add additional benefit after local RT.
Observation might be the reasonable alternative especially for stage II patients who are not ideal candidates for RT due to the location of their disease and expected toxicities, or if the patient chooses not to receive radiation.7 Two retrospective studies examined effectiveness of RT in 177 and 80 patients with FL stage I or II respectively and found that freedom from relapse was significantly better for patients aged under 60 and for those who received radiation to both sides of the diaphragm as well as the factors influencing progression-free survival, including tumour size and Ann Arbor stage.8,9 In a third study, 6568 FL patients were analysed through SEER database and it was concluded that patients who received initial RT had superior rates of disease-specific survival at 5 (90% versus 81%), 10 (79% versus 66%), 15 (68% versus 57%), and 20 (63% versus 51%) years.10
Treatment of advanced stage (III/IV) FL
Decision on treatment of patients with advanced stage (III/IV) FL is usually made using GELF (Groupe d’Etude des Lymphomes Folliculaires) or BLNI (British National Lymphoma Investigation) criteria. Three strategies have been proposed and used in asymptomatic, non-bulky FL patients: watchful waiting; rituximab induction (rituximab 375mg/m2 weekly for four doses); or rituximab induction followed by maintenance rituximab (administered every two months for two years). In a study that included 379 patients, three strategies were compared and no difference was found in overall survival or rate of histological transformation.11 Although rituximab improves quality of life, postpones induction of chemotherapy and reduces stress in patients, the preferred strategy is to watch and wait based on large prospective trials that have demonstrated no difference in survival as well as the avoidance of cost, complications and potential drug resistance.
Key treatment of patients with symptomatic FL is immunotherapy with monoclonal antibodies. Moreover, chemoimmunotherapy results in superior response rates, progression-free survival, and overall survival, although ideal timing of monoclonal antibody administration (for example, before, with, or following chemotherapy) and preferred agent is yet unknown. Several randomised trials have demonstrated the benefit of adding rituximab to combination chemotherapy in terms of improved response rates and time to progression when rituximab was added. Progression-free survival rates at three years were increased (approximately 15–30%). First-line therapy for treatment of advanced stage FL implies one of the following regimens:12
- Bendamustine + rituximab
- RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone)
- RCVP (rituximab, cyclophosphamide, vincristine, prednisone)
- Rituximab (375mg/m2 weekly for four doses).
Radioimmunotherapy, especially 90Y-ibritumomab tiuxetan was found to be effective in patients with previously untreated FL receiving chemotherapy without rituximab. Single therapy with radioimmunoconjugates is showing promising results in treatment-naïve patients, but this approach needs to be confirmed in large randomised trials.
Autologous haematopoietic cell transplantation (HCT) after high dose chemotherapy was studied in trials that were analysed in a Cochrane systematic review, and it was found that HCT resulted in significantly improved progression-free survival (hazard ratio (HR) 0.42; 95% CI 0.33–0.54) but similar overall survival (HR 0.97; 95% CI 0.76–1.24) when compared with combination chemotherapy or immunochemotherapy.13
Maintenance therapy with rituximab (every eight weeks for a maximum of two years) is shown to be beneficial after chemoimmunotherapy (at least partial response with RCVP or RCHOP), after immunotherapy alone, and after chemotherapy alone.
Treatment of relapsed or refractory FL
There are few treatment options for patients with relapsed or refractory FL and the choice among these options is made by taking into account the patient’s response to previous treatment, their performance status as well as tumour characteristics. Immunotherapy is a treatment option for most patients with relapsed or refractory FL, whether rituximab is used as a monotherapy due to low toxicity and high response rates of approximately 40%, (which is a good option for patients with poor performance status) or rituximab in combination with chemotherapy that has higher response rates but increased toxicity, which might be the option for patients with better performance status.14
Radioimmunotherapy is a good treatment option for eligible patients (for example, good bone marrow reserve) due to its high response rates of 60–80% but the treatment administration is quite complex. The use of allogenic or autologous HCT is still controversial and is performed usually in patients with clinically aggressive disease who relapse to initial treatment with immunotherapy. Radiation can be used as a palliation therapy in patients with a single disease site.
Sometimes the best treatment option for patients is enrolment onto a well designed, scientifically valid, peer-reviewed clinical trial. A number of new approaches are being studied at the moment and these include: new monoclonal antibodies such as ofatumumab and obinutuzumab; other B-lineage antigen-directed antibodies (CD22 and CD23) such as epratuzumab or lumiliximab; drugs targeting the PI3K/Akt/mTOR pathway as well as B-cell receptor signalling such as temsirolimus, everolimus, idelalisib, fostamatinib and ibrutinib; BCL-2 inhibitors such as navitoclax; and immunomodulatory drugs such as lenalidomide.15
- Sant M et al. Incidence of hematologic malignancies in Europe by morphologic subtype: results of the HAEMACARE project. Blood 2010;116:3724–34.
- Fisher RI et al. New treatment options have changed the survival of patients with follicular lymphoma. J Clin Oncol 2005;23:8447–52.
- Friedman A. Follicular lymphoma: 2014 update on diagnosis and management. Am J Hematol 2014;89(4):429–36.
- Solal-Celigny P et al. Follicular lymphoma international prognostic index. Blood 2004;104:1258–65.
- Freedmen AS. Biology and management of histologic transformation of indolent lymphoma. Hematol Am Soc Hematol Educ Program 2005;314–20.
- Lister TA et al. Report of a committee convened to discuss the evaluation and staging of patients with Hodgkin’s disease: Cotswolds meeting. J Clin Oncol 1989;7(11):1630–6.
- Friedberg J et al. Initial therapeutic strategy in follicular lymphoma: An analysis from the National LymphoCare Study. J Clin Oncol 2006;24:428s
- 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.
- Wilder RB et al. Long-term results with radiotherapy for Stage I-II follicular lymphomas. Int J Radiat Oncol Biol Phys 2001;51:1219–27.
- Pugh TJ et al. Improved survival in patients with early stage low-grade follicular lymphoma treated with radiation: a Surveillance, Epidemiology, and End Results database analysis. Cancer 2010;116:3843–51.
- Ardeshna KM 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;15:424–35.
- National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: Non-Hodgkin’s lymphomas;Version 4. 2014.
- Schaaf M et al. High-dose therapy with autologous stem cell transplantation versus chemotherapy or immuno-chemotherapy for follicular lymphoma in adults. Cochrane Database Syst Rev 2012;1:CD007678.
- Forstpointner R et al. The addition of rituximab to a combination of fludarabine, cyclophosphamide, mitoxantrone (FCM) significantly increases the response rate and prolongs survival compares to FCM alone in patients with relapsed and refractory follicular and mantle cell lymphomas: Results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood 2004;104:3064–71.
- Hiddeman W, Cheson BD. How we manage follicular lymphoma. Leukemia 2014;28:1388–95.