Follicular Lymphoma

Follicular lymphomas are the most common, indolent non-Hodgkin lymphomas (NHL) in Western Europe and the United States. It accounts for 20 – 35% of all patients with newly diagnosed NHL. The median age at diagnosis is 60 to 65 years, displaying a broad range of variation. Females are somewhat more often affected than males.

Epidemiological studies have identified the following risk factors:

• Exposure to benzene; in Germany, exposure is officially acknowledged as an occupational disease

• Occupational exposure to pesticides

• Smoking, including passive smoking

The histological diagnosis should be based on the surgical extirpation of a suspicious lymph node. Lymph node biopsy may be taken alternatively in case the lymph nodes are not accessible (e.g. retroperitoneal lymph nodes). A fine-needle aspiration (cytology) is not sufficient. The histology report should state the diagnosis in terms of the WHO classification and specify grading (grade 1–2, 3A or 3B). Grade 3B follicular lymphomas are considered as aggressive lymphomas and treated according to the recommendations for “Diffuse Large B Cell Lymphomas”.

As the therapy of indolent lymphomas depends on the stage of disease thorough diagnostics are essential prior to onset of therapy (staging).

Diagnostics include (initial examination):

• Medical history, particularly inquiry about B symptoms

• Physical examination

• Complete blood cell count, including leukocyte count with differential, reticulocytes

• ESR, electrophoresis, total protein

• AST (GOT), ALT (GPT), AP, γ-GT, bilirubin, creatinine, uric acid, blood sugar

• LDH, β_²-microglobulin

• Prothrombin Time (Quick’s test), PTT

• Quantitative analysis of immunoglobulins, plus immune electrophoresis in case of suspected paraproteinemia

• Immunophenotyping of cell surface markers based on FACS analysis (only in case of leukemic course)

• Bone-marrow cytology*, bone-marrow histology*

• Cytogenetics (FISH, PCR) for (14;18) to distinguish from other indolent NHL**

• CT of the neck/thorax/abdomen
  (alternatively: sonography for follow-up procedures)

* not mandatory in case of “watch and wait” strategy“ when an advanced stage has already been corroborated by the existence of other lymphoma manifestations.

** not mandatory: supplementary diagnostics if findings are not unambiguous

Positron emission tomography (PET) in the scope of initial staging is only being discussed for the localized Stages I/II, as no therapeutic consequences result in the much more frequent advanced stages of follicular lymphomas [1].

In order to identify patients with an increased risk for acute and/or late complications, tests of lung function, the heart (ECG, cardiac echo) and renal function are mandatory prior to onset of therapy.

Staging is performed according to the modified Ann Arbor Classification, see Table 1.

Lymphatic tissues include: lymph nodes, spleen, thymus gland, Waldeyer’s tonsillar ring, appendix. Cervical, axillary, or inguinal lymph node enlargements as well as enlargements of liver or spleen are each considered as one region.

Stages are additionally denoted “A” in the absence, and “B” in the presence of

• fever of unknown origin > 38°C

• night sweats

• unintentional weight loss > 10% within a period of 6 months

The “Follicular Lymphoma International Prognostic Index” (FLIP Index) permits the differentiation of three prognostic subgroups [2], see Table 2. The particular factors are:

One point is assigned to each risk factor. The relative risk is summarized in a score system:

The FLIP Index was originally validated in patients who exclusively received chemotherapy [2]. However, studies revealed that the prognostic significance of the FLIP index also applies to patients treated with rituximab containing combination therapy [3]. At present, FLIPI should only be used for risk assessment, not for indication of therapy.

All inflammatory lymph node enlargements of bacterial or viral etiology (e.g. tuberculosis, toxoplasmosis, Epstein-Barr virus, cytomegalovirus, HIV) present possible differential diagnoses. In addition, differential diagnostic considerations must include, or if possible exclude, all other malignant lymphomas, lymph node metastases of solid tumors, thymomas, germinal cell tumors, or sarcoidosis.

Local radiotherapy (“involved field”) with a total dose of at least 30 Gy is able to induce long term disease-free survival and potentially cure. After 10 years, about 85 percent of patients in Stage I (or LN < 2cm) and merely 35 percent in Stage II (or LN > 3-5 cm) remain disease-free. A current study investigates whether the additional administration of rituximab further improves the therapeutic outcome (MIR Study of GLSG).

A watch & wait approach is indicated in asymptomatic patients. Therapy should be initiated only in patients with lymphoma-associated symptoms (B symptoms, hematopoietic insufficiency, rapid lymphoma progression, compression of vital organs).

First-line therapy can include the following components: induction, consolidation, and maintenance.

Immunochemotherapy, hence the combination of rituximab and chemotherapy, is the standard for medically fit patients [5].

R-CHOP: Standard therapy with good efficacy and sufficiently good tolerability: low stem-cell toxicity, therefore especially recommended for younger patients [4, 5]; however, risk for cardiotoxicity, neurotoxicity, and alopecia.

R-Bendamustine: Good efficacy combined with very good tolerability, therefore recommended especially to elderly patients [6, 7]; R-bendamustine is at least as effective as R-CHOP in patients with grade I and II follicular lymphomas.

R-MCP: Good efficacy and satisfactory tolerability; please note: high stem-cell toxicity, therefore recommended to elderly patients only [8].

R-FC(M): Only to be considered in case of predominantly leukemic course; increased risk of persistent pancytopenia; stem-cell mobilization may be hampered subsequent to more than 3-4 cycles.

Radioimmunotherapy (RIT): Monotherapy with monoclonal antibodies (rituximab, radioimmunotherapy (RIT) with Yttrium-90– Ibritumomab-Tiuxetan) represents a therapeutic alternative for patients who do not tolerate combined immunochemotherapy.

Different immunochemotherapy protocols are currently compared within active clinical trials.

In addition, oral chemotherapy (e.g. trofosfamide) is a therapeutic option in elderly medically non-fit patients.

Details regarding the therapeutic regimes are summarized in Systemic Therapy – Protocols.

1. Maintenance with rituximab (every 8 weeks 1 x 375 mg/m² over a period of 2 years) in patients responding to first-line immunochemotherapy significantly prolongs progression-free survival [15]. Overall survival was not improved in the most recent evaluation. Unexpected toxicity, in particular an increased rate of grade 3-4 infections, did not occur compared with the observation arm. Considering its high efficacy and low toxicity, maintenance therapy with rituximab is considered standard therapy in patients responding to first-line induction containing rituximab plus chemotherapy.

2. Interferon-alpha is an effective drug in patients with follicular lymphoma. However, these data were obtained prior to the introduction of rituximab into induction therapy. Interferon treatment is associated with severe side effects [16].

3. Consolidation in first remission with means of RIT leads to a significant prolongation of progression-free survival after induction chemotherapy. At present, data on the efficacy of RIT subsequent to initial rituximab-chemotherapy are limited.

4. The benefit of myeloablative high-dose therapy with autologous stem cell transplantation (ASCT) is currently not established in first remission. It is therefore recommended to perform myeloablative therapy with subsequent ASCT only within clinical studies.

More information on the drugs used is summarized in the Section Authorization Status.

1. A further lymph node extirpation or biopsy is recommended prior to initiation of relapse therapy, in order to exclude secondary malignant transformation into an aggressive lymphoma. The risk of transformation is at about 3% / year.

2. Immunochemotherapy is the standard for induction also at the time of relapse (duration of remission > 6 months). The selection of the regime depends on primary therapy, e.g. in case of a pretreatment with R-CHOP a therapy with B-R or R-FC will be recommendable, in case of an initial therapy with B-R, for example, a therapy with R-CHOP. If the relapse occurs after initial rituximab/chemotherapy within a period of 6 months, refractoriness to rituximab has to be assumed and treatment with chemotherapy alone is recommended (e.g. bendamustine).

1. For consolidation after successful induction, myeloablative high-dose therapy with subsequent autologous stem cell transplantation is an option particularly for younger patients and in cases of early relapses. However, only retrospective data are as yet available to prove the efficacy of ASCT after rituximab-containing salvage therapy [9].

2. Maintenance therapy with rituximab (one infusion every 3 months over a period of 2 yeas) significantly prolongs progression-free survival and is authorized for application in relapse treatment [10, 11].

3. Alternatively, RIT is to be discussed in this situation [12, 13].

4. Allogenic stem cell transplantation is not a standard for relapsed patients. However, it can be taken into consideration in young chemotherapy-sensitive patients who are in good general condition. Allogeneic stem cell transplantation should preferentially be performed within clinical studies [14].