A recent primer explores follicular lymphoma (FL), including genetic susceptibility; environmental and occupational exposures; pathogenesis; tumor microenvironment; disease progression; B-cell receptor (BCR) signaling in FL survival; diagnosis; classification and management based on disease stage and response to therapy; novel management therapies; quality-of-life issues; and transformation of FL to a more aggressive form of disease.
FL accounts for 20% to 25% of non-Hodgkin lymphoma (NHL) cases in the United States and is characterized morphologically by a follicular or nodular appearance and marked heterogeneity. FL is a type of B-cell lymphoma that starts in precursor B cells and eventually involves the germinal centers of B cells in the lymph nodes and the spleen. The germinal centers are where mature B cells grow, differentiate, and undergo mutation of their antibody genes. Although the median survival for FL is 15 years or more, about 20% of patients relapse or progress within the first 2 years of diagnosis, and these patients typically have more aggressive disease, termed transformed FL.
FL usually doesn’t manifest until the sixth decade; other negative prognosticating factors include not achieving event-free survival at 24 months and having a high Follicular Lymphoma International Prognostic Index score. FL occurs more commonly in developed, high-income countries and in non-Hispanic whites. A family history of either NHL or FL increases the risk of developing FL. Multiple single-nucleotide polymorphisms in human leukocyte antigen class 1 and II genes on chromosome 6p21.3 significantly increase the risk of developing FL.
Other potential risk factors include high body-mass index and pesticide exposure. A genetic hallmark and recurrent feature in over 85% of FL cases is t(14;18)(q32;q21) translocation. This leads to B-cell overexpressing BCL2 protein, which does not undergo apoptosis. However, BCL2 dysregulation doesn’t cause FL because regulatory impairment can be present in persons without FL or NHL. Nonetheless, t(14:18) frequencies of >1 per 10,000 cells is associated with an increased risk of developing FL.
Diagnostic features of FL include lymphadenopathy, especially involving the lymph nodes in the neck and abdomen, and symptoms of fatigue, fever, night sweats, weight loss, and recurrent infection, although it is common for patients to remain asymptomatic. Other accompanying features of FL include anemia, thrombocytopenia, and/or neutropenia.
Lymph node biopsy is diagnostic, and once confirmation has been made, a needle biopsy is performed to stage FL. Positive immunohistochemical tests for BCL2, BCL5, CD10, and CD20 are indicative of FL.
Treatment for early-stage disease involves external-beam radiotherapy with or without systemic therapy. Early-stage disease is often asymptomatic, and only 20% to 30% of patients are diagnosed in Stages I and II. For Stage I or contiguous Stage II nonbulky disease, only localized radiotherapy is indicated. For Stage I or bulky, noncontiguous Stage II disease, anti-CD20 monoclonal antibody therapy +/- chemotherapy or anti-CD20 monoclonal antibody +/- chemotherapy and and/or radiotherapy is recommended. In advanced disease (Stage III or IV), which accounts for 70% to 80% of FL disease, treatment involves anti-CD20 monoclonal antibody if there is low tumor burden or the patient is elderly. Otherwise, anti-CD20 monoclonal antibody + chemotherapy (+/- maintenance anti-CD20) is utilized. Radiotherapy combined with systemic immunotherapy or chemotherapy improves progression-free survival but not overall survival.
Due to its slow growth, “watch and wait” may be a treatment option for patients with a lower tumor burden or who are asymptomatic. These patients may also be treated with rituximab, which may delay symptomatic disease for an average of 8 years. However, if a higher tumor burden is present or the patient is symptomatic, first-line therapy includes rituximab plus bendamustine or R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone). Maintenance therapy with rituximab every 2 months for 2 years is being investigated as a treatment option. Similar to rituximab, obinutuzumab, a glycoengineered type II anti-CD20 monoclonal antibody, has been shown to increase PFS but does not affect OS.
For relapsed or treatment-naïve FL, lenalidomide and rituximab regimens have high overall and complete response rates and are effective as standard chemotherapy-based regimens, but more studies are needed.
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Published January 16, 2020