Follicular lymphoma (FL) is the most common form of indolent, or slow-growing, non-Hodgkin lymphoma, accounting for up to 30% of all cases. This cancer arises from B-lymphocytes, white blood cells that normally reside in the germinal centers of lymph nodes, and often expresses the protein CD20 on its cell surface. While FL is generally considered treatable, it is not often curable with standard therapies, meaning the disease typically follows a relapsing and remitting course over many years. The personalized treatment strategy for FL is highly dependent on the disease stage, tumor burden, presence of symptoms, and the patient’s overall health, aiming for long-term disease control and quality of life.
Initial Management Strategy
For many patients with advanced-stage follicular lymphoma who are asymptomatic and have a low tumor burden, the initial approach is often “Watch and Wait,” or active surveillance. Delaying therapy until symptoms appear does not negatively affect overall survival. Deferring treatment avoids the immediate side effects and potential long-term complications associated with early intervention, such as chemotherapy-related toxicity.
The decision to transition from observation to active treatment is guided by specific criteria. These criteria typically include B symptoms (unexplained fever, drenching night sweats, or significant weight loss). Other triggers for treatment include rapid disease progression, the presence of a large tumor mass (often defined as greater than seven centimeters), or lymphoma that is causing compression on vital organs.
Standard Active Treatment Regimens
When active treatment is necessary, the current standard approach combines immunotherapy with chemotherapy. The immunotherapy component involves a monoclonal antibody that targets the CD20 protein found on the surface of the lymphoma cells, such as rituximab or obinutuzumab. These anti-CD20 antibodies work by directly killing the B-cells and enhancing the immune system’s ability to attack the cancer.
The choice of chemotherapy agent, or backbone, is selected to achieve a deep and durable remission. Common combination regimens include R-CHOP or R-CVP (which substitutes doxorubicin). A less intensive but highly effective option is the combination of bendamustine and an anti-CD20 antibody (BR or BO), which is often favored due to its favorable toxicity profile compared to anthracycline-containing regimens like R-CHOP.
Following the initial course of chemoimmunotherapy, maintenance therapy may be recommended, typically using the anti-CD20 antibody alone. This phase, which can last up to two years, has been shown to prolong the time until the lymphoma returns. The primary goal of these first-line systemic treatments is to achieve a complete or partial response, allowing patients to enter a period of disease-free survival.
Localized Treatment Options
For the minority of patients (approximately 10 to 15%) who present with localized disease (Stage I or non-contiguous Stage II FL), radiation therapy serves as a primary treatment option. Radiation uses high-energy beams to target and destroy the lymphoma cells confined to a specific area. This treatment is often delivered as involved-site radiation therapy (ISRT) to the affected lymph node regions.
A typical curative dose for localized FL is delivered over several weeks. Radiation therapy in this setting offers the potential for long-term control and even cure for a subset of patients, without the systemic side effects of chemotherapy. Furthermore, for patients with advanced disease, a lower dose of radiation, such as 4 Gy in two fractions, can be used palliatively to rapidly relieve symptoms like pain or obstruction caused by bulky tumor masses.
Managing Relapsed and Refractory Disease
Follicular lymphoma tends to relapse, necessitating subsequent lines of therapy. The treatment strategy for relapsed disease is influenced by the duration of the initial remission, with a shorter progression-free interval—such as relapse within 24 months of initial chemoimmunotherapy (known as “POD24”)—indicating a poorer prognosis. For patients who relapse later, a different chemoimmunotherapy regimen may be utilized, often switching the chemotherapy backbone or the anti-CD20 antibody.
If the disease relapses early or is considered refractory, more intensive options are considered. High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is a common strategy reserved for younger, fitter patients who experience an early relapse. In this procedure, the patient’s own stem cells are collected before high-dose chemotherapy is given to eradicate the lymphoma, and then reinfused to restore blood cell production.
The combination of an anti-CD20 antibody with an immunomodulatory agent like lenalidomide, known as the R-squared regimen, is also used for relapsed disease. Treatment decisions in this setting are highly individualized, weighing the efficacy of the treatment against the potential for cumulative toxicity and the patient’s performance status.
Emerging and Targeted Therapies
The landscape of follicular lymphoma treatment is rapidly evolving with the introduction of novel targeted agents and cellular therapies. PI3K inhibitors, such as copanlisib, idelalisib, and duvelisib, have been approved for use in patients with relapsed or refractory FL after two or more prior systemic therapies. These oral drugs work by blocking signaling pathways that are aberrantly active in the lymphoma cells, inhibiting their growth and survival.
Another targeted approach involves EZH2 inhibitors, such as tazemetostat, approved for patients whose lymphoma harbors a specific mutation in the EZH2 gene. Bispecific antibodies, like mosunetuzumab and odronextamab, represent a newer form of immunotherapy that simultaneously binds to a protein on the lymphoma cell (CD20) and a protein on the patient’s T-cells (CD3). This dual-binding mechanism redirects the body’s own T-cells to attack and destroy the cancer cells, showing promising response rates in the relapsed setting.
For heavily pretreated patients with multiply relapsed or refractory disease, Chimeric Antigen Receptor (CAR) T-cell therapy is available. This complex therapy involves genetically engineering the patient’s own T-cells to express a receptor that recognizes and targets the CD19 protein on the lymphoma cells. CAR T-cell therapy is a one-time treatment that has demonstrated high rates of durable complete remission in patients whose disease has failed to respond to other lines of therapy.