Follicular lymphoma (FL) is a slow-growing type of non-Hodgkin lymphoma (NHL) that arises from B-cells within the lymph nodes and other lymphoid tissues. As the second most common form of NHL, FL is often considered incurable, but it is highly treatable, and many people live for decades with the condition. Treatment is highly personalized, determined by factors including the extent of the disease, the presence of symptoms, the total amount of tumor (tumor burden), and the patient’s overall health. Management ranges from observation to intensive systemic therapies. The goal of therapy is to control the cancer for as long as possible, manage symptoms, and improve quality of life.
Initial Management Strategy: Observation or Intervention
The first decision in managing follicular lymphoma is whether to begin active treatment immediately or monitor the disease without intervention. This approach, frequently called “Watchful Waiting” or Active Surveillance, is suitable for patients who are asymptomatic and have a low tumor burden. Studies show that immediate treatment for low-burden disease does not significantly improve overall survival compared to postponing therapy, thus avoiding unnecessary side effects.
The transition from observation to active therapy is prompted by specific changes in the disease or the patient’s health. Clinicians use established criteria, such as the Groupe d’Étude des Lymphomes Folliculaires (GELF) criteria, to determine the need for intervention. Triggers for starting treatment include the development of systemic symptoms (unexplained fever, drenching night sweats, or significant weight loss). Active treatment is also initiated if the tumor burden becomes substantial (a mass greater than seven centimeters), if the disease threatens organ function, or if there is rapid disease progression. Immediate intervention is also necessary if the lymphoma causes cytopenias, such as a low platelet or white blood cell count.
Systemic First-Line Therapies
When active treatment is indicated for advanced-stage or symptomatic follicular lymphoma, the standard first-line approach is chemoimmunotherapy. The backbone of nearly all initial systemic regimens is an anti-CD20 monoclonal antibody, such as rituximab or obinutuzumab. These antibodies target the CD20 protein found on the surface of the malignant B-cells, marking them for destruction.
The monoclonal antibody is combined with one of several established chemotherapy regimens to maximize the response. Common combinations include R-CVP, R-CHOP, or combining the antibody with bendamustine. The choice between these regimens is influenced by the patient’s age, overall health, and specific disease characteristics.
Following the initial course of chemoimmunotherapy, a maintenance phase is often recommended to extend remission. This typically involves giving the anti-CD20 antibody alone every two or three months for up to two years. This maintenance strategy improves the duration of progression-free survival.
An alternative, non-chemotherapy approach involves combining the anti-CD20 antibody with lenalidomide, an immunomodulatory drug. This regimen is considered for patients who may not tolerate the side effects of traditional chemotherapy. These systemic treatments are considered palliative, aiming for long-term control rather than a cure, as most follicular lymphoma presents at an advanced stage.
Treatment for Localized Follicular Lymphoma
For the small percentage of patients (typically less than 10%) who present with localized follicular lymphoma, the treatment strategy shifts toward a potentially curative approach. This localized disease is usually classified as Stage I or limited Stage II, confined to one or two adjacent lymph node areas. The preferred intervention for these cases is involved-site radiation therapy (ISRT).
ISRT delivers a focused dose of radiation, often between 24 and 30 Gray, directly to the affected lymph node sites. This targeted treatment is highly effective and can lead to long-term remission or even cure for approximately half of the patients. Systemic therapy, such as an anti-CD20 antibody alone or with chemotherapy, is generally reserved for situations where radiation is not feasible or if the patient prefers a systemic approach.
Managing Relapsed or Refractory Disease
Despite effective initial therapy, follicular lymphoma frequently relapses, necessitating further treatment. The choice of therapy for relapsed or refractory disease depends heavily on the prior treatments used and the duration of the initial remission. If the remission lasted for several years, the original chemoimmunotherapy regimen may be successfully repeated. For shorter remissions, particularly those lasting less than two years, different agents are generally selected.
Second-line chemoimmunotherapy options often involve combinations not used initially, such as an alternative anti-CD20 antibody paired with bendamustine or other chemotherapy drugs. Beyond traditional chemoimmunotherapy, targeted agents represent an expanding area of therapy. These include phosphoinositide 3-kinase (PI3K) inhibitors and enhancer of zeste homolog 2 (EZH2) inhibitors, such as tazemetostat, which target specific pathways within the cancer cells.
For patients who have undergone multiple prior lines of therapy, cellular therapies have emerged as highly effective options. Chimeric Antigen Receptor (CAR) T-cell therapy involves genetically modifying a patient’s own T-cells to specifically recognize and destroy the CD19 protein on the lymphoma cells. Products like axicabtagene ciloleucel and tisagenlecleucel have demonstrated high response rates and durable remissions in heavily pretreated patients.
Bispecific antibodies, such as mosunetuzumab, are another innovative, off-the-shelf immunotherapy. They function by physically linking the patient’s T-cells to the CD20 protein on the lymphoma cells, facilitating a direct immune attack.
High-dose chemotherapy followed by an autologous stem cell transplant (ASCT) is still considered for some patients with chemosensitive relapsed disease. A serious complication requiring immediate, aggressive treatment is histological transformation, where the indolent FL converts into a more aggressive form, such as diffuse large B-cell lymphoma. This transformation is typically treated with regimens designed for aggressive lymphomas.