Relapsed or Refractory Follicular Lymphoma: Understanding When Treatment Doesn’t Work as Expected
Follicular lymphoma is a type of cancer that affects the lymphatic system, and while it typically grows slowly and responds well to initial treatment, the disease often returns or stops responding to therapy over time, requiring patients and their healthcare teams to navigate new treatment options and considerations.
Table of contents
- What Is Follicular Lymphoma?
- Understanding Relapsed and Refractory Disease
- Causes and Biology
- Clinical Presentation and Diagnosis
- Prognosis and Risk Factors
- Treatment Options for Relapsed or Refractory Disease
- When Treatment May Not Be Needed Immediately
What Is Follicular Lymphoma?
Follicular lymphoma is a type of blood cancer that develops when white blood cells called lymphocytes (cells that help your body fight infections) grow out of control.[1] More specifically, it is a form of non-Hodgkin lymphoma (a broad category of lymphomas) that arises from B cells, a type of lymphocyte that normally produces antibodies.[2]
The disease gets its name from the way abnormal B cells typically grow in clumps called follicles inside lymph nodes.[2] Lymph nodes are small, bean-shaped structures located throughout your body that are part of your immune system. Follicular lymphoma is the second most common type of non-Hodgkin lymphoma and the most common among slow-growing (indolent) lymphomas.[1] It accounts for approximately 20 to 30 percent of all non-Hodgkin lymphoma cases.[6]
Follicular lymphoma originates from cells in the germinal center of lymph nodes, specifically from two types of cells called centrocytes and centroblasts.[1][5] The disease can affect lymph nodes, bone marrow, and other organs throughout the body.[3]
- Lymph nodes
- Bone marrow
- Spleen
- Blood
Understanding Relapsed and Refractory Disease
Follicular lymphoma is typically considered an incurable disease with a pattern of relapsing and remitting over time.[1] This means the cancer often responds well to treatment initially, but tends to return at some point, requiring additional rounds of therapy. Understanding what happens when the disease returns or doesn’t respond to treatment is important for patients and their families.
The term relapsed refers to disease that reappears or grows again after a period of remission (a time when the cancer cannot be detected and symptoms have disappeared).[18] Many patients experience remission lasting for years after their first treatment, but the disease commonly returns at some point.[18]
The term refractory describes lymphoma that does not respond to treatment or when the response to treatment does not last very long.[18] This can happen with the first treatment or after the disease has already relapsed and been treated again.[1]
Most people with follicular lymphoma have a clinically indolent (slow-growing) course, needing only intermittent therapy over many years or even decades.[1] Although the disease has a relapsing and remitting pattern, it also has the potential to transform into a more aggressive type of lymphoma.[1]
Causes and Biology
Researchers believe follicular lymphoma originates from germinal center B cells in the lymph nodes.[1] While the exact cause of follicular lymphoma is not fully understood, the disease is characterized by a specific genetic change found in about 90 percent of cases.[1]
This genetic change is called the t(14;18) translocation, which involves two chromosomes swapping pieces of genetic material.[1] This translocation causes the BCL2 gene to be positioned next to the immunoglobulin heavy chain gene, leading to increased production of a protein called Bcl-2.[1] This protein helps cancer cells survive when they should normally die, allowing them to continue growing and multiplying.[1]
In recent years, researchers have discovered that mutations in genes that control how other genes are turned on and off (called epigenetic changes) are also important in follicular lymphoma.[1] These changes represent a second distinguishing characteristic of the disease.[1]
Doctors don’t know exactly what causes follicular lymphoma in most cases. The genetic changes that lead to the cancer happen at some point during a person’s lifetime and are not inherited from parents.[7] Certain factors may increase risk, including having a family history of lymphoma, age (people are typically around 60 years old when diagnosed), being white, or having certain immune system disorders.[3][7]
Clinical Presentation and Diagnosis
Follicular lymphoma often grows slowly and may not cause symptoms for a long time. Many cases are discovered during routine medical exams or tests done for other reasons.[6] When symptoms do occur, the most common is painless swelling in the neck, armpit, or groin, which indicates enlarged lymph nodes.[1][3]
Other symptoms that may appear include:
- Fatigue or feeling very tired
- Fever
- Night sweats and chills
- Unexplained weight loss (especially losing 10 percent or more of body weight)
- Shortness of breath
- Feeling full quickly or abdominal discomfort if lymph nodes or the spleen are enlarged
These symptoms are based on information from multiple sources.[1][3][6]
To diagnose follicular lymphoma and determine if it has relapsed or become refractory, doctors use several tests and procedures. The only definitive way to diagnose the disease is through a biopsy, which involves removing all or part of a lymph node for examination under a microscope.[3][17]
Additional tests may include:
- Blood tests to rule out infections and measure certain markers
- Imaging tests such as CT scans, PET scans, or MRI to see where the cancer is located and how far it has spread
- Bone marrow aspiration and biopsy to check if cancer cells are present in the bone marrow
These diagnostic procedures are outlined in various medical sources.[3][17]
After diagnosis, doctors assign a stage to the lymphoma (from stage I to stage IV) based on how many lymph nodes are affected, where they are located, and whether cancer has spread to other organs.[7] They also assign a grade based on how the cancer cells look under the microscope. Grades include 1, 2, 3A, and 3B, with grades 1 and 2 being low-grade (slow-growing) and grade 3B being high-grade (fast-growing).[13]
Because follicular lymphoma often doesn’t cause symptoms early on, most people are diagnosed at stage III or IV, meaning the disease has already spread widely in the body.[7]
Prognosis and Risk Factors
Despite being considered incurable, many people with follicular lymphoma can live for many years with the disease.[6] The overall survival for most patients is prolonged, with more than 90 percent of patients surviving beyond 5 years after initial diagnosis.[12] The median overall survival is approximately 14 years, and some research suggests this has improved even further with newer treatments.[12]
However, prognosis can vary considerably depending on several factors. About 20 percent of patients with follicular lymphoma develop disease progression within the first 2 years of starting chemotherapy, and these patients have a much poorer outlook, with an overall 5-year survival rate of only 50 percent.[1]
The timing of relapse appears to have important prognostic significance. Patients who relapse within 24 months of chemotherapy or within 12 months of receiving rituximab (a common treatment medication) are reported to have a poor prognosis.[1] This group of patients who experience early disease progression is associated with poor survival outcomes.[12]
For patients with relapsed or refractory disease, treatment selection depends on several factors, including:
- Age and overall health
- Presence of other medical conditions (comorbidities)
- Disease burden (how much lymphoma is present in the body)
- Performance status (how well the patient can carry out daily activities)
- How long the previous remission lasted
- Patient preferences regarding quality of life and treatment intensity
These factors are important considerations in treatment planning, as noted in medical literature.[1][12]
Treatment Options for Relapsed or Refractory Disease
When follicular lymphoma relapses or becomes refractory, several treatment options are available. Many of the same therapies used for newly diagnosed patients can be used again, but additional treatments have also become available in recent years.[18] While anti-CD20-based chemoimmunotherapy (combining chemotherapy with antibodies that target cancer cells) remains an important standard treatment, more biologically active agents are increasingly being used.[1]
Treatment approaches for relapsed or refractory follicular lymphoma may include:
Chemotherapy: Various chemotherapy drugs, often used in combination, can be effective. Common regimens include bendamustine, fludarabine, cyclophosphamide, doxorubicin, and vincristine, often combined with other medications.[18]
Monoclonal antibody therapy: These are medications that target specific proteins on cancer cells. Rituximab is the most common, but obinutuzumab is another option. These are often combined with chemotherapy.[18]
Immunotherapy: Newer treatments work by helping the immune system recognize and attack cancer cells. This category includes targeted therapies and checkpoint inhibitors.[3]
Targeted therapy: These medications target specific abnormalities in cancer cells. Options include drugs like copanlisib, idelalisib, tazemetostat, and lenalidomide, often used in combination with rituximab.[3][18]
CAR T-cell therapy: This advanced treatment involves collecting a patient’s own immune cells, modifying them in a laboratory to better fight cancer, and then returning them to the patient. Options include axicabtagene ciloleucel (Yescarta), tisagenlecleucel (Kymriah), and lisocabtagene maraleucel (Breyanzi).[3][18]
Radiation therapy: High-energy beams can be used to kill cancer cells, particularly for localized disease or to relieve symptoms.[3]
Hematopoietic stem cell transplantation: In select cases, this intensive treatment may be considered, though it is not commonly used for follicular lymphoma.[3]
The choice of treatment depends on many factors, and no single standard of care exists for treatment in the third-line setting or later, as approved therapies have not been directly compared in randomized clinical trials.[12] Physicians must consider patient and disease factors, safety profiles of different medications, dosing schedules, and patient preferences when selecting therapy.[12]
When Treatment May Not Be Needed Immediately
An important aspect of managing relapsed follicular lymphoma is recognizing that not all patients need treatment right away. Some patients who relapse do not require immediate treatment, and an approach called active surveillance (also known as “watch and wait” or “watchful waiting”) might be used.[18]
Asymptomatic relapsed cases can be observed and monitored closely for symptom development without immediate treatment.[1] With this strategy, doctors monitor patients’ overall health and disease through regular checkup visits and various tests, such as laboratory work and imaging scans.[18]
Active treatment is started only if the patient begins to develop lymphoma-related symptoms or if there are signs that the disease is progressing based on testing during follow-up visits.[18] Research has shown that early treatment of asymptomatic follicular lymphoma does not improve survival, which supports this approach for appropriate patients.[7]
This management strategy recognizes that follicular lymphoma typically grows slowly and that the side effects and burdens of treatment may outweigh the benefits for patients who are not experiencing symptoms from their disease. Most people with follicular lymphoma will have a clinically indolent course, needing only intermittent therapy over decades.[1]