What is Relapsed and Refractory Follicular Lymphoma?
Follicular lymphoma is a type of cancer affecting B-cells, a type of immune cell, which is incredibly varied in its behaviour and symptoms. It is the most common type of slow-developing lymphoma, a blood cancer affecting the lymph nodes, and the second most common type of non-Hodgkin lymphoma, another category of blood cancer. The nature of this cancer often involves periods of improvement and worsening, with a possibility of becoming a more aggressive form of the disease.
About 20% of patients with follicular lymphoma see their disease progress with the first 2 years of chemotherapy. The overall likelihood of a patient living 5 years after diagnosis is around 50%. The length of time a patient remains in remission, or symptom-free, can indicate how their disease might progress in the future. Patients who see their symptoms return within 24 months of chemotherapy or 12 months of another treatment called rituximab often have a less favourable outlook.
Although anti-CD20-based chemoimmunotherapy, a treatment that combines medication and the body’s immune system, is a primary course of action, other more targeted treatments are increasingly being employed. Especially in cases where the follicular lymphoma has returned or become resistant to the initial treatment.
What Causes Relapsed and Refractory Follicular Lymphoma?
Follicular lymphoma is thought to start in a type of cell in our bodies called germinal center B-cells. Scientists still need to learn more about what causes follicular lymphoma, but one key factor is a genetic change referred to as t(14;18) which happens in about 90% of people with this disease. This genetic change leads to higher levels of a protein called Bcl-2, which helps cells survive.
In addition, other changes in genes that control how our DNA (the building blocks of our genes) is arranged and used by the cells, have been found. We call these changes ‘epimutations’ and they are another distinguishing feature of follicular lymphoma.
These include changes in genes like KMT2D, CREBBP, EZH2, and EP300. These changes cause the germinal center cells to grow more quickly, block the process of cells changing into other types, and impede the immune system’s ability to invade the cells. When you couple these changes with the earlier mentioned Bcl-2 change, these are the key events that commonly happen in the cell that gives rise to follicular lymphoma.
Risk Factors and Frequency for Relapsed and Refractory Follicular Lymphoma
Follicular lymphoma is a condition that impacts people everywhere, irrespective of their race or where they live. It’s a type of non-Hodgkin lymphoma (NHL), forming about 35% of NHL cases in the United States. The average number of new cases in the US is around 3.18 per 100,000 persons. However, in Europe, this number is slightly less, with about 2.18 new cases per 100,000 people each year.
- White individuals are more than twice as likely to develop this condition compared to Black and Asian populations.
- Follicular lymphoma is less common in Central and South America, where it makes up approximately 20% of NHL cases.
- There isn’t a significant difference in how often it occurs in men compared to women.
- The majority of people who are diagnosed with this condition are around 65 years old.
- The chances of developing follicular lymphoma increase as people get older, with middle-aged and elderly people most likely to be affected.
- It is rare for teenagers or children to develop follicular lymphoma.
Signs and Symptoms of Relapsed and Refractory Follicular Lymphoma
Follicular lymphoma is a type of cancer that usually shows itself through painless swelling of the lymph nodes, which can change in size but never completely disappear. Some people might get large abdominal masses with or without any signs of problems with their digestive or urinary systems. The disease could also affect the spleen, liver, or bone marrow. It’s worth noting that only about 20% of people with this condition experience symptoms like fever, night sweats, or unintentional weight loss. Regular check-ups are needed after initial therapy to monitor any complications and if the disease is progressing. These check-ups typically include a detailed medical history, a physical examination, complete blood count, a comprehensive metabolic panel, and measurement of lactate dehydrogenase. A quick increase in the size and number of swollen lymph nodes or the appearance of symptoms such as night sweats, fevers, weight loss, and fatigue usually mean the disease has returned.
Testing for Relapsed and Refractory Follicular Lymphoma
Imaging with a type of scanning technology known as positron emission tomography/computed tomography (PET/CT) can provide important information about the current status of the disease, which areas of the body are affected, and how active the disease is in those areas. A biopsy, which is a procedure to take a small sample of tissue, should be performed on the lymph node with the highest level of disease activity.
A bone marrow biopsy, which involves taking a sample from the soft tissue inside bones, is usually only performed on people who have unexplained changes in their blood cell counts. It’s important to know that follicular lymphoma, a type of cancer that starts in white blood cells, can become a more aggressive and severe type of lymphoma, known as diffuse large B-cell lymphoma.
So, if the disease returns, a biopsy is very important to verify this change. This information can help doctors accurately diagnose and treat the disease in its new, more aggressive form.
Treatment Options for Relapsed and Refractory Follicular Lymphoma
Early relapse means that the follicular lymphoma, a type of blood cancer, progresses or gets worse within 24 months of starting a combination of chemotherapy and immunotherapy, or within 12 months of starting a treatment called rituximab. Patients who relapse but are not showing any symptoms may not need immediate additional treatment but should be watched carefully for the development of symptoms.
A worldwide study of more than 5000 patients discovered that those whose disease progressed within 24 months of initial treatment had a worse long-term survival rate. This was seen regardless of the type of treatment they received. To properly assess any early relapse, doctors recommend taking a tissue sample (biopsy).
If traditional therapies don’t work, there are other options that may increase survival rates, such as stem cell transplantation or a procedure that uses genetically altered T cells (the body’s disease-fighting cells) to fight the lymphoma. This treatment is known as chimeric antigen receptor T-cell (CAR-T) therapy. Other medicines can also be used for patients who can’t undergo a transplant, including lenalidomide, copanlisib, and tazemetostat.
CAR-T therapy has been successful for patients whose lymphomas have relapsed multiple times. The process involves taking T cells from the patient, genetically modifying them to target the lymphoma cells, then growing them in a lab and introducing them back into the patient. This therapy is complex and can lead to severe side effects, such as severe systemic reactions and neurological events.
For late relapses (more than 24 months or 12 months after the first cycle of chemotherapy and immunotherapy or a single-agent rituximab), the disease progression is typically slower, needing treatments over decades and resulting in survival rates similar to those seen in the general population. Treatment options after late relapse include anti-CD20 monoclonal antibodies, chemoimmunotherapy, or a new generation of drugs.
The choice of treatment depends on several factors like how they responded to previous therapies, whether certain gene mutations exist, their physical performance status, and whether other diseases are present that may affect their tolerance to systemic therapy (treatment involving the whole body).
The treatment goals in these cases include relieving symptoms, restoring normal blood cell counts, and improving the quality of life. Several potential treatments can be considered, including rituximab monotherapy (especially for patients who cannot handle chemotherapy and who had a good response to prior rituximab treatment), chemoimmunotherapy regimens combining different drugs, and alternative therapies such as tazemetostat or lenalidomide with rituximab.
Copanlisib, approved by the Food and Drug Administration, can be used in cases where the lymphoma has returned or worsened after at least two prior systemic therapies. For patients with multiple relapses, other potential treatments include high-dose chemotherapy with autologous stem cell transplantation, CAR-T therapy or other experimental treatments.
What else can Relapsed and Refractory Follicular Lymphoma be?
When doctors are trying to diagnose a case of recurring or resistant follicular lymphoma, they may consider other conditions that can cause similar symptoms. These conditions may include:
- Autoimmune disorders
- Chronic infections
- Reactive follicular hyperplasia – a condition characterized by an abnormal increase in the number of cells in a tissue or organ
- Chronic lymphocytic leukemia/small lymphocytic lymphoma – a type of cancer that starts in the white blood cells
- Diffuse large B-cell lymphoma – a form of lymphoma that affects B cells
- Acute lymphoblastic lymphoma – a rapid-growing type of lymphoma
- Marginal zone lymphoma – a slow-growing type of lymphoma that begins in areas of the immune system around the lymphoid tissue
- Mucosa-associated lymphoid tissue (MALT) lymphoma – lymphomas that start in immune system cells that are in the body’s mucosal tissues
- Mantle cell lymphoma – a rare and aggressive form of lymphoma
- Lymphoplasmacytic lymphoma – a rare type of non-Hodgkin lymphoma characterized by small, abnormal-looking lymphocytes that are present throughout the body
What to expect with Relapsed and Refractory Follicular Lymphoma
Follicular lymphoma, a type of cancer, varies greatly between patients. Some may see periods where the condition comes and goes over a number of years without the need for treatment. In contrast, others who have more widespread disease and fast-growing tumors need treatment due to organ dysfunction.
At the time of the initial diagnosis, doctors use two main evaluation tools to assess follicular lymphoma: the Follicular Lymphoma International Prognostic Index (FLIPI) and the PRIMA prognostic index (PRIMA-PI). FLIPI considers five indicators of worse prognosis including being over 60, having stage III or IV disease, low hemoglobin levels, more than four involved lymph node regions, and high levels of a protein called ‘LDH’ in the blood. The PRIMA-PI index uses the presence of a protein called ‘beta-2 microglobulin’ and involvement of the bone marrow to identify risk groups. Roughly 20 percent of patients tend to have a faster pace of disease with shorter periods of remission.
When the disease recurs, the best way to assess its aggressiveness is the duration of remission after the first treatment. Patients who progress within 24 months of receiving a treatment called ‘immunochemotherapy’ or within 12 months of a medicine called ‘rituximab’ are classified as early treatment failures. Furthermore, a small number of individuals with follicular lymphoma can end up developing more aggressive types of lymphomas. These patients typically have a worse outlook and require stronger treatment.
Possible Complications When Diagnosed with Relapsed and Refractory Follicular Lymphoma
As stated, approximately 20% of people with follicular lymphoma, a type of cancer that affects the lymphatic system, experience a more severe progression of the disease. This includes having shorter periods of remission (when the cancer is less active or dormant), experiencing frequent recurrences of the disease, and generally a decreased lifespan.
Preventing Relapsed and Refractory Follicular Lymphoma
It is crucial that patients understand the progression of follicular lymphoma, which is a type of cancer that can come back (relapse) and then improve (remit), as well as the different treatment options available. Although follicular lymphoma generally grows slowly, it remains uncertain whether most cases can be completely cured with current treatments.
Patients need to be aware of the potential risks, side effects, and harm that can occur from treatments such as chemotherapy, immunotherapy, and stem cell transplantation. These treatments help to manage follicular lymphoma, but most patients will likely need several different types of these treatments over time.
It’s essential for patients to take their medication regularly as directed and to attend all clinic appointments for their safety. This is because they need to be closely watched for any complications from treatment, to check how well the treatment is working, and to monitor if the lymphoma comes back or changes.
