Understanding Follicular Lymphoma

Symptoms, Staging, and Diagnostic Procedure

Typically, patients with FL have no obvious symptoms of the disease at diagnosis. Patients often only have an enlarged lymph node examined by their doctor or found by chance on an imaging scan. Most patients with FL are aged 55 years or older when they are diagnosed.

To make a definite diagnosis of FL, doctors need to collect a sample of the affected lymph node. This procedure is called a biopsy. The biopsy is typically studied by a pathologist (doctor who specializes in the diagnosis of diseases by studying the cells from a patient’s body fluids and tissue samples) and preferably a hematopathologist (pathologist who has undergone additional training in the diagnosis of blood cancers, including lymphoma) who is experienced in diagnosing lymphoma. Determining the grade (level of large lymphocytes present in the affected lymph nodes) and if and how far the lymphoma has spread (staging) is important to define the best treatment for each patient.

For staging, the results of the different tests (such as biopsies and scans) are used to determine the severity of the disease and the appropriate treatment. The Lugano staging system is used for FL and is depicted in Figure 2 below. This system categorizes FL from Stage I (limited disease) to IV (advanced disease), based on whether the disease is restricted to a single group of lymph nodes, has spread to other lymph nodes, or has reached the bone marrow (the spongy tissue inside the bones) and/or other organs (like the liver or lungs). Because FL is an indolent disease and might not cause any symptoms initially, it is often advanced (stage III or IV) when it is diagnosed.

To predict the prognosis (how well the patient will do) of a patient with FL, physicians commonly use a score called the Follicular Lymphoma International Prognostic Index (FLIPI). The FLIPI score determines the risk level of each patient and predicts the chance of survival based on factors such as age and number of lymph nodes affected. Keep in mind that no two patients are alike and that statistics can only predict how a large group of patients will do (not what will happen to an individual patient). The doctor most familiar with the patient’s situation is in the best position to interpret these statistics, understand how well they apply, and respond to any questions you might have.

The physician will use the results of these tests to assess the stage of the lymphoma. NHL is categorized as Stages I (limited disease) to IV (advanced disease), as shown in the figure below.

Figure 2. Staging of NHL according to the Lugano system. The Lugano system categorizes NHL from Stage I (limited disease) to IV (advanced disease), based on whether the cancer is restricted to a single group of lymph nodes, has spread to other lymph nodes, or has reached the bone marrow (the spongy tissue inside the bones) and/or other organs (like the liver or lungs).

Staging is needed to choose an appropriate treatment. The majority of patients with DLBCL have advanced-stage disease but treatment can help achieve long-term remission (disappearance of signs of cancer for a long period) or cure (permanent disappearance of the cancer without ever returning).

Subtypes

The most common subtypes of FL are:

Classic FL:

The classic FL is the most frequent (85%) subtype of FL, and includes FLs previously classified as grade 1, grade 2, or grade 3A. This type of FL is characterized by a genetic mutation (permanent change) in the DNA (deoxyribonucleic acid, the molecule that carries the genetic information) named translocation, where a chromosome (a structure made of DNA and proteins found inside the cell) breaks and part of it reattaches to another chromosome.

Follicular large B-cell lymphoma:

FL grade 3B is called follicular large B-cell lymphoma. This subtype is very rare among follicular lymphomas.

Pediatric-type follicular lymphoma:

Pediatric-type follicular lymphoma is an uncommon type of FL that occurs mainly in children and adolescents. It is indolent and almost always presents as a lowgrade (stage I-II) disease. This type of FL is often
localized, often presenting as a painless and isolated enlarged lymph node in the head or neck. It has a high cure rate and negligible risk of relapse (return after treatment) or transformation (turn into a fast-growing type of lymphoma).

Transformed lymphoma:

In some patients (about 2-3% per year), FL may transform into a more aggressive type of lymphoma, most commonly DLBCL. This transformed lymphoma is often more aggressive and usually requires more intensive treatment. This change is characterized by an increase in the number of DLBCL cancer cells in the affected lymph node, which changes the follicular appearance of the cancer. The risk of developing a transformed lymphoma increases each year from the time of diagnosis until approximately 10 years afterwards, after which point transformations become rare. For more information on transformed lymphomas, view the Other Aggressive B-cell Lymphoma guide on the Lymphoma Research Foundation’s (Foundation’s) website
(visit lymphoma.org/publications).

If patients show no or very few symptoms (including those with advanced stage disease), physicians may recommend to not treat the disease right away. This approach is referred to as active surveillance (also known as “watchful waiting” or “observation”). Patients managed with active surveillance have survival outcomes similar to those treated early. In this case, patients’ overall health and disease are monitored through regular physical exams (to check for any swollen lymph nodes) or periodic imaging tests (like computed tomography [CT] scans). For more information on active surveillance, view the Active Surveillance fact sheet on the Foundation’s website (visit lymphoma.org/publications). If patients begin to have symptoms or signs of disease progression, treatment is initiated.

First Treatment after Diagnosis

There are various first line therapeutic options for FL based on how severe the symptoms are and how fast the cancer is growing. The treatments for FL include:

Radiation therapy (uses high-energy radiation to kill cancer cells). Radiation alone can provide long-lasting remission (disappearance of disease signs and symptoms of cancer) in some patients with early-stage disease.

Chemoimmunotherapy (a combination of chemotherapy [drugs that stop the growth of or kill cancer cells] with monoclonal antibodies [a protein made in the laboratory that binds to cancer cells and helps the immune system destroy them]). Commonly used monoclonal antibodies are obinutuzumab (Gazyva), rituximab (Rituxan), and rituximab hyaluronidase human (Rituxan Hycela), a rituximab product that is administered under the skin.

Patients seeking information about monoclonal antibodies should view the Immunotherapy and Other Targeted Therapies fact sheet on The Foundation’s website (lymphoma.org/publications).

Some monoclonal antibodies such as obinutuzumab (Gazyva) or rituximab (Rituxan), can also be used as maintenance therapy to prolong remission in patients with no signs of lymphoma after initial treatment. Patients seeking information about maintenance therapy should view the Understanding Lymphoma and Maintenance Therapy fact sheet on The Foundation’s website (visit lymphoma.org/publications)

Relapsed and Refractory FL

FL is generally very responsive to first-line therapies, and many patients go into long-lasting remission for a long time. However, the disease often relapses or becomes refractory (no longer responds to current treatment). In this case, additional therapies (second- and third-line treatment given when first-line or initial therapy does not work or stops working) are often successful in providing another remission.

For patients with relapsed or refractory FL, the same treatments listed above as first-line
treatments for FL may be used, depending on the number and type of past treatments, duration
of previous remission, age, health status, and patient preference. With newer therapeutic regimens, many patients can achieve remissions after second line or third line treatments.
Although remissions in the range of one year or longer can be seen with some of the treatments, they may be shorter with each round of therapy. Common second or later line treatment options for relapsed/refractory FL include:

• Chemotherapy
• Radiation therapy
• Chemoimmunotherapy.
  • Bendamustine (Treanda) ± rituximab (Rituxan) or obinutuzumab (Gazyva), if not used for first line treatment.
  • R-CHOP (rituximab [Rituxan], cyclophosphamide, doxorubicin, vincristine, and prednisone).
  • R-CVP (rituximab [Rituxan], cyclophosphamide, vincristine, and prednisone).
• Immunotherapy.
  • Monoclonal antibodies.
    • Rituximab (Rituxan, given by injection).
    • Rituximab and hyaluronidase human (Rituxan Hycela).
    • Obinutuzumab (Gazyva).
  • Bispecific antibodies (an antibody that recognizes two different antigens, which can be on the same cell [a cancer cell] or two different cells [a cancer cell and a healthy immune cell]).
    • Mosunetuzumab (Lunsumio) and Epcoritamab (Epkinly) are approved for the treatment of adult patients with relapsed or refractory FL after two or more lines of systemic therapy (treatment delivered throughout the body). These drugs are T-cell engagers, and work by binding to CD20 at the surface of cancer B-cells and to CD3 in healthy T-cells. To learn more about bispecific antibodies, view the Bispecific Antibodies fact sheet on the Foundation’s website (visit lymphoma.org/ publications).
  • Antibody-drug conjugates (a chemotherapy drug attached to a monoclonal antibody) such as Loncastuximab tesirine (Zynlonta).
  • Immunomodulatory drugs (drugs that work on the immune system directly by regulating [activating or slowing down] the activity of specific proteins).
    • Lenalidomide (Revlimid) ± rituximab (Rituxan).
  • Chimeric antigen receptor (CAR) T-cell therapy is a special type of immunotherapy that uses the patient’s immune cells to f ight cancer. Common CAR T-cell therapies are axicabtagene ciloleucel (Yescarta), lisocabtagene maraleucel (Breyanzi), and tisagenlecleucel (Kymriah). To learn more about CAR T-cell therapy, view the Understanding Cellular Therapy Guide on The Foundation website (visit lymphoma.org/publications).

Other treatment options for relapsed/ refractory FL include:

Radiation therapy can be effective in some patients with relapsed/refractory FL who have localized disease. Often very low doses of radiation can be quite beneficial.

Stem cell transplantation (the patient is treated with high-dose chemotherapy or radiation to remove their blood-forming cells or stem cells and then receives healthy stem cells to restore the immune system and the bone marrow’s ability to make new blood cells).

For more information on transplantation, view the Understanding Cellular Therapy Guide on The Foundation’s website (visit lymphoma.org/publications).

Many treatments (also referred to as investigational drugs) are currently being tested in clinical trials in patients who are previously untreated or newly diagnosed with FL and in patients with relapsed/refractory FL. Results from these clinical trials may improve or change the current standard of care (the proper treatment that is widely used by healthcare professionals and accepted by medical experts). Table 1 (below) lists some of these investigational drugs that can be accessed through a clinical trial.

Table 1. Selected Agents Under Investigation for Previously Untreated Follicular Lymphoma and/or Relapsed/Refractory Follicular Lymphoma

Agent (drug)	Class (type of treatment)	Under investigation for
Abexinostat (PCI-24781)	Targeted therapy; HDAC inhibitor	R/R FL
Acalabrutinib (Calquence)	Targeted therapy; BTK inhibitor	FL and R/R FL
AZD0486 (TNB-486)	Bispecific monoclonal antibody; anti-CD19	R/R FL
AZD5492	Trispecific monoclonal antibody; anti-CD20	R/R FL
CB-010	Allogeneic CAR T-cell; anti-CD19	R/R FL
CTX112	Allogeneic CAR T-cell; anti-CD19	R/R FL
EO2463	Immunotherapy; vaccine	FL and R/R FL
GLPG5101 (19CP02)	Autologous CAR T-cell; anti-CD19	R/R FL
Glofitamab (RO7082859)	Bispecific monoclonal antibody; anti-CD20	FL and R/R FL
Golcadomide (CC-99282)	Immunomodulatory therapy; Cereblon E3 ligase modulator	FL
Magrolimab	Monoclonal antibody; anti-CD47	R/R FL
Nivolumab (Opdivo)	Immune checkpoint inhibitor; anti-PD-1 receptor	R/R FL
Odronextamab (REGN1979)	Bispecific monoclonal antibody; anti-CD20	FL and R/R FL
Pembrolizumab (Keytruda)	Immune checkpoint inhibitor; anti-PD-1 receptor	R/R FL
Polatuzumab vedotin (Polivy)	Antibody-drug conjugate; anti-CD79b	FL and R/R FL
Retifanlimab (Zynyz)	Immune checkpoint inhibitor; anti-PD-1 receptor	FL
Tafasitamab (Monjuvi)	Monoclonal antibody; anti-CD19	R/R FL
Utomilumab	Monoclonal antibody; CD137 agonist	R/R FL
Valemetostat	Targeted therapy; EZH inhibitor	R/R FL
Venetoclax (Venclexta)	Targeted therapy; BCL-2 inhibitor	FL and R/R FL

It is important to remember that scientific research is always evolving. Treatment options may change as new treatments are discovered, and current treatments are improved. Therefore, it is important that patients check with their physician or with The Foundation for any treatment updates that may have recently appeared. It is also very important that patients consult with a specialist to clear up any questions.

How to Be a Self-Advocate

Being a self-advocate and an active participant in healthcare decisions can be a positive experience. It may help patients regain a sense of control that they may have lost following the lymphoma diagnosis by making sure patients receive the best care. Patients and caregivers should remember they are partners in their treatment plan.

• Do not be afraid to ask your doctors or nurses questions about your care. An educated patient asking questions is not ‘being a challenge to your physician’ (or ‘being a difficult patient’).
• Learn more about lymphoma by asking your doctor for information and visiting reliable websites, such as the Foundation’s at www.lymphoma.org.
• Take advantage of counseling, support groups, nutritional counseling, fitness classes, expressive arts, and other services offered at your doctor’s office, cancer center, or hospital.
• Consider joining the Foundation’s Lymphoma Support Network, a nationwide peer support program that matches patients and caregivers with people who have had similar experiences. For information about the program, call (800) 500-9976 or email [email protected].
• Finally, it is important that patients not be afraid to talk with the healthcare team about nonmedical issues such as transportation, finances, insurance, working through treatment or taking time off, and childcare. There are nurses, social workers, physician’s assistants that are be able to provide the support and resources to help.

 Clinical trials are crucial in identifying effective drugs and optimal treatment doses for patients with lymphoma. They are not a “last resort” for patients. Every drug available today had to be tested in clinical trials before it was approved for general use, and all new and emerging treatments. There are four main types or phases of clinical trials. The phase is based on the study’s objective and the number of participants.

Patients interested in participating in a clinical trial should view the Understanding Clinical Trials fact sheet on the Foundation’s website (visit lymphoma.org/publications), and the Clinical Trials Search Request Form at lymphoma.org, talk to their physician, or contact the Foundation’s Lymphoma Resource Center for an individualized clinical trial search by calling (800) 500-9976 or emailing [email protected].

Survivorship

As a cancer survivor, it is important that you practice self-care regularly to reset your physical and emotional well-being. Adopting routines of self-care will help you recharge your batteries and stay healthy. Talk with your healthcare team about developing a wellness plan to help you stay physically and emotionally healthy and improve your mood. Consider the following suggestions:

• Watch your health. Stay up-to-date with your own medical appointments and take any medications as prescribed.
• Exercise. Stay active with short periods of daily exercise (30 minutes of power walking, jogging or biking). If not possible, take the stairs instead of the elevator or park farther away than usual.
• Eat well. Include fruits and vegetables in your meals and maintain a balanced diet.
• Cut down on risk factors. Quit smoking and reduce alcohol intake.
• Sleep. Try to get 7 hours of sleep per night, or take naps when needed.
• Rest. Meditation, deep breathing and stretching can help you relax and reduce stress.
• Write it down. Keeping a journal with thoughts and feelings may help to let go of worries and fears.

View the Foundation’s Survivorship Series factsheet on the Foundation’s website at lymphoma.org/publication for more info.

Care Partners

There are many ways you can help a loved one with lymphoma, as follows:

• Be present. The most important thing that a care partner can do is to “just show up.”
• Be prepared. Talk with the healthcare team so that you know what to expect throughout the treatment, how to manage symptoms and when to ask for help.
• Listen. Each person asks for help in different ways, verbally (through words) and nonverbally, and some may require more comfort while others are more action oriented.
• Avoid “cheerleading”. Do not disregard your love one’s negative feelings (sadness, anger or worry).
• Organize the help. A rush of sudden help upon diagnosis can make the situation harder to manage and create unproductive tension.
• Set up remote access with computer and/or phone access. This is helpful for regular communication with your loved one.
• Offer rides. This is important for people with decreased mobility or limited resources.
• Take notes. If you go into the appointments, write down notes with the doctor’s plan, medications, potential side effects and other relevant information.

Patients and their care partner are encouraged to keep copies of all medical records. This includes test results as well as information on the types, amounts, and duration of all treatments received. Medical records are important for keeping track of any side effects resulting from treatment or potential disease recurrences. The Foundation can help patients manage this documentation.

View the Care Partners factsheet on the Foundation’s website at lymphoma.org/publication for more info.

• What is my exact diagnosis? What subtype of lymphoma do I have? May I have a copy of the report from the pathologist?
• What is the stage of my disease? In what area of the body is it specifically located?
• What are my treatment choices? Which do you recommend for me and why? Would choosing one treatment prevent me from getting a different kind of treatment later on? How are the different treatments administered?
• Do I need more than one type of treatment?
• What is the goal of treatment? What are the expected benefits of each type of treatment?
• How will we know if the treatment is working? What tests will I need to determine if treatment is working, and how often will I need to be tested?
• How long will the treatment last?
• What are the chances the treatment will be successful?
• What is a clinical trial? Are clinical trials available that are studying new treatments for my type of lymphoma? Would a clinical trial be appropriate for me? How would I benefit? Are there any drawbacks of participating in a clinical trial?
• Will I be able to work during treatment? Will I be able to drive or take public transportation during my treatment?
• Should I take care of other medical or dental issues before I start treatment?
• How much will the treatment cost? Will my insurance cover some or all of it? What will my out-of-pocket costs be?