Overview of Follicular Lymphoma

Follicular lymphoma, a type of indolent non-Hodgkin’s lymphoma (NHL), accounts for 20% of all NHLs.

If you have been diagnosed with follicular lymphoma, you probably have many questions and concerns about your disease and its treatment. This patient treatment summary, which is based on the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines™) for non-Hodgkin’s lymphoma, will help you understand the best available treatments for follicular lymphoma. Talk to your doctors about these therapies so that together you can decide on a treatment plan that is right for you.

Background

NHL is a group of blood cancers that affect the lymphatic system, which is part of the immune system. The immune system defends the body against infections and other diseases. The lymph system is made up of blood, lymph, lymph vessels, lymph nodes, spleen, thymus, tonsils, and bone marrow. NHL originates in lymphocytes, a type of white blood cell in the immune system that makes antibodies. NHL is divided into 3 major types depending on the nature of the lymphocytes from which it originates: B-cell lymphoma, T-cell lymphoma, and NK-cell lymphoma.

Follicular lymphoma is an indolent, slow-growing B-cell lymphoma that affects B-lymphocytes, and comprises 70% of all indolent lymphoma cases. It often starts in the lymph nodes and spreads to other parts of the body. There are generally two presentations of follicular lymphoma: limited-stage, which can be managed with radiation therapy with the intent to cure, and advanced-stage, which can be treated like a chronic condition. Approximately 85% of patients with follicular lymphoma present with advanced-stage disease.

Lymph nodes are found in the neck, underarms, chest, abdomen, and groin. The lymph nodes trap and remove harmful bacteria and other substances in the lymph. Lymph nodes often become enlarged when the body is fighting infections, such as when you have a cold or sore throat. Most of the time enlarged lymph nodes are not a problem. However, if they stay swollen for more than 2 weeks, a doctor should be consulted, because swollen lymph nodes are one of the common symptoms of follicular lymphoma.

Diagnosis of Follicular Lymphoma

The most common symptom of NHL is an enlarged lymph node. You may also experience other symptoms, which may include fever, night sweats, feeling tired, loss of appetite, weight loss, and rash. The initial diagnosis of NHL will involve an incisional or excisional lymph node biopsy, during which your doctor will remove part or all of the enlarged lymph node for examination by a hematopathologist. It is recommended that your biopsy sample be reviewed by an expert hematopathologist, because diagnosing lymphoma can be difficult. Once it is confirmed to be lymphoma, more tests will need to be performed on the sample to determine if it is follicular lymphoma or another subtype of NHL.

The hematopathologist will perform a cytogenetic analysis to help determine what type of NHL you have, and may also perform a procedure known as immunophenotypic analysis (IPA) on the sample to identify the specific type of tumor markers. IPA enables your doctor to determine whether you have a B-cell or T-cell lymphoma. IPA also helps to differentiate follicular lymphoma from other subtypes of NHL.

Staging of Follicular Lymphoma

A formal system called staging is used to identify how localized or widespread your cancer is. Staging is an important part of developing the best treatment plan for you.

Follicular lymphoma is divided into three grades (1–3), and each grade is broken down into four stages:

• Stage I: Involvement of a single lymph node group
• Stage II: Involvement of multiple lymph node groups on the same side of the diaphragm (thin muscle that separates the chest from the abdomen)
• Stage III: Involvement of multiple lymph node groups on both sides of the diaphragm
• Stage IV: Involvement of multiple lymph nodes groups and spread to other organs besides the lymph nodes

Some doctors will also divide patients into “A” and “B” categories, depending on their symptoms, if any. If you are experiencing B symptoms, you have unexplained high fever, weight loss of more than 10% of your original body weight, heavy sweating during the day and drenching night sweats. If you are not experiencing these symptoms, you are in the “A” category.

In order to stage your cancer, your doctors will perform several tests, including:

• A thorough physical exam, which will include several questions about any symptoms you might have had, your general health, and your medical history

• Blood tests, including CBC, metabolic panel, and LDH (lactate dehydrogenase)
• Computerized tomography (CT) scan of chest, abdomen, and pelvic region
• Bone marrow biopsy and aspirate

In some circumstances, a positron emission tomography (PET) scan may be needed, usually together with a CT scan.

Treatment of Follicular Lymphoma

Treatment for follicular lymphoma involves a number of specialists who plan and work as a team to coordinate a patient’s care, and most often uses a combination of several approaches. Therefore, it is very important that you receive your medical care at a hospital or cancer center where doctors are experienced in treating patients with lymphoma. If the doctors at your hospital do not have a lot of experience treating these illnesses, ask your physician for a referral to a large cancer center where the staff have seen and treated many cases of these diseases. Treatment of follicular lymphoma aims to relieve symptoms, slow progression, improve quality of life, and provide a cure. Your doctor will consider the need for future treatment when making the initial treatment decisions.

There are generally two presentations of follicular lymphoma: limited-stage, which can be managed with radiation therapy with the intent to cure, and advanced-stage, which can be treated like a chronic disease. If you have advanced follicular lymphoma, you may go through periods of treatment followed by periods of observation and monitoring.

Before you begin treatment, your doctor may need to perform the following tests:

• MUGA scan or echocardiograms to monitor heart function. One of your treatment options, chemotherapy, may involve a class of drugs called anthracyclines, which can damage your heart. It is important to know the health of your heart before beginning treatment.
• Hepatitis B testing. Your doctor will also need to know if you are a carrier of hepatitis B or if you have recovered from hepatitis B infection. Treatment with chemotherapy and immunotherapy may reactivate hepatitis B, but your doctor can give you antiviral drugs to prevent this from happening.
• Pregnancy testing for women with childbearing potential.
• Some treatment options may affect fertility. Depending on your age and future plans, you may wish to discuss with your doctor how treatment may impact your fertility, and options for preservation.

This treatment summary details treatment for grades 1–2 follicular lymphoma. Follicular lymphoma grade 3 is treated as described in the treatment summary for diffuse large B-cell lymphoma.

In general, treatments rely on the following approaches, often in combination:

• Chemotherapy: Drugs are used to kill or slow the growth of cancer cells, including any that have broken away from the original tumor.
• Immunotherapy: Antibodies are used to identify cancerous cells and destroy them. Rituximab is a monoclonal antibody used to treat NHL.
• Chemoimmunotherapy: The combination of chemotherapy and immunotherapy agents is used to treat NHL.
• Radioimmunotherapy: Radioactive molecules are attached to antibodies to deliver radiation directly to the lymphoma cells. Tositumomab and ibritumomab are the two radioactive antibodies used to treat follicular lymphoma.Radiation therapy (or radiotherapy): High-energy beams are used to kill tumor cells.
• High-dose chemotherapy with autologous stem cell rescue (HDT/ASCR): High-dose chemotherapy is used to destroy any residual lymphoma cells in your bone marrow. However, because this form of treatment will also destroy your own developing blood cells, the bone marrow cells that have been destroyed by chemotherapy are then replaced with an infusion of your own healthy stem cells (see later section on Stem Cell Rescues and Transplants Overview).
• High-dose chemotherapy with allogeneic stem cell transplant (HDT/ASCT): High-dose chemotherapy is used to destroy any residual lymphoma cells in your bone marrow. However, because this form of treatment will also destroy your own developing blood cells, the bone marrow cells that were destroyed by chemotherapy are then replaced with an infusion of stem cells from a matched donor (see later section on Stem Cell Rescues and Transplants Overview).
• Clinical trials: Investigational drugs and protocols will be tried. Despite improvements in outcomes, there is still need for better treatment options. Clinical trials may test novel drugs or alternative ways of giving established drugs that may lead to improved outcomes for all patients.

Below you will find more detailed treatment information based on the stage of your follicular lymphoma. Treatment plans are divided between stage I/II and stage II(bulky)/III/IV.

Treatment of Stage I/II Follicular Lymphoma

More tests will be needed to confirm that you have stage I/II than if you have further advanced follicular lymphoma. It is very important that the staging be accurate so that you receive the best treatment plan.

Early-stage follicular lymphoma is potentially curable. Therefore, your doctor will begin treatment soon after your diagnosis is confirmed. If you are diagnosed with stage I/II follicular lymphoma, radiation therapy is the preferred treatment option. Other options include immunotherapy with rituximab, either alone or in combination with chemotherapy and/or radiation therapy.  

Chemotherapy may consist of a single drug such as fludarabine or a combination of two or more drugs. Two common chemotherapy regimens are CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) and CVP (cyclophosphamide, vincristine, and prednisone).

If your disease responds to initial treatment, your doctor will perform follow-up tests every 3 to 6 months to monitor you for symptoms and signs of recurrence, or return of your disease.

If your disease does not respond to initial treatment, your treatment options are detailed below under Treatment of Recurrent or Refractory Follicular Lymphoma.

Treatment of Stage II (Bulky)/III/IV Follicular Lymphoma

Advanced-stage follicular lymphoma is best thought of as a chronic illness like arthritis. Immediate treatment is not needed for all patients. You will need treatment only when you have lymphoma-related symptoms. You may have periods in which you show no signs of symptoms (even if you have widespread disease), and therefore do not need treatment. Observation is not inferior to immediate treatment with chemoimmunotherapy.

If you are diagnosed with stage II (bulky), III, or IV disease, your initial treatment will depend on your symptoms and other indications. No treatment will be given as long as you do not have any lymphoma-related symptoms. Instead, your doctor will monitor the course of your lymphoma, which is known as observation or the watch and wait approach.

Observation is not inferior to immediate treatment. Your doctor will begin treatment as soon as you begin to have any of the following indications or lymphoma-related symptoms:

• Candidacy for clinical trial
• Symptoms such as high fever, weight loss, or night sweats
• Signs of lymphoma-related inhibition of organ function, which might be caused by compression of organs by nearby enlarged lymph nodes
• Low blood counts
• Bulky disease
• Progressive disease
• Patient preference

When you and your doctor decide it is time to start treatment, you will have several first-line treatment options, including:

• Immunotherapy with rituximab, alone or in combination with chemotherapy
• Radioimmunotherapy with tositumomab or ibritumomab
• Chemotherapy followed by radioimmunotherapy

Chemoimmunotherapy is the standard treatment. Two common chemoimmunotherapy regimens are RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) and RCVP (rituximab, cyclophosphamide, vincristine, and prednisone). Radiation therapy may be given to relieve the lymphoma-related symptoms.

If you are an elderly patient or if you are not able to tolerate any of the treatments listed above, you will be treated with single drugs such as rituximab, chlorambucil, or cyclophosphamide.

If your disease responds to initial treatment, your doctor will perform follow-up tests every 3 to 6 months to monitor for symptoms and signs of recurrence, or return of disease.

If your disease does not respond to initial treatment, your treatment options are detailed below under Treatment of Recurrent or Refractory Follicular Lymphoma 

Treatment of Recurrent or Refractory Follicular Lymphoma

If your follicular lymphoma returns after treatment (recurrence) or does not respond to initial treatment (refractory), you will be given second-line therapy. The choice of second-line treatment depends on your previous treatment, duration of response (how long you remained free of disease before your lymphoma returned), and your current disease state. Depending on your clinical situation, you may be given additional cycles of the same chemoimmunotherapy regimens that you received previously, or your doctor may recommend radioimmunotherapy or new chemotherapy regimens (with or without rituximab) that you did not receive before. Radiation therapy may be given to relieve your lymphoma-related complications. You can also enroll in a clinical trial.

Autologous stem cell rescue or allogeneic stem cell transplant are also an option for patients with refractory, recurrent, or progressive disease, if a subsequent remission can be induced. Please see below for more information on stem cell rescues and stem cell transplants.

In some patients whose disease does not respond to treatment, their follicular lymphoma will change into an aggressive (fast-growing) form of NHL called diffuse large B-cell lymphoma (DLBCL). The treatment options for this group of patients are described in the treatment summary for DLBCL.

Postremission Therapy

Several treatment options are available for patients experiencing remission after treatment with chemoimmunotherapy. These treatment options include radioimmunotherapy, rituximab, or observation. Radioimmunotherapy is commonly used for maintenance therapy after first-line remission, but rituximab for the same indication should only be used in a clinical trial. If your lymphoma enters remission after second-line therapy, your doctor may recommend maintenance therapy with rituximab to prevent it from returning.

Stem Cell Rescues and Transplants Overview

Stem cell rescues and transplants are demanding treatments. Both treatments use chemotherapy at a higher dose than the regular chemotherapy regimens. High-dose chemotherapy is used to destroy the rapidly dividing cancer cells in the bone marrow, but the dose is also high enough to destroy other rapidly dividing normal blood cells in the bone marrow. Therefore, these blood cells are replaced with an infusion of either your own blood and marrow (autologous) or blood and marrow from a matched donor (allogeneic). These cells then seed your own bone marrow and your body starts making new blood cells.

High-Dose Chemotherapy With Autologous Stem Cell Rescue (HDT/ASCR)

HDT/ASCR is an appropriate option for patients with refractory, recurrent, or progressive disease, if a subsequent remission can be induced. Before undergoing an autologous stem cell rescue, your own stem cells will be harvested from your body when you are free of disease (after second line chemotherapy). This can be done in two ways: the stems cells can be removed from your bone marrow in a procedure called a bone marrow aspiration, or the stem cells can be removed from your blood through filtration. Most patients will need to be treated with a growth factor (granulocyte colony-stimulating factor [G-CSF]) to encourage the body to make and release more stem cells into the bloodstream before harvesting.

Once your stems cells have been harvested, you will receive high-dose chemotherapy that wipes out your own developing blood cells in the bone marrow along with any residual lymphoma cells that remain after prior treatment. This high-dose chemotherapy is called conditioning.

There are two different conditioning regimens: myeloablative and non-myeloablative. Myeloablative conditioning destroys all bone marrow cells along with any residual lymphoma cells and is harder on the patient, and therefore is often used in younger patients. Non-myeloablative (or reduced-intensity) conditioning uses lower-intensity chemotherapy that suppresses your immune system and allows the transplant to take, but is not strong enough to destroy all bone marrow cells, and is an option for patients who are not considered candidates for myeloablative conditioning, such as those who are older than 55 years.

Once conditioning is complete, your own new stem cells are infused into your bone marrow. These cells will begin to grow and divide in your bone marrow, and grow new blood cells.

Because of the risks associated with stem cell transplants, the decision to pursue this option must be made after careful discussion with your doctor.

High-Dose Chemotherapy With Allogeneic Stem Cell Transplant (HDT/ASCT)

Allogeneic stem cell transplants are generally considered for select patients. In order to have an allogeneic stem cell transplant, you must have a donor who is a close match to you. Most often the donated stem cells will come from a close relative such as a sibling or from a matched unrelated donor (MUD) or cord blood. These donated stem cells provide a powerful form of immunotherapy.

Prior to allogeneic stem cell transplantation, you will undergo high-dose chemotherapy (conditioning) that wipes out your own developing blood cells in the bone marrow along with any residual lymphoma cells that remain after prior treatment.

There are two different conditioning regimens: myeloablative, and non-myeloablative. Myeloablative conditioning destroys all bone marrow cells along with any residual lymphoma cells and is harder on the patient, and therefore is often used in younger patients. Non-myeloablative (or reduced-intensity) conditioning uses lower-intensity chemotherapy that suppresses your immune system and allows the transplant to take, but is not strong enough to destroy all bone marrow cells, and is an option for patients who are not considered candidates for myeloablative conditioning, such as those who are older than 55 years.

Once conditioning is complete, new stem cells are infused into your bone marrow. These cells begin to grow and divide in your bone marrow, and grow new blood cells.

Graft-versus-host disease (GVHD) is a potentially life-threatening long-term side effect of allogeneic stem cell transplant. In GVHD, transplanted donor blood cells attack the patient’s immune system. Acute GVHD occurs immediately after transplant, and chronic GVHD may occur from 3 months to 1 year after transplant.

You will receive immunosuppressive drugs (1 or 2 days prior to transplant) to prevent GVHD and related complications. You may need to take immunosuppressive drugs regularly for many months after transplantation to prevent GVHD.

Because of the risks associated with stem cell transplants and the possibility of rejection of the new stem cells by your immune system, the decision to pursue this option must be made after careful discussion with your doctor.

Side Effects of Treatment

Follicular lymphoma treatments may result in uncomfortable side effects. Talk to your doctor about what to expect from each treatment and how to manage the possible effects. For example:

• A common side effect of treatment is low blood counts. Many patients suffer from febrile neutropenia (low white blood cell counts), which can lead to increased risk of infection. Your doctor may prescribe growth factors to encourage your body to make more white blood cells. Your doctor may also prescribe antibiotics to decrease your chance of infection and treat any infections you develop.
• After radiation therapy, people are often fatigued; some may have shortness of breath. Your health care provider can use the NCCN Clinical Practice Guidelines in Oncology™ on cancer-related fatigue to help you reduce fatigue caused by cancer treatments. Also, see Fighting Cancer Fatigue.
• After chemotherapy, people may experience mouth sores, hair loss, fatigue, and/or loss of appetite.
• Your doctor may give you antiemetic (anti-vomiting/anti-nausea) drugs to decrease or prevent nausea and/or vomiting. The NCCN Clinical Practice Guidelines in Oncology™ on antiemesis can help your doctor determine the most appropriate antiemetic regimen for your situation.
• After chemotherapy, many patients experience constipation. Be sure to report this problem to your doctor so that proper medication and diet changes can be prescribed. Constipation can become life-threatening when accompanied by low blood counts, and it is also associated with a higher risk of infection.
• Damage to the heart muscle by chemotherapy drugs is called cardiac toxicity. As a result of this damage, the heart is not able to pump enough blood to supply the body with essential oxygen and nutrients. The most common cause of cardiac toxicity is treatment with chemotherapy drugs called anthracyclines. Doxorubicin is a frequently used anthracycline in chemotherapy. If you have impaired cardiac function, you doctor will monitor your condition and adjust the dose of chemotherapy accordingly. You may also be treated with regimens containing other anthracyclines that cause considerably lower cardiac toxicity.
• Hepatitis B virus reactivation can occur mainly in patients who received chemotherapy and rituximab and who are carriers of hepatitis B or have recovered from hepatitis B infection. Your doctor will give you antiviral drugs, such as lamivudine, to prevent the viral reactivation. Hepatitis B–positive patients may be asked to consult a hepatologist.

Talk to your doctor or oncology nurse about the best ways to manage side effects. It is important for you to discuss any possible side effects as soon as they appear.

Prognosis

If you are diagnosed with follicular lymphoma, your outcomes are highly variable. You may not need treatment for many years, or you may need immediate aggressive treatment. In determining a prognosis—the likely course or outcome of a disease and its treatment—a doctor may look at survival statistics taken from studies of large groups of patients with follicular lymphoma. However, such statistics:

• Are estimates only
• Can vary widely with each cancer stage
• Are sometimes based on older data that do not reflect recent advances in treatment options
• Cannot be used to precisely predict your survival

Your individual prognosis, although difficult to predict, will be affected by many factors, including:

• Your age
• Your overall health, including other diseases you may have
• The risk category of your cancer
• Your response to the treatment(s) being used

Newer therapies and combinations of therapies are enabling people with cancer to live longer, better quality lives than ever before. You may want to find out whether you are eligible to participate in a clinical trial, which may test novel drugs or alternative ways of giving established drugs that may lead to improved outcomes for all patients.

Life After Treatment

Once your treatment is completed, you will need to see your doctor for follow-up visits at regular intervals to make sure that you remain healthy and that any long-term effects of cancer or its treatment can be attended to.