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Non-Hodgkin Lymphoma – Treatment Options

In cancer care, different types of doctors often work together to create a patient’s overall treatment plan that combines different types of treatments. This is called a multidisciplinary team. Cancer care teams include a variety of other health care professionals, such as physician assistants, oncology nurses, social workers, pharmacists, counselors, dietitians, and others.

There are 4 main treatments for NHL:

Often, patients receive a combination of these treatments. Occasionally, the doctor and patient may consider surgery or bone marrow/stem cell transplantation.

Descriptions of the common types of treatments used for NHL are described below. Your care plan may also include treatment for symptoms and side effects, an important part of cancer care.

Treatment options and recommendations depend on several factors, including:

Take time to learn about all of your treatment options and be sure to ask questions about things that are unclear. Talk with your doctor about the goals of each treatment and what you can expect while receiving the treatment. These types of talks are called “shared decision making.” Shared decision making is when you and your doctors work together to choose treatments that fit the goals of your care. Shared decision making is particularly important for NHL because there are different treatment options.

Watchful waiting

Some people with indolent lymphoma may not need immediate treatment if they are otherwise healthy and the lymphoma is not causing any symptoms or problems with other organs. This is called watchful waiting, or sometimes called watch-and-wait or active surveillance. During watchful waiting, doctors closely monitor patients using physical examinations, CT scans or other imaging tests, and laboratory tests on a regular basis. Treatment only begins if the person develops symptoms or tests indicate that the cancer is getting worse. For some people with indolent lymphoma, watchful waiting does not affect the chances of survival, but regular and careful follow-up care is recommended.

Therapies using medication

Systemic therapy is the use of medication to destroy cancer cells. This type of medication is given through the bloodstream to reach cancer cells throughout the body. Systemic therapies are generally prescribed by a medical oncologist, a doctor who specializes in treating cancer with medication, or a hematologist, a doctor who specializes in treating blood disorders. A medical oncologist or hematologist is most often the primary cancer specialist for people with lymphoma.

Common ways to give systemic therapies include an intravenous (IV) tube placed into a vein using a needle or in a pill or capsule that is swallowed (orally).

The types of systemic therapies used for NHL include:

Each of these types of therapies is discussed below in more detail. A person may receive 1 type of systemic therapy at a time or a combination of systemic therapies given at the same time. They can also be given as part of a treatment plan that includes radiation therapy.

The medications used to treat cancer are continually being evaluated. Talking with your doctor is often the best way to learn about the medications prescribed for you, their purpose, and their potential side effects or interactions with other medications. It is also important to let your doctor know if you are taking any other prescription or over-the-counter medications or supplements. Herbs, supplements, and other drugs can interact with cancer medications. Learn more about your prescriptions by using searchable drug databases.

Chemotherapy

Chemotherapy is the use of drugs to destroy cancer cells, usually by keeping the cancer cells from growing, dividing, and making more cells. It is the main treatment for NHL.

A chemotherapy regimen, or schedule, usually consists of a specific number of cycles given over a set period of time. A patient may receive 1 drug at a time or a combination of different drugs given at the same time. The stage and type of NHL determines which chemotherapy is used. The most common chemotherapy combination for the first treatment of aggressive NHL is called CHOP and contains 4 medications:

For patients with B-cell lymphoma, adding an anti-CD20 monoclonal antibody, such as rituximab or obinutuzumab, to CHOP works better than using CHOP alone (see “Targeted therapy,” below). There are other common combinations of chemotherapy regimens, including:

The side effects of chemotherapy depend on the individual drug and the dose used. They can include fatigue, temporary lowering of blood counts, risk of infection, nausea and vomiting, hair loss, loss of appetite, rash, and diarrhea. These side effects can be managed during treatment and usually go away after treatment is finished.

Chemotherapy may also cause long-term side effects, also called late effects. People with lymphoma may also have concerns about if or how their treatment may affect their sexual health and fertility. Talk with the members of the health care team about these topics before treatment begins.

Targeted therapy

Targeted therapy is a treatment that targets the cancer’s specific genes, proteins, or the tissue environment that contributes to cancer growth and survival. This type of treatment blocks the growth and spread of cancer cells while limiting damage to healthy cells.

Not all tumors have the same targets. To find the most effective treatment, your doctor may run tests to identify the genes, proteins, and other factors in your tumor. This helps doctors better match each patient with the most effective treatment whenever possible. In addition, research studies continue to find out more about specific molecular targets and new treatments directed at them. Learn more about the basics of targeted treatments.

Talk with your doctor about possible side effects for a specific medication and how they can be managed.

Monoclonal antibodies

For NHL, monoclonal antibodies are the main form of targeted therapy used in the treatment plan. A monoclonal antibody recognizes and attaches to a specific protein and does not affect cells that do not have that protein. A monoclonal antibody called rituximab is used to treat many different types of B-cell NHL. Rituximab works by targeting a molecule called CD20 that is located on the surface of all B cells and B-cell NHL. When the antibody attaches to this molecule, the patient’s immune system is activated to destroy some lymphoma cells or to make lymphoma cells more susceptible to being destroyed by chemotherapy.

Although the antibody may work well by itself, research shows that it worked better when added to chemotherapy for patients with most types of B-cell NHL. Rituximab is also given after remission for indolent lymphoma to increase the length of the remission. There are 3 other monoclonal antibodies against CD20 that are approved by the FDA for use in lymphomas: obinutuzumab (Gazyva), ofatumumab (Arzerra), rituximab-abbs (Truxima), and rituximab-pvvr (Ruxience). Rituximab-abbs and rituximab-pvvr are called biosimilars, which means they function in a way similar to rituximab (Rituxan).

Brentuximab vedotin (Adcetris) is another type of monoclonal antibody, called an antibody-drug conjugate. Antibody-drug conjugates attach to targets on cancer cells and then release a small amount of chemotherapy or other toxins directly into the tumor cells. Brentuximab vedotin combined with chemotherapy is approved to treat adults with certain types of peripheral T-cell lymphoma, such as systemic anaplastic large cell lymphoma, angioimmunoblastic T-cell lymphoma, and peripheral T-cell lymphoma, not otherwise specified, as long as they express the CD30 protein. The drug was previously approved for people with Hodgkin lymphoma who did not benefit from or were unable to have a bone marrow/stem cell transplant and for preventive treatment following a bone marrow transplant for higher-risk Hodgkin lymphoma. Research on the benefits of other newer monoclonal antibodies for lymphoma is ongoing.

Polatuzumab vedotin-piiq (Polivy) is a monoclonal antibody that targets CD79b. Like brentuximab vedotin, it is also an antibody-drug conjugate. Polatuzumab is used in combination with bendamustine and rituximab to treat DLBCL that has come back after at least 2 other treatments.

Radiolabeled antibodies are monoclonal antibodies with radioactive particles attached. The particles are designed to focus the radiation directly to the lymphoma cells. In general, the radioactive antibodies are thought to be stronger than regular monoclonal antibodies but more damaging to the bone marrow. This type of therapy is also called radioimmunotherapy (RIT).

Talk with your doctor about possible side effects for a specific medication and how they can be managed.

Kinase inhibitors 

Kinase inhibitors are another type of targeted therapy used to treat NHL.

Acalabrutinib (Calquence) targets the Bruton’s tyrosine kinase pathway. It is approved to treat adults with mantle cell lymphoma who have received at least 1 other treatment. It is also approved to treat adults with small lymphocytic lymphoma, which is the same disease as chronic lymphocytic leukemia. The most common side effects of acalabrutinib are headache, diarrhea, muscle and join pain, upper respiratory tract infection, and bruising.

Copanlisib (Aliquopa) targets the phosphoinositide 3-kinase (PI3K) pathway. It is used to treat adults with follicular lymphoma that has come back after treatment with at least 2 previous therapies. The common side effects of copanlisib include high blood sugar, diarrhea, fatigue, high blood pressure, low white blood cell count, nausea, lung infections, and low blood platelet count.

Duvelisib (Copiktra) also targets the PI3K pathway. It is used to treat adults with small lymphocytic lymphoma that has not been stopped by at least 2 previous therapies. This targeted therapy is also used to treat chronic lymphocytic leukemia. The common side effects of duvelisib include diarrhea, intestinal problems, low white blood cell count, rash, fatigue, pain, cough, nausea, respiratory infection, pneumonia, pain, and anemia.

Ibrutinib (Imbruvica) targets the Bruton’s tyrosine kinase pathway. This drug is approved to treat several B-cell lymphomas, including mantle cell lymphoma, marginal zone lymphoma, and small lymphocytic lymphoma, as well as chronic lymphocytic leukemia and Waldenström’s macroglobulinemia. Common side effects of ibrutinib include diarrhea, muscle and bone pain, rash, nausea, bruising, tiredness, and, less commonly, bleeding, irregular heartbeat (atrial fibrillation), or fever.

Zanubrutinib (Brukinsa) is another Bruton’s tyrosine kinase inhibitor. It is approved to treat mantle cell lymphoma in people who have received at least 1 previous therapy. The common side effects of zanubrutinib are lowered white blood cell counts, lowered platelet count, upper respiratory tract infection, lowered hemoglobin levels, rash, bruising, diarrhea and cough.

Immunomodulatory drugs

Immunomodulatory drugs modulate, or influence, how the body’s immune system responds or works. Lenalidomide (Revlimid) is a thalidomide analog used to treat follicular lymphoma and mantle cell lymphoma that have not been stopped by other treatments. Lenalidomide is also used to treat multiple myeloma and myelodysplastic syndromes.

Immunotherapy

Immunotherapy, also called biologic therapy, is designed to boost the body’s natural defenses to fight the cancer. It uses materials made either by the body or in a laboratory to improve, target, or restore immune system function.

In chimeric antigen receptor (CAR) T-cell therapy, some T cells are removed from a patient’s blood. Then, the cells are changed in a laboratory so they have specific proteins called receptors. The receptors allow those T cells to recognize the cancer cells. The changed T cells are grown in large numbers in the laboratory and returned to the patient’s body. Once there, they seek out and destroy cancer cells.

Axicabtagene ciloleucel (Yescarta) is a CAR T-cell therapy that is approved to treat patients with DLBCL who have received at least 2 previous types of treatment. Tisagenlecleucel (Kymriah) is another CAR T-cell therapy that is approved for the treatment of refractory B-cell lymphoma, including DLBCL, after 2 previous systemic treatments or more. Further CAR T-cell therapies are in development and being studied in clinical trials.

Checkpoint inhibitors block specific pathways to stop or slow the growth of cancer. The PD-1 pathway is a target for several checkpoint inhibitors. One of these, pembrolizumab (Keytruda), can be used to treat primary mediastinal large B-cell lymphoma that has not been stopped by at least 2 other treatments.

Different types of immunotherapy can cause different side effects. Common side effects include skin reactions, flu-like symptoms, diarrhea, and weight changes. Talk with your doctor about possible side effects for the immunotherapy recommended for you. 

Radiation therapy

Radiation therapy is the use of high-energy x-rays, electrons, or protons to destroy cancer cells. A doctor who specializes in giving radiation therapy to treat cancer is called a radiation oncologist. Radiation treatment for NHL is usually external-beam radiation therapy, which is radiation given from a machine outside the body.

A radiation therapy regimen, or schedule, usually consists of a specific number of treatments given over a set period of time.

Radiation therapy is usually given after or in addition to chemotherapy, depending on the NHL subtype. It is most often given to people who have localized lymphoma, which means that it involves only 1 or 2 adjacent areas, or to people who have a lymph node that is particularly large, usually more than 7 to 10 centimeters across. It may also be given for the treatment of pain or in very low doses (just 2 treatments) to people with advanced disease who have localized symptoms that can be relieved using radiation therapy.

General side effects from radiation therapy may include fatigue and nausea. Most side effects are related to the region of the body receiving radiation. These side effects may include mild skin reactions, dry mouth, temporary hair loss, or loose bowel movements. People who have had radiation therapy directed at the chest may experience lung inflammation called pneumonitis. People who had radiation therapy directed at the bones may experience low blood counts. Talk with your doctor about what you can expect regarding side effects and how they can be managed.

Most side effects go away soon after treatment is finished, but radiation therapy may also cause late effects, such as second cancers or damage to the heart and blood vessels if they were within the field of radiation. Sexual problems and infertility may occur after radiation therapy to the pelvis. Before treatment begins, talk with your doctor about possible sexual and fertility-related side effects of your treatment and the available options for preserving fertility for both men and women.

Bone marrow transplantation/stem cell transplantation

A bone marrow transplant is a medical procedure in which bone marrow or peripheral blood cells containing highly specialized cells, called hematopoietic stem cells, are used as part of a treatment plan. Hematopoietic stem cells are blood-forming cells found in the bloodstream and the bone marrow. This procedure is also called a stem cell transplant. This is because stem cells collected from the blood are typically being transplanted, not cells from the actual bone marrow tissue.

Transplantation is considered an aggressive treatment. It is generally used only for people with NHL whose disease is progressive or recurrent (see Stages). For some NHL subtypes, such as mantle cell lymphoma and some T-cell lymphomas, doctors may recommend transplantation as part of the initial treatment plan to prevent recurrence.

Before recommending transplantation, the doctor will talk with you about the risks of this treatment. Doctors also consider several other factors, such as the type of NHL, results of any previous treatment, and your age and general health. It is important to talk with an experienced doctor at a specialized transplant center about the risks and benefits of this treatment.

There are 2 types of bone marrow transplantation, depending on the source of the replacement blood stem cell:

Side effects of a bone marrow transplant depend on the type of transplant, your general health, and other factors. 

Physical, emotional, and social effects of cancer

Cancer and its treatment cause physical symptoms and side effects, as well as emotional, social, and financial effects. Managing all of these effects is called palliative care or supportive care. It is an important part of your care that is included along with treatments intended to slow, stop, or eliminate the cancer.

Palliative care focuses on improving how you feel during treatment by managing symptoms and supporting patients and their families with other, non-medical needs. Any person, regardless of age or type and stage of cancer, may receive this type of care. And it often works best when it is started right after a cancer diagnosis. People who receive palliative care along with treatment for the cancer often have less severe symptoms, better quality of life, and report they are more satisfied with treatment.

Palliative treatments vary widely and often include medication, nutritional changes, relaxation techniques, emotional and spiritual support, and other therapies. You may also receive palliative treatments similar to those meant to get rid of the cancer, such as chemotherapy, surgery, or radiation therapy.

Before treatment begins, talk with your doctor about the goals of each treatment in the treatment plan. You should also talk about the possible side effects of the specific treatment plan and palliative care options.

During treatment, your health care team may ask you to answer questions about your symptoms and side effects and to describe each problem. Be sure to tell the health care team if you are experiencing a problem. This helps the health care team treat any symptoms and side effects as quickly as possible. It can also help prevent more serious problems in the future.

Remission and the chance of recurrence

A complete remission is when lymphoma cannot be detected in the body and there are no symptoms. This may also be called having “no evidence of disease” or NED. Partial remission is when the lymphoma has regressed by more than 50% from its pretreatment state but can still be detected.

A remission may be temporary or permanent. This uncertainty causes many people to worry that the cancer will come back. While many remissions are permanent, it is important to talk with your doctor about the possibility of the disease returning. Understanding your risk of recurrence and the treatment options may help you feel more prepared if the lymphoma does return. 

As explained in the Stages section, if the cancer returns after the original treatment, it is called recurrent cancer. It may come back in the same place (called a local recurrence), nearby (regional recurrence), or in another place (distant recurrence).

When this occurs, a new cycle of testing will begin again to learn as much as possible about the recurrence. In most cases, another tissue biopsy is needed to prove that the lymphoma has not changed or transformed into a more aggressive subtype. After this testing is done, you and your doctor will talk about the treatment options.

Treatment for recurrent NHL depends on 3 factors:

Often the treatment plan will include the treatments described above, such as chemotherapy, radiation therapy, targeted therapy, immunotherapy, or bone marrow/stem cell transplantation. However, they may be used in a different combination or given at a different pace. Your doctor may suggest clinical trials that are studying new ways to treat recurrent NHL. Whichever treatment plan you choose, palliative care will be important for relieving symptoms and side effects.

People with recurrent cancer often experience emotions such as disbelief or fear. You are encouraged to talk with the health care team about these feelings and ask about support services to help you cope. 

Progressive NHL

Some people with NHL may not experience a complete remission and will have small amounts of residual disease that is stable. Or, they will have residual disease that is actively growing despite treatment. If there is a small amount of residual disease that is stable, some people with indolent NHL may be observed with watchful waiting for a period of time or be treated with targeted therapy or other drugs. Radiation therapy to the local area may also be a possibility. These patients may have breaks in treatment, sometimes lasting many years. If the lymphoma begins to grow or spread, this is called progression of disease, and active treatment will begin again.

It is important to understand that remission is not always possible in some indolent lymphomas. However, some people can be safely monitored even if there is leftover disease. This is possible as long as there are no symptoms and the lymphoma has not affected blood counts or other organs.

If there is residual disease that is growing despite active treatment, it is called “refractory NHL,” see below.

Refractory NHL

If standard treatments stop working well for NHL or the lymphoma comes back within 6 months after treatment, this is called refractory NHL. Patients with this diagnosis are encouraged to talk with doctors who are lymphoma experts to discuss options for the best treatment plan. This discussion may include clinical trials.

Treatment options for refractory NHL depend on 4 factors:

The doctor may suggest chemotherapy, immunotherapy, bone marrow/stem cell transplantation, or a clinical trial. Palliative care will also be important to help relieve symptoms and side effects.

For most people, a diagnosis of refractory NHL is very stressful and, at times, difficult to bear. You and your family are encouraged to talk about how you fell with doctors, nurses, social workers, or other members of the health care team. It may also be helpful to talk with other patients, including through a support group.

If treatment does not work

Recovery from NHL is not always possible. If the cancer cannot be cured or controlled, the disease may be called advanced or terminal.

This diagnosis is stressful, and for many people, advanced cancer is difficult to discuss. However, people with advanced NHL, especially those with indolent lymphoma, may continue to live for a long time after a diagnosis of advanced cancer. It is important to have open and honest conversations with your health care team to express your feelings, preferences, and concerns. The health care team has special skills, experience, and knowledge to support patients and their families and is there to help. Making sure a person is physically comfortable, free from pain, and emotionally supported is extremely important.

People who have advanced cancer and who are expected to live less than 6 months may want to consider hospice care. Hospice care is designed to provide the best possible quality of life for people who are near the end of life. You and your family are encouraged to talk with the health care team about hospice care options, which include hospice care at home, a special hospice center, or other health care locations. Nursing care and special equipment can make staying at home a workable option for many families.

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