Lymphoma - Non-Hodgkin

General treatment information

Once non-Hodgkin lymphoma has been diagnosed and staged, your cancer care team will discuss treatment options with you. Several different types of treatment can be used against non-Hodgkin lymphoma. The treatment options depend on the type of lymphoma and its stage (extent), as well as the other prognostic factors. Of course, no 2 patients are exactly alike, and standard options are often tailored to each patient’s situation.

The main types of treatment for non-Hodgkin lymphoma are:

Chemotherapy

Radiation

Immunotherapy

Stem cell transplant

In rare cases, surgery is also used.

Based on your treatment options, you may have different types of doctors on your treatment team. These doctors may include:

A hematologist: a doctor who treats disorders of the blood, including lymphomas.

A medical oncologist: a doctor who treats cancer with medicines.

A radiation oncologist: a doctor who treats cancer with radiation therapy.

Many other specialists may be involved in your care as well, including nurse practitioners, nurses, nutrition specialists, social workers, and other health professionals. 

It’s important to discuss all of your treatment options as well as their possible side effects with your doctors to help make the decision that best fits your needs.  In choosing a treatment plan, consider your health and the type and stage of the lymphoma. Be sure that you understand all the risks and side effects of the various treatments before making a decision.

If time permits, it’s often a good idea to seek a second opinion. Getting a second opinion can give you more information and help you feel confident about the treatment plan you choose. Your doctor should be willing to help you find another cancer doctor who can give you a second opinion.

The next few sections describe the types of treatment used for non-Hodgkin lymphoma. This is followed by a discussion of the typical treatment options based on the type of lymphoma, stage, and other prognostic factors when these are important.

The “Additional resources for non-Hodgkin lymphoma” section also includes a list of other, more detailed materials on the different types of cancer treatments and their side effects.

Chemotherapy for non-Hodgkin lymphoma

Chemotherapy (chemo) is the use of anti-cancer drugs that are usually injected into a vein or taken by mouth. These drugs enter the bloodstream and reach almost all areas of the body, making this treatment very useful for lymphoma. In some cases where the lymphoma may have reached the brain or spinal cord, chemo may also be given into the cerebrospinal fluid (CSF). This is called intrathecal chemo.

Depending on the type and the stage of the lymphoma, chemo may be used alone or combined with radiation therapy.

Doctors give chemo in cycles, in which a period of treatment is followed by a rest period to allow the body time to recover. Each chemo cycle generally lasts for several weeks. Most chemo treatments are given on an outpatient basis (in the doctor’s office or clinic or hospital outpatient department), but some may require a hospital stay.

Many chemo drugs are useful in treating lymphoma patients. Often, several drugs are combined. The number of drugs, their doses, and the length of treatment depend on the type and stage of the lymphoma. Some of the drugs commonly used to treat lymphoma include:

Cyclophosphamide (Cytoxan^®)

Vincristine (Oncovin^®)

Doxorubicin (Adriamycin^®)

Prednisone

Fludarabine (Fludara^®)

Cytarabine (ara-C)

Chlorambucil

Mitoxantrone

Methotrexate

Etoposide (VP-16)

Dexamethasone (Decadron^®)

Cisplatin

Carboplatin

Ifosfamide (Ifex^®)

Bleomycin

Bendamustine (Treanda^®)

Gemcitabine (Gemzar^®)

Pralatrexate (Folotyn^®)

One of the most common combination of drugs is called CHOP. This includes the drugs cyclophosphamide, doxorubicin (which has a chemical name beginning with H), vincristine (Oncovin) and prednisone. Another common combination leaves out doxorubicin and is called CVP.

Chemo is often combined with immunotherapy, especially the monoclonal antibody rituximab (Rituxan^®).

Sometimes a patient may get one chemo combination for several cycles and later switch to a different one if the first combination doesn’t seem to be working.

Possible side effects

Chemo drugs attack cells that are dividing quickly, which is why they work against lymphoma cells. But other cells in the body, such as those in the bone marrow, the lining of the mouth and intestines, and the hair follicles, also divide quickly. These cells are also likely to be affected by chemotherapy, which can lead to certain side effects.

The side effects of chemo depend on the type and dose of drugs given and the length of time they are taken. These side effects can include:

Hair loss

Mouth sores

Loss of appetite

Nausea and vomiting

Diarrhea

Low blood cell counts

These side effects are usually short-term and go away after treatment is finished. If serious side effects occur, the dose of chemo may be reduced or treatment may be delayed.

There are often ways to lessen these side effects. For example, drugs are given that prevent or reduce nausea and vomiting.

Certain drugs have specific possible side effects. For example, drugs such as doxorubicin can damage the heart. Your doctor may order a test of heart function (like a MUGA scan or echocardiogram) before starting you on one of these drugs. Bleomycin can damage lungs. Doctors often test lung function before starting someone on this drug.

Other serious side effects can occur, depending on the chemo drugs used. For example, many chemo drugs can affect fertility (the ability to have children). Nerve damage, causing numbness, tingling, or even pain in the hands and feet, can also occur. Ask your health care team about what side effects you can expect based on the specific drugs you will be getting.

Chemo can also cause side effects that might not occur until years after treatment. For example, in rare cases, people may develop leukemia several years later.

Low blood cell counts: Chemo can cause low blood cell counts because it affects the cells that form blood in the bone marrow. This can lead to:

Increased chance of infections (from low white blood cell counts)

Easy bruising or bleeding (from low blood platelet counts)

Fatigue (from low red blood cell counts)

Infections can be very serious in people getting chemo. Drugs known as growth factors (G-CSF or GM-CSF, for example) are sometimes given to help the white blood cells recover from the effects of chemo and thus reduce the chance of infection. Antibiotics may also be given at the earliest sign of an infection, such as a fever.

If your white blood cell counts are very low during treatment, you can help reduce your risk of infection by carefully limiting your exposure to germs. During this time, your doctor may advise you to:

Wash your hands often.

Avoid fresh, uncooked fruits and vegetables and other foods that might carry germs.

Avoid fresh flowers and plants because they may carry mold.

Make sure other people wash their hands before they touch you.

Avoid large crowds and people who are sick (wearing a surgical mask offers some protection in these situations).

If your platelet counts are very low, you may be given drugs or platelet transfusions to help protect against bleeding. Fatigue caused by anemia (very low red blood cell counts) can be treated with drugs or with red blood cell transfusions.

Tumor lysis syndrome is a possible side effect of chemo in patients who had large numbers of lymphoma cells in the body before treatment. It occurs most often with the first cycle of chemo. When the cancer cells are killed, they break open and release their contents into the bloodstream. This can overwhelm the kidneys, which cannot get rid of all of these substances at once. This can lead to the build-up of excess amounts of certain minerals in the blood and even kidney failure. The excess minerals can lead to problems with the heart and nervous system. Doctors work to prevent these problems by giving the patient extra fluids and certain drugs, such as sodium bicarbonate, allopurinol, and rasburicase.

Other drugs used to treat lymphoma

As researchers have learned more about the changes in cells that cause cancer, they have been able to develop newer drugs that specifically target these changes. These drugs are often referred to as targeted therapy. These drugs work differently from standard chemotherapy drugs and often have different (and less severe) side effects.

Bortezomib (Velcade^®) is a type of drug known as a proteasome inhibitor. It is most often used to treat other cancers of lymphocytes. But it can also be used to treat some lymphomas, usually after other treatments have been tried. Bortezomib is given as an infusion into a vein (IV) or an injection under the skin (sub-q), typically twice a week for 2 weeks, followed by a rest period. Side effects can be similar to those of standard chemo drugs, including low blood counts, nausea, loss of appetite, and nerve damage.

Romidepsin (Istodax^®) is in a class of drugs called histone deacetylase (HDAC) inhibitors. It is used to treat some T-cell lymphomas, usually after at least one other treatment has been tried. This drug is given as an IV infusion, usually once a week. Side effects tend to be mild, but can include lowered blood cell counts and effects on the rhythm of the heart.

Radiation therapy for non-Hodgkin lymphoma

Radiation therapy uses high-energy rays to kill cancer cells.

When radiation is used to treat non-Hodgkin lymphoma, it’s most often done with a carefully focused beam of radiation, delivered from a machine outside the body. This is known as external beam radiation. The treatment is much like getting an x-ray, but the radiation is more intense. The procedure itself is painless. Before the treatments start, the radiation team takes careful measurements to determine the correct angles for aiming the radiation beams and the proper dose. Each treatment lasts only a few minutes, although the setup time – getting you into place for treatment – usually takes longer. Most often, radiation treatments are given 5 days a week for several weeks.

Radiation can also be given as a drug in some cases .

Radiation might be used as the main treatment for some types of lymphoma if they are found early (stage I or II), because these tumors respond very well to radiation. For more advanced lymphomas and for some lymphomas that are more aggressive, radiation is sometimes used along with chemotherapy.

People who are getting a stem cell transplant may get radiation to the whole body along with high-dose chemotherapy, to try to kill lymphoma cells throughout the body. 

Radiation therapy can also be used to ease (palliate) symptoms caused by lymphoma that has spread to internal organs, such as the brain or spinal cord, or when a tumor is causing pain because it’s pressing on nerves.

Possible side effects

The side effects of radiation therapy depend on where the radiation is aimed. Common side effects include:

Skin changes similar to sunburn

Extreme tiredness (fatigue)

Nausea

Diarrhea

Lower blood cell counts

Nausea and diarrhea are more common if the abdomen (belly) is treated with radiation.

Low blood cell counts can lead to problems with:

Fatigue and weakness (from anemia – too few red blood cells)

Increased risk of infection (from having too few white blood cells)

Problems with excess bleeding and easy bruising (from thrombocytopenia – having low platelet counts)

Radiation to the head and neck area can lead to mouth sores and trouble swallowing. Some patients later have problems with dry mouth.

Radiation to the chest can lead to irritation of the esophagus (the tube that connects the throat to the stomach). This can lead to pain with swallowing and trouble eating.

Often these effects go away shortly after treatment is finished.

Possible long-term side effects of radiation therapy can be more serious.

Chest radiation therapy may cause lung damage and lead to trouble breathing. It can also affect the heart, making you more likely to have a heart attack later on.

Radiation to the neck can lead to thyroid problems later in life. This can lead to fatigue and weight gain and is treated with pills containing thyroid hormone. Radiation to the neck may also increase the risk of stroke many years later.

Side effects of brain radiation therapy usually become most serious 1 or 2 years after treatment and may include headaches and problems such as memory loss, personality changes, and trouble concentrating.

Other types of cancer can form in the area that received radiation. For example, radiation to the chest may increase the risk of lung cancer (especially in smokers) and of breast cancer. This happens rarely.

Side effects tend to be worse if radiation and chemotherapy are given together.

Immunotherapy for non-Hodgkin lymphoma

Immunotherapy is treatment that either boosts the patient’s own immune system or uses man-made versions of the normal parts of the immune system. These treatments may kill lymphoma cells or slow their growth.

Monoclonal antibodies

Antibodies are proteins made by the body’s immune system to help fight infections. Man-made versions, called monoclonal antibodies, can be designed to attack a specific target, such as a substance on the surface of lymphocytes (the cells in which lymphomas start).

Several monoclonal antibodies are now being used to treat lymphoma.

Rituximab (Rituxan^®): This is an antibody that attaches to a substance called CD20 found on some types of lymphoma cells. This attachment seems to cause the lymphoma cell to die. The treatments are given as intravenous (IV) infusions in the doctor’s office or clinic.

When used by itself to treat lymphoma, it’s given weekly for 4 to 8 weeks. When combined with chemotherapy, it is most often given on the first day of each chemo cycle. For some lymphomas, it may be given after chemo as maintenance therapy. In that case it’s given weekly for 4 weeks in a row, every 6 months for up to 2 years.

Common side effects are usually mild but may include chills, fever, nausea, rashes, fatigue, and headaches. Rarely, more severe side effects occur during infusions, such as trouble breathing and low blood pressure. Even if these symptoms occur during the first rituximab infusion, it is very unusual for them to recur with later doses. This drug may also increase a person’s risk of certain infections for up to 6 months after the drug is stopped.

Rituximab can cause hepatitis B infections that were dormant (inactive) to become active again, sometimes leading to severe liver problems or even death. For that reason, your doctor may check your blood for signs of an old hepatitis infection before starting this drug.

Ibritumomab (Zevalin^®) and tositumomab (Bexxar^®): These drugs are monoclonal antibodies aimed at CD20 (like rituximab) that have radioactive molecules attached to them. The antibodies bring radiation directly to the lymphoma cells, which may help them work better. These drugs are given as intravenous (IV) infusions. Side effects are similar to those seen with rituximab, although low blood cell counts are seen more often with these drugs.

These drugs are not used as often as rituximab, in part because they are somewhat harder for doctors to give (because of the radiation dosing involved). They cannot be used with chemotherapy because they also lower blood counts, which may raise the risk of infections, bleeding, or other problems. At this time these drugs are most often used if chemotherapy and/or rituximab are no longer working.

Alemtuzumab (Campath^®): This antibody is directed at the CD52 antigen. It is useful in some cases of chronic lymphocytic leukemia (CLL) and also some types of peripheral T-cell lymphomas. It is given by infusion into a vein (IV), usually 3 times a week for up to 12 weeks. The most common side effects are fever, chills, nausea, and rashes. It can also cause very low white blood cell counts, which increases the risk for serious infections. Antibiotic and antiviral medicines are given to help protect against them, but severe and even life-threatening infections can still occur.

Ofatumumab (Arzerra^®): Ofatumumab is another antibody that targets the CD20 antigen. It is approved to treat chronic lymphocytic leukemia and is used mainly when other treatments such as chemotherapy, rituximab, and alemtuzumab are no longer working. It is being studied for use in treating other lymphomas. Side effects are similar to those that are seen with rituximab.

Brentuximab vedotin (Adcetris^®): This drug is an anti-CD30 antibody attached to a chemotherapy drug. Some lymphoma cells have the CD30 molecule on their surface. The antibody acts like a homing signal, bringing the chemo drug to the lymphoma cells, where it enters the cells and causes them to die when they try to divide into new cells.

Brentuximab can be used to treat anaplastic large cell lymphoma (ALCL) that has come back after other treatments. It is given as an infusion into a vein (IV) every 3 weeks. Common side effects include nerve damage (neuropathy), low blood counts, fatigue, fever, nausea and vomiting, infections, diarrhea, and cough.

Interferon

Interferon is a hormone-like protein made by white blood cells to help the immune system fight infections. Some studies have suggested that giving man-made interferon can make some types of lymphomas shrink or stop growing.

Common side effects of this treatment include fatigue, fever, chills, headaches, muscle and joint aches, and mood changes. Because of these side effects, interferon is not used very often. It may be given to some patients in addition to chemotherapy.

Immunomodulating agents

These drugs are thought to work against certain cancers by affecting parts of a person’s immune system, although exactly how they work isn’t clear. They are sometimes used to help treat certain types of lymphoma, usually after other treatments have been tried.

Thalidomide (Thalomid^®): The main use of this drug is to treat another cancer of the lymphocytes known as multiple myeloma, but it may also be used to treat some types of lymphoma.

Side effects of thalidomide include drowsiness, fatigue, severe constipation, low white blood cell counts (with an increased risk of infection), and neuropathy (painful nerve damage). The neuropathy can be severe, and may not go away after the drug is stopped. There is also an increased risk of serious blood clots (that start in the leg and can travel to the lungs). Because thalidomide causes severe birth defects if taken during pregnancy, this drug should not be used by women who are or may become pregnant.

Lenalidomide (Revlimid^®): This is a newer drug that is similar to thalidomide. It may be used to treat some types of lymphoma.

The most common side effects of lenalidomide are low platelet counts (with an increased risk of bleeding) and low white blood cell counts (with an increased risk of infection). It can also cause painful nerve damage. The risk of blood clots isn’t as high as with thalidomide, but it is still increased. Like thalidomide, access to lenalidomide is tightly controlled out of concern about possible serious birth defects.

High-dose chemotherapy and stem cell transplant for non-Hodgkin lymphoma

Stem cell transplants are sometimes used to treat lymphoma patients who are in remission or who have a relapse during or after treatment. Although only a small number of patients with lymphoma are treated with this therapy, this number is growing.

Stem cell transplants allow doctors to use higher doses of chemotherapy (and sometimes radiation) than would normally be tolerated. High-dose chemotherapy destroys the bone marrow, which prevents new blood cells from being formed. This could lead to life-threatening infections, bleeding, and other problems due to low blood cell counts.

Doctors try to get around this problem by giving an infusion of blood-forming stem cells after the high-dose treatment. Stem cells are very primitive cells that can create new blood cells.

Blood-forming stem cells used for a stem cell transplant can come from:

The blood (for a peripheral blood stem cell transplant, or PBSCT)

The bone marrow (for a bone marrow transplant, or BMT)

Umbilical cord blood (for a cord blood transplant)

Most stem cell transplants are now PBSCTs.

Types of transplants

There are 2 main types of stem cell transplants. The blood-forming stem cells come from different sources.

Autologous stem cell transplant

In an autologous stem cell transplant, the patient’s own stem cells are removed from his or her bone marrow or peripheral blood. They are collected on several occasions in the weeks before treatment. The cells are frozen and stored while the person gets treatment (high-dose chemotherapy and/or radiation) and are then reinfused into the patient’s blood.

This is the most common type of transplant used to treat lymphoma, but it generally isn’t an option if the lymphoma has spread to the bone marrow or blood. If that occurs, it may be hard to get a stem cell sample that is free of lymphoma cells. Even after purging (treating the stem cells in the lab to kill or remove lymphoma cells), it’s possible to return some lymphoma cells with the stem cell transplant.

Allogeneic stem cell transplant

In an allogeneic stem cell transplant, the stem cells come from someone else. The donor’s tissue type (also known as the HLA type) needs to match the patient’s tissue type as closely as possible to help prevent the risk of major problems with the transplant. Usually this donor is a brother or sister if they have the same tissue type as the patient. If there are no siblings with a good match, the cells may come from an HLA-matched, unrelated donor – a stranger who has volunteered to donate their cells.

The stem cells for an allogeneic SCT are usually collected from a donor’s bone marrow or peripheral (circulating) blood on several occasions. In some cases, the source of the stem cells may be blood collected from an umbilical cord (the cord that attaches a baby to the placenta) after a baby is born. This blood is rich in stem cells. Regardless of the source, the stem cells are then frozen and stored until they are needed for the transplant.

The use of allogeneic transplants is limited in treating lymphoma because they can have severe side effects that make them hard to tolerate, especially for patients who are older or who have other medical problems. It can also be hard to find a matched donor. About 1 out of 4 transplants for lymphoma is of this kind.

Non-myeloablative transplant (mini-transplant): This is a type of allogeneic transplant in which lower doses of chemo and radiation are used than in a standard SCT. These lower doses do not completely destroy the cells in the bone marrow. When the donor stem cells are given, they enter the body and establish a new immune system, which sees the lymphoma cells as foreign and attacks them (a “graft-versus-lymphoma” effect).

Doctors have learned that if they use small doses of certain chemo drugs and low doses of total body radiation, an allogeneic transplant can still sometimes work with less serious side effects.

This type of transplant may be an option for some patients who couldn’t tolerate a regular allogeneic transplant because it’s too toxic. In fact, a patient can receive a non-myeloablative transplant as an outpatient.

The major side effect is graft-versus-host disease, which can be serious (this is discussed later in this section).

Non-myeloablative transplants are not a standard treatment for patients with lymphoma, but they may help some patients.

Practical points

Bone marrow or peripheral blood SCT is a complex treatment that can cause life-threatening side effects. If the doctors think a patient might benefit from a transplant, it should be done at a hospital where the staff has experience with the procedure and with managing the recovery phase. Some stem cell transplant programs may not have experience in certain types of transplants, especially transplants from unrelated donors.

SCT is very expensive (often costing well over $100,000) and often requires a long hospital stay. Autologous transplant is considered a standard treatment for lymphoma under certain conditions, so most medical insurance will cover the cost. Still, some insurance companies may view other types of SCT as an experimental treatment, and they may not pay for those procedures. Even if the transplant is covered by your insurance, your co-pays or other costs could easily amount to tens of thousands of dollars. Find out what your insurer will cover before deciding on a transplant so you will have an idea of what you might have to pay.

Possible side effects

Side effects from a stem cell transplant are generally divided into early and long-term effects.

Early or short-term effects: The early complications and side effects are basically the same as those caused by any other type of high-dose chemotherapy, and can be severe. They are caused by damage to the bone marrow and other quickly growing tissues of the body and can include:

Low blood cell counts (with fatigue and increased risks of infection and bleeding)

Nausea and vomiting

Loss of appetite

Diarrhea

Mouth sores

Hair loss

One of the most common and serious short-term effects is the increased risk for infection. Antibiotics are often given to try to keep this from happening. Other side effects, like low red blood cell and platelet counts, may require blood product transfusions or other treatments.

Long-term side effects: Some complications and side effects can persist for a long time or may not occur until months or years after the transplant. These include:

Graft-versus-host disease (GVHD), which occurs only in allogeneic transplants (see below)

Infertility and premature menopausal symptoms in female patients (caused by damage to the ovaries)

Infertility in male patients

Damage to the thyroid gland that can cause problems with metabolism

Cataracts (damage to the lens of the eye that can affect vision)

Damage to the lungs, causing shortness of breath

Bone damage called aseptic necrosis (if damage is severe, the patient may need to have part of the affected bone and the joint replaced)

Possible development of leukemia several years later

Graft-versus-host disease (GVHD): This is one of the most serious complications of allogeneic (donor) stem cell transplants. It occurs because the immune system of the patient is taken over by that of the donor. The donor immune system then may recognize the patient’s own body tissues as foreign and may react against them.

Symptoms can include severe skin rashes, itching, mouth sores (which can affect eating), nausea, and severe diarrhea. Liver damage may cause yellowing of the skin and eyes (jaundice). The lungs may also be damaged. The patient may also become easily fatigued and develop muscle aches.

GVHD is often described as either acute or chronic, based on how soon after the transplant it begins. Sometimes GVHD can become disabling, and if it’s severe enough, it can be life-threatening. Usually, immune-suppressing drugs can be used to help control GVHD, although they may have their own side effects.

On the positive side, the graft-versus-host disease also leads to “graft-versus-lymphoma” activity. Any lymphoma cells remaining after the chemotherapy and radiation therapy are often killed by donor immune cells since the lymphoma cells are seen as foreign by the donor’s immune system as well. Mild graft-versus-host disease can be a good thing.

Surgery for non-Hodgkin lymphoma

Surgery is often used to get a biopsy sample to diagnose and classify a lymphoma, but it’s rarely used as a form of treatment.

In rare cases surgery may be used to treat lymphomas that start in the spleen or in certain organs outside of the lymph system, such as the thyroid or stomach, and that have not spread beyond these organs. But for treating lymphoma that’s completely confined to one area, radiation therapy is usually preferred over surgery.

Complementary and alternative therapies for non-Hodgkin lymphoma

Palliative care for non-Hodgkin lymphoma