Chemotherapy, radiation, and immunotherapy are among the options

By James Myhre & Dennis Sifris, MD 

Updated on August 29, 2023

 Medically reviewed by Lindsay Cook, PharmD

• Coping With Lymphoma

To someone newly diagnosed with lymphoma, the treatment options may be difficult to understand. There are nearly 30 different types of lymphoma, numerous subtypes, and a variety of disease stages, each of which requires different treatment approaches.

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The two main types, Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL), may involve chemotherapy, radiation therapy, immunotherapy, or a combination of therapies. People with NHL may also benefit from newer biologic drugs and CAR T-cell therapy. Stem cell transplants are sometimes needed if lymphoma relapse occurs.

Not all lymphomas can be cured. Of the two main types, HL tends to be the most treatable. Certain aggressive forms of NHL can also be cured with aggressive chemotherapy. By contrast, indolent (slow-growing) NHL is not curable, although it can be managed successfully for years and even decades. Many indolent lymphomas may not even require treatment until there are overt signs of disease progression.

The response to treatment can also change over time. Treatments that once kept the disease under control may suddenly become ineffective, making it necessary to keep abreast of new and experimental therapies.

 How Hodgkin and Non-Hodgkin Lymphoma Differ

Active Surveillance

Many low-grade lymphomas remain indolent for years. Rather than exposing you to drugs that are likely to cause side effects, your healthcare provider may recommend the active monitoring of the disease, also known as a "watch-and-wait" approach.

On average, people with indolent lymphoma live just as long if they delay therapy compared to those who start treatment immediately.¹ If you have mild symptoms you can cope with, it is often better to reserve treatment until the lymphoma symptoms are harder to manage.

Active surveillance is commonly used for certain types of indolent NHL, including follicular lymphoma, marginal cell lymphoma (including MALT lymphoma), small lymphocytic lymphoma, Waldenström's macroglobulinemia, and mantle cell lymphoma.

Active surveillance is sometimes used for a form of HL, known as nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL), once the affected lymph nodes have been surgically removed.²

Active monitoring requires regular follow-up visits with your healthcare provider, typically every two months for the first year and every three to six months thereafter.

 Common Signs and Symptoms of Lymphoma

Chemotherapy

Chemotherapy involves the use of cytotoxic (cell-killing) drugs that can halt the spread of cancer cells. Chemotherapy is usually prescribed when the disease is systemic, meaning that the cancer has spread throughout the body. The advantage of chemotherapy is that it can travel throughout the bloodstream to kill cancer cells wherever they are located.

Lymphoma is caused by the uncontrolled growth in one of two different types of white blood cells, known as T-cells and B-cells. The various drugs are tailored based on the type of lymphoma type you have as well as the stage of disease (ranging from stage 1 to stage 4). There are a number of standard chemotherapy regimens used in the United States:

• ABVD regimen is used to treat all stages of HL. It involves the drugs Adriamycin (doxorubicin), Blenoxame (bleomycin), Velban (vinblastine), and DTIC (dacarbazine), which are delivered intravenously (into a vein) in four-week cycles. Depending on the disease stage, anywhere from one to eight cycles may be needed.

• BEACOPP regimen may be prescribed to treat aggressive forms of HL using a combination of intravenous (IV) and oral drugs. BEACOPP stands for bleomycin, etoposide, doxorubicin, cyclophosphamide, Oncovin (vincristine), procarbazine, and prednisone. Treatment typically involves six to eight 21-day cycles.

• CHOP regimen is used to treat both indolent and aggressive NHL types. CHOP is an acronym for cyclophosphamide, hydroxydaunomycin (a.k.a. doxorubicin), Oncovin, and prednisone. The drugs, some of which are delivered by IV and others by mouth, are given in six to eight 21-day cycles.

• R-CHOP regimen is used to treat diffuse large B cell lymphoma (DLBCL) and involves an additional biologic drug known as Rituxan (rituximab). It is also delivered in six to eight 21-day cycles.

Most of these chemotherapy drugs have been in use for decades. In recent years, newer agents have been developed that appear to be extremely effective and offer fewer side effects.

Newer chemotherapy drugs include Treanda (bendamustine), an intravenous drug used for people with indolent B-cell lymphoma,³ and the injectable drug Folotyn (pralatrexate) used for those with relapsed or treatment-resistant T-cell lymphoma.⁴

O'Connor OA, Amengual J, Colbourn D, et al. Pralatrexate: a comprehensive update on pharmacology, clinical activity, and strategies to optimize use. Leukemia Lymphoma. 2017;58(11):2548-57. doi:10.1080/10428194.2017.1306642

There are other combinations used to treat specific types of lymphoma, known by such acronyms as CVP, DHAP, and DICE. Other are used in combination with immunotherapy drugs that are not directly cytotoxic but spur the immune system to kill cancer cells.

Side effects of chemotherapy vary by the type of drug used and may include fatigue, nausea, vomiting, hair loss, mouth sores, changes in taste, and an increased risk of infection.

Radiation Therapy

Radiation therapy, also known as radiotherapy, uses high-energy X-rays to kill cancer cells and shrink tumors. Radiation is a local therapy, which means that it only affects cancer cells in the treated area.

Radiation is often used on its own to treat lymphomas that have not spread. These include nodal lymphomas (those occurring within the lymphatic system) and extranodal lymphomas (those occurring outside of the lymphatic system). In other cases, radiation will be combined with chemotherapy.

Radiation treatment is generally confined to the lymph nodes and surrounding tissues, a procedure referred to as involved-field radiation therapy (IFRT). If the lymphoma is extranodal, the radiation will be focused on tissues from which the cancer originated (known as the primary tumor site). In rare cases, extended field radiation (EFR) may be used to treat lymphoma that is widespread (although it is far less commonly used today than it once was).

The indications for radiation vary by the type and stage:

• HL is typically treated with radiation alone as long as the malignancy is localized. Advanced HL (stages 2B, 3, and 4) usually require chemotherapy with or without radiation.⁵

• Low-grade NHL (stages 1 and 2) tends to respond well to radiation.⁶ Advanced NHL typically requires aggressive CHOP or R-CHOP chemotherapy with or without radiation.

• Lymphoma that has spread to the brain, spinal cord, or other organs may require radiation to alleviate pain and other symptoms (referred to as palliative radiotherapy).

Radiotherapy is delivered externally from a machine using a highly focused beam of photons, protons, or ions. Referred to as external beam radiation, the dose and target of radiation will be determined by a specialist known as a radiation oncologist.

Radiation treatments are typically given five days a week for several weeks. The procedure itself is painless and lasts only a few minutes. Common side effects include fatigue, skin redness, and blistering.

Radiation to the abdomen can cause nausea, diarrhea, and vomiting. Radiation to the lymph nodes of the neck may cause mouth dryness, mouth sores, hair loss, and difficulty swallowing.

 How to Prepare for RadiationTherapy

Immunotherapy

Immunotherapy, also called immune-oncology, refers to treatments that interact with the immune system. Some of the immunotherapeutic drugs used in lymphoma are designed to recognize proteins on the surface of lymphoma cells, called antigens. The drugs target and attach to these antigens, and thereafter signal the immune system to attack and kill the "tagged" cells.

Unlike chemotherapy drugs, which kill all fast-replicating cells (both normal and abnormal), immunotherapy drugs target cancer cells alone. Other forms of immunotherapy are designed to stimulate and restore the immune system so that it can better fight lymphoma.

Monoclonal Antibodies

Monoclonal antibodies are the most common immunotherapeutic agents used in lymphoma therapy. They are classified as biologic drugs because they occur naturally in the body. Those used in lymphoma are genetically engineered to recognize specific lymphoma antigens. Approved monoclonal antibodies include:

• Adcetris (brentuximab)

• Arzerra (ofatumumab)

• Campath (alemtuzumab)

• Gazyva (obinutuzumab)

• Lunsumio (mosunetuzumab-axgb)

• Rituxan (rituximab)

• Zevalin (ibritumomab)

Adcetris is unique in that it is attached to a chemotherapy drug and "piggybacks a ride" to the lymphoma cell it intends to kill.⁷ Zevalin is paired with a radioactive substance that delivers a targeted dose of radiation to the cancer cells it attaches to.⁸

Monoclonal antibodies are given by injection. The choice of drug is based on the type of lymphoma you have as well as the stage of treatment. Some agent are used in first-line therapy (including certain types of follicular lymphoma or B-cell lymphoma), while others are used when first-line chemotherapy has either failed or there is a relapse.

Common side effects of monoclonal antibody therapy include chills, cough, nausea, diarrhea, constipation, allergic reactions, weakness, and vomiting.

Checkpoint Inhibitors

Immune checkpoint inhibitors are a newer class of drug that blocks proteins which regulate the immune response. These proteins, produced by T-cells and certain cancer cells, can promote the spread of cancer by "putting the brakes" on the immune response. By blocking these proteins, checkpoint inhibitors "release the brakes" on the immune response, allowing the body to fight cancer more effectively. Approved checkpoint inhibitors include:

• Keytruda (pembrolizumab)

• Opdivo (nivolumab)

Opdivo and Keytruda are both approved for the treatment of relapsed or treatment-resistant classical Hodgkin lymphoma (cHL).⁹¹⁰ Opdivo is administered by injection every two to four weeks, while Keytruda shots are delivered every three weeks.

Common side effects include headache, stomach pain, loss of appetite, nausea, constipation, diarrhea, fatigue, runny nose, sore throat, rash, itching, body aches, shortness of breath and fever.

Other Immunotherapy Drugs

Revlimid (lenalidomide) is an immunomodulating drug that stimulates the immune system to fight tumor growth. It is used to treat mantle cell lymphoma after other medications have failed. Revlimid is taken by mouth on an ongoing basis (25 milligrams once daily). Common side effects include fever, fatigue, cough, rash, itching, nausea, diarrhea, and constipation.¹¹

Cytokine drugs, such as interferon alfa-2b and Ontak (denileukin diftitox), are less commonly used today to treat lymphoma. They are synthetic versions of naturally occurring cytokines that the body uses to signal immune cells. Delivered intravenously or by injection, the drugs may cause side effects, including injection site pain, headache, fatigue, nausea, diarrhea, loss of appetite, flu-like symptoms, and thinning hair.

Stem Cell Transplant

A stem cell transplant is a procedure that replaces damaged or destroyed stem cells in the bone marrow with healthy ones. It is typically used when a person has relapsed from intermediate- or high-grade lymphoma.¹²

According to research published in Current Hematologic Malignancy Reports, 30% to 40% of people with NHL and 15% of those with HL will experience a relapse after the initial treatment.

Stem cells have the unique ability to transform into many different types of cells in the body. When used to treat lymphoma, the transplanted cells will stimulate the production of new blood cells. This is important since high-dose chemotherapy can damage bone marrow and impair the production of red and white blood cells needed to fight disease and function normally.

A stem cell transplant allows you to be treated with a higher dose of chemotherapy than you might otherwise be able to tolerate.

Before the transplant, high doses of chemotherapy (and sometimes radiation) are used to "condition" the body for the procedure. By doing so, the body is less likely to reject the stem cells. The conditioning process takes one to two weeks and is performed in a hospital due to the high risk of infection and side effects.

The main types of stem cell transplant used are:

• Autologous transplantation uses a person's own stem cells which are harvested, treated, and returned to the body after the conditioning procedure.

• Allogeneic transplantation uses stem cells from a donor. The cells can be taken from a family member or a non-related person.

• Reduced-intensity stem cell transplantation is a form of allogeneic transplant that involves less chemotherapy (usually for older or sicker people).

• Syngeneic transplantation is the type that occurs between identical twins who have identical genetic makeup.

Although the safety and effectiveness of stem cell transplant continue to improve every year, there are considerable risks. Not everyone is eligible for a transplant, particularly those unable to withstand the conditioning process. Moreover, the procedure does not work for people with tumors that are unresponsive to drugs. 

Recovery from a stem cell transplant may take months to years and can permanently affect fertility. An in-depth consultation with a specialist oncologist is needed to fully weigh the benefits and risks of the procedure.

 What to Expect From a Stem Cell Transplant

CAR T-Cell Therapy

CAR T-Cell Therapy

CAR T-cell therapy is an immunotherapy procedure in which T-cells are harvested from the blood to create specially engineered molecules known as chimeric antigen receptors (CARs).

T-cells are obtained through a process known as leukapheresis, which is similar to dialysis and takes around three to four hours to perform. The T-cells are then genetically engineered in the lab to match a specific type of lymphoma.

Prior to the infusion, low-dose chemotherapy is used to suppress the immune system so that the cells won't be rejected. This is followed by the CAR T-cell infusion several days later, which takes an hour or so to complete.

There are three different agents used to modify harvested T-cells:

• Breyanzi (lisocabtagene maraleucel)

• Kymriah (tisagenlecleucel)

• Yescarta (axicabtagene ciloleucel)

Kymriah and Yescarta were both approved by the U.S. Food and Drug Administration (FDA) in 2017 for people with diffuse large B-cell lymphoma who have had two or more relapses.¹³ Kymriah is also approved for adults with certain types of relapsed or refractory follicular lymphoma after two or more lines of systemic therapy.¹⁴

Breyanzi was first approved by the FDA in 2021 for people with relapsed or refractory DLBCL after two or more lines of systemic therapy. In 2022, it was approved for people with relapsed or refractory DLBCL after one line of systemic therapy.¹⁵

Common side effects include fever, headache, chills, fatigue, loss of appetite, nausea, diarrhea, constipation, dizziness, trembling, vomiting, rapid heartbeats, irregular heartbeats, and an increased risk of infection.

FREQUENTLY ASKED QUESTIONS

What is the survival rate for lymphoma?

The overall five-year relative survival rate for non-Hodgkin lymphomas is 72%.¹⁶ For Hodgkin lymphoma, the rate is 87%.¹⁷ These rates include localized, regional, and metastatic cancers.

Who is most likely to develop lymphoma?

Risk factors typically associated with lymphoma include age (most commonly over 60), gender, immune dysfunction associated with B-cells and T-cells, gene mutations, environmental factors such as exposure to insecticides, and previous radiation therapy for other solid tumors.¹⁸