Indolent (slow-growing) types of non-Hodgkin lymphoma (NHL) are among the most common forms of this blood cancer. Approximately 40 percent of NHL cases are classified as indolent. Types of indolent NHL include:

• Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL)
• Follicular lymphoma
• Mantle cell lymphoma (MCL)
• Marginal zone lymphoma (MZL)

• Waldenström’s macroglobulinemia (WM)

Because indolent NHL is often diagnosed later in life and tends to progress slowly, doctors often recommend a “watch and wait” approach before beginning any treatment. This approach allows doctors to monitor the cancer without active intervention until symptoms arise or the disease progresses. Newer treatment options, including oral therapies and advanced chemotherapy regimens, are becoming available for individuals with indolent NHL.

Chemotherapy for NHL

Until recently, traditional chemotherapy was the main treatment option for most indolent types of lymphoma. Chemotherapy works by stopping fast-growing cancer cells from dividing and spreading.

Most types of chemotherapy drugs are administered intravenously (IV) through a catheter or central line — a device implanted in a vein, typically in the chest, to ensure direct access to the bloodstream. However, some chemotherapy medications are available in oral (pill) form and can be taken by mouth.

Chemotherapy affects both cancerous and healthy cells, leading to possible side effects, which may include:

• Nausea and vomiting
• Hair loss
• Decreased appetite
• Sores in your mouth
• Increased risk of infection
• Easy bruising and bleeding
• Fatigue (extreme tiredness)

Non-Hodgkin lymphoma often develops in older people — more than half are 65 or older when first diagnosed. Unfortunately, older adults are more likely to experience serious side effects from chemotherapy.

Newer treatments, like targeted therapies, have different side effects from chemotherapy. Many targeted therapies can be taken orally, making them potentially more convenient for daily use.

Oral Therapies for NHL

Over the past 10 years, new oral targeted therapies have been developed to treat indolent NHL with different types of side effects than traditional chemotherapy. Chemotherapy indiscriminately kills any rapidly growing cells. In contrast, oral targeted therapies act on proteins or genes specific to the cancerous cell type. By more precisely targeting cancer cells, these new drugs may be both more effective and more tolerable than chemotherapy.

Oral targeted therapies also eliminate the need for clinic visits for injections or IV infusions. Instead, NHL can often be managed by taking pills or capsules at home.

The following table provides an overview of the oral therapies — including targeted therapies and immunotherapies — currently approved by the U.S. Food and Drug Administration (FDA) for treating indolent NHL.

Types of Oral Therapies for NHL

The FDA has approved several different types of oral therapies to treat indolent NHL. Most of these new treatments are targeted therapies. Additionally, an oral immunotherapy is available to treat some types of NHL. Immunotherapy treatments work by strengthening the body’s immune response to help fight NHL.

Each oral therapy targets cancer cells differently. Some targeted therapies are used as monotherapies — prescribed alone to treat NHL. In other cases, they are combined with chemotherapy, immunotherapy, or other treatments to maximize effectiveness.

Bruton’s Tyrosine Kinase Inhibitors

There are two main types of lymphocytes: B cells and T cells. About 85 percent of NHL cases involve malignant (cancerous) B cells, including CLL/SLL, MCL, WM, and MZL.

Bruton’s tyrosine kinase (BTK) inhibitors are especially useful against B-cell NHL because they target the chemical signals responsible for the production of new B lymphocytes. By blocking these signals, BTK inhibitors help prevent the growth of new lymphoma cells.

Acalabrutinib

Acalabrutinib (Calquence) is a BTK inhibitor that’s FDA-approved to treat NHL. Acalabrutinib is currently recommended most often as a treatment for refractory and relapsed CLL/SLL. Refractory CLL/SLL refers to disease that does not respond, or stops responding, to initial treatment. Relapsed CLL/SLL is when the disease returns after a period of remission.

Although acalabrutinib is FDA-approved for any adult with CLL/SLL, it’s also approved as a treatment for people with MCL who have already undergone at least one round of another treatment.

Acalabrutinib is generally taken in capsule form twice a day. Side effects include:

• Anemia (low red blood cell count)
• Neutropenia (low count of neutrophils, a type of white blood cell)
• Thrombocytopenia (low platelets)
• Headache
• Diarrhea
• Muscle and joint pain

Rare but more serious side effects include infection, hemorrhage, irregular heartbeat.

Sunscreen use is important for people taking acalabrutinib, as skin cancers can be a side effect.

Ibrutinib

Ibrutinib (Imbruvica), the first BTK inhibitor indicated to treat non-Hodgkin lymphoma, was approved for use in CLL/SLL by the FDA in 2014. Since then, it has become a first-line treatment for CLL/SLL, as well as a widely used treatment for people with refractory or relapsed cases.

Ibrutinib can be used alone or in combination with rituximab (Rituxan), obinutuzumab (Gazyva), or bendamustine (Bendeka). Rituximab and obinutuzumab are immunotherapy drugs called monoclonal antibodies that enhance the immune system’s ability to target B cells. Bendamustine is a chemotherapy agent.

Ibrutinib with or without rituximab is also a first-line treatment for WM.

Ibrutinib’s side effects are often more tolerable than traditional chemotherapy. In one clinical trial, people receiving a drug combination of ibrutinib and rituximab for CLL/SLL were less likely to experience severe side effects than those receiving the standard chemotherapy regimen FCR (fludarabine, cyclophosphamide, and rituximab).

Ibrutinib is available in a tablet, capsule, or liquid form. The most common side effects include:

• Anemia
• Neutropenia
• Thrombocytopenia
• Diarrhea
• Fatigue (extreme tiredness)
• Muscle pain
• Nausea

Pirtobrutinib

Pirtobrutinib (Jaypirca) is a BTK inhibitor that’s FDA-approved to treat MCL that’s relapsed or refractory after at least two other treatments have been tried. At least one of the previous treatments should be another BTK inhibitor. It can also be used to treat CLL/SLL in people who have tried two other treatments, including another BTK inhibitor or a BCL-2 inhibitor.

Pirotobrutinib is a pill that’s usually taken once a day.

The most common side effects of pirtobrutinib include:

• Fatigue
• Pain
• Diarrhea
• Bruising
• Cough

Zanubrutinib

Zanubrutinib (Brukinsa) is a BTK inhibitor that’s approved to treat several types of indolent NHL, including:

• MCL in people who have undergone at least one previous round of treatment
• WM
• Relapsed or refractory MZL after at least one anti-CD20-based regimen
• CLL/SLL
• Relapsed or refractory follicular lymphoma in combination with obinutuzumab, after at least two other treatments have been tried

It’s taken as a pill once or twice a day. Common side effects include:

• Anemia
• Neutropenia
• Rash
• Bruising
• Diarrhea
• Cough

Rare but serious side effects include hemorrhage, infections, low blood cell counts, secondary cancers (such as skin and nonskin carcinomas), irregular heartbeat, and liver damage. It may also harm an unborn baby if taken during pregnancy.

Phosphoinositide 3-Kinase Inhibitors

Certain proteins signal cancer cells to grow. Phosphoinositide 3-kinase (PI3K) inhibitors work to eliminate lymphoma cells by blocking these proteins.

Duvelisib

The PI3K inhibitor duvelisib (Copiktra) is approved by the FDA for people with CLL/SLL who have already undergone at least two rounds of treatment. It’s taken in pill form twice a day. Some common side effects include:

• Diarrhea
• Fatigue
• Nausea
• Cough
• Fever

Rare but serious side effects include liver problems, breathing problems, and infections.

Idelalisib

The PI3K inhibitor idelalisib (Zydelig) is FDA-approved for use in combination with rituximab for people with relapsed CLL who could also be treated with rituximab alone. This medication isn’t recommended as a first-line treatment for anyone.

Idelalisib is taken in pill form twice a day. Some common side effects include:

• Diarrhea
• Fatigue
• Nausea
• Cough
• Fever

Rare but serious side effects include liver problems, breathing problems, and infections.

Idelalisib has similar side effects to duvelisib.

BCL-2 Antagonists

Some malignant cells produce excessive amounts of a protein called BCL-2 due to a specific genetic mutation. This protein prevents the damaged tumor cells from self-destructing in response to their abnormalities. BCL-2 antagonists block this protein to help treat CLL/SLL.

Venetoclax

The BCL-2 antagonist venetoclax (Venclexta) works by targeting the extra BCL-2 protein and causing tumor cells to self-destruct. Venetoclax is FDA-approved to treat adults with CLL/SLL. A combination of venetoclax and obintuzumab is a preferred first-line treatment for CLL/SLL. A combination of venetoclax and rituximab is a preferred treatment for refractory or relapsed CLL/SLL.

Venetoclax is a pill that’s taken once a day.

Possible side effects of Venclexta include:

• Anemia
• Neutropenia
• Diarrhea
• Nausea

Among rare but serious side effects of some oral therapies, including venetoclax, is tumor lysis syndrome. Venetoclax works by rapidly killing cancer cells, but the sudden release of cellular contents can overwhelm the kidneys, potentially leading to kidney failure. To reduce this risk, a person may need to stay in the hospital when starting venetoclax, where they can receive intravenous fluids and other preventive treatments to ensure proper kidney function.

Other significant risks include neutropenia, serious infections, and harm to an unborn baby in pregnant individuals.

EZH2 Inhibitors

EZH2 is a protein that encourages cancer cells to grow. Some cancer cells also have a mutation (variation) in this protein that can make EZH2 overactive. Blocking EZH2 can help prevent cancer cell growth from this protein.

Tazemetostat

Tazemetostat (Tazverik) is FDA-approved to treat relapsed or refractory follicular lymphoma in people with an EZH2 mutation after they’ve tried at least two other treatments. People with relapsed or refractory follicular lymphoma with no satisfactory treatment options can also take tazemetostat, whether they have an EZH2 mutation or not.

Tazemetostat is available as a pill that’s usually taken twice a day.

The most common side effects of tazemetostat include:

• Fatigue
• Nausea
• Muscle or bone pain
• Symptoms similar to those of the flu

Additionally, this medication may increase your risk of other blood cancers.

Immunomodulating Drugs

Immunomodulating drugs are a type of immunotherapy that affects the immune system to help treat certain types of NHL. Lenalidomide (Revlimid) is an oral immunotherapy that’s FDA-approved to treat relapsed or refractory MCL after at least two other treatments have been tried, one of which should be bortezomib (Velcade). It can also be used to treat previously treated follicular lymphoma or MZL in combination with rituximab.

Lenalidomide is available as a pill that’s taken twice a day.

The most common side effects of lenalidomide include:

• Increased risk of infection
• Nerve damage with pain
• Increased risk of blood clots

Additionally, lenalidomide can result in severe birth defects if it’s taken during pregnancy.

Speaking With Your Doctor

There are many different types of NHL, and new therapies are researched all the time. As new drugs are further studied, researchers learn more and more about which cancer treatments best combat specific types of NHL with the fewest side effects. Read this guide for advice on starting a conversation with your cancer care team about NHL treatment options, including whether oral therapies are right for you.

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