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Oral Therapy vs. Traditional Chemotherapy for CLL/SLL

Updated on November 09, 2021
Medically reviewed by
Mark Levin, M.D.
Article written by
Jessica Wolpert

  • Several new targeted therapies have been approved to treat CLL/SLL in recent years.
  • Targeted therapies often have fewer or milder side effects than traditional chemotherapy.
  • Many targeted therapies can be taken orally as a pill or capsule at home.
  • Newer targeted therapies may be safer than traditional chemotherapy for older or less healthy people.

Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) advances slowly and often occurs in older people. For these reasons, doctors may recommend a “watch and wait” approach in some cases, instead of beginning treatment immediately upon diagnosis. When treatment is recommended, newer oral therapies are now among the first-line choices of treatment for most forms of CLL/SLL.

How Do Oral Therapies Compare With Traditional Chemotherapy for CLL/SLL?

There are several types of oral therapies and different regimens of chemotherapy that differ in how they are administered and how they work. The following table compares general characteristics of oral therapies and traditional chemotherapy.

Read more about beginning CLL/SLL treatment and how genetic testing of cancer cells guides treatment recommendations in Watchful Waiting With CLL/SLL.

The History of CLL/SLL Treatment

A person undergoing treatment for CLL/SLL in 1976 — the year the disease was defined — could expect to be treated with one of two chemotherapy drugs available for the condition. They might also receive steroids along with chemotherapy. People with enlarged lymph nodes from CLL/SLL might be able to avoid chemotherapy by undergoing radiation therapy instead.

Over time, treatment for CLL/SLL has evolved. New drugs — both chemotherapy and nonchemotherapy treatments — have been developed. However, traditional chemotherapy, albeit with more available drug options, remained part of the CLL/SLL treatment experience for most people. By the 2010s, standard treatment for CLL/SLL combined chemotherapy drugs with Rituxan (rituximab), a drug that targets proteins found on the surface of B cells.

These combinations are described as chemoimmunotherapy. Chemoimmunotherapy combinations included the pairing of the chemotherapy drug Treanda (bendamustine) with Rituxan or the “FCR” combination — the chemotherapy drugs Fludara (fludarabine) and Cytoxan (cyclophosphamide), with Rituxan added. However, chemoimmunotherapy treatments still had disadvantages. Chemotherapy drugs are still difficult for older people to tolerate, which makes it an especially poor treatment for CLL/SLL, as the average age at diagnosis is 70. In addition, chemotherapy can increase the risk of developing other cancers years later.

In the last 20 years, many new treatments for CLL/SLL were developed. These treatments aren’t traditional chemotherapy, although some of them can be used in combination with chemotherapy drugs. Unlike chemotherapy, which kills any rapidly growing cells — potentially causing severe side effects, such as the loss of red blood cells (anemia), the loss of white blood cells (neutropenia), and infection — these new targeted therapies search out targets specific to the type of cell involved in the cancer. By better targeting cancer cells, these therapies reduce side effects.

What’s more, many targeted therapies for CLL/SLL don’t need to be administered at a clinic through an injection or IV. Instead, people with CLL/SLL can simply take a pill at home. In many cases, these oral targeted therapies are more convenient, more effective, and easier to tolerate than traditional chemotherapy.

Types of Oral Therapies

There are several classes of oral therapies approved by the U.S. Food and Drug Administration (FDA) to treat CLL/SLL. Each works in a different way to target the cells involved in cancer. Some oral targeted therapies are used as monotherapies — used alone to treat CLL/SLL — while in other cases they may be combined with chemotherapy, immunotherapy, or other types of treatment to be most effective.

BTK Inhibitors

CLL/SLL occurs when the body produces malignant B cells, a type of white blood cell. Bruton’s tyrosine kinase (BTK) inhibitors work by targeting the chemical signals that start the production of new B cells. By blocking these signals, BTK inhibitors keep new CLL/SLL tumor cells from forming.

Imbruvica (ibrutinib), the first type of BTK inhibitor indicated to treat CLL/SLL, was approved for use in CLL/SLL by the FDA in 2014. Since then, Imbruvica has become a first-line treatment for almost all types of CLL/SLL. A 2018 study of people undergoing a first round of CLL/SLL treatment found that Imbruvica, when used alone, reduced the risk of disease progression by 63 percent compared to treatment with bendamustine and Rituxan. Imbruvica has also become a preferred treatment for people whose CLL/SLL has not responded to a first round of treatment (refractory CLL/SLL) or whose CLL/SLL has recurred (relapsed CLL/SLL). Imbruvica can be used alone or in combination with Rituxan or with Gazyva (obinutuzumab), another drug that targets proteins on B cells.

Imbruvica is especially useful because its side effects are more tolerable than traditional chemotherapy. In a study of people undergoing a first round of treatment for CLL/SLL, people receiving a drug combination of Imbruvica and Rituxan were less likely to experience severe side effects than those receiving treatment with FCR chemotherapy. For example, only 23 percent of people receiving the Imbruvica-Rituxan combination experienced neutropenia, compared with 44 percent of those receiving FCR.

Imbruvica is available in once-a-day tablet form and as capsules taken three times a day. The most common side effect is mild diarrhea. Other side effects include anemia, neutropenia, nausea, constipation, fatigue, achiness, and rash.

Other BTK inhibitors have been approved for use against CLL/SLL. Calquence (acalabrutinib) is a next-generation BTK inhibitor that was FDA-approved for use in adults with CLL/SLL in 2019. Calquence is currently recommended most often as a treatment for refractory and relapsed CLL/SLL, although it is FDA-approved for any adult with CLL/SLL.

Calquence is usually taken in capsule form twice a day. Side effects include headache, diarrhea, muscle and joint pain, infection, hemorrhage, and irregular heartbeat. As with Imbruvica, Calquence can cause low red and white blood cell counts and low platelet counts. Skin lesions can be a side effect of Calquence, so sunscreen is essential for people taking this drug.

PI3K Inhibitors

Phosphoinositide 3-kinase (PI3K) inhibitors work by blocking proteins that signal cancer cells to grow. The PI3K inhibitor Zydelig (idelalisib) is FDA-approved for use in combination with Rituxan for people with relapsed CLL who cannot be treated with Rituxan alone because it might be too harsh. It is also approved for people with SLL who have undergone at least two previous rounds of treatment. It is used along with Rituxan.

Zydelig is taken in pill form twice a day. Some common side effects include diarrhea, tiredness, nausea, cough, and fever. Rare but serious side effects include liver problems, breathing problems, and infections.

Copiktra (duvelisib) is another PI3K inhibitor that has been approved by the FDA for people with CLL/SLL who have already undergone at least two rounds of treatment. It is taken in pill form twice a day. Copiktra has similar side effects to Zydelig (idelalisib).

BCL-2 Antagonists

All CLL/SLL cancer cells produce too much of a protein called BCL-2. This protein acts to protect the abnormal cells, preventing them from self-destructing as cells are supposed to do when they are damaged. The BCL-2 antagonist Venclexta (venetoclax) works by targeting the extra BCL-2 protein, which causes tumor cells to die.

Venclexta is FDA-approved to treat adults with CLL/SLL. A combination of Venclexta and Rituxan is a preferred treatment for refractory or relapsed CLL/SLL. Venclexta is taken as a once-a-day pill. Side effects of Venclexta include anemia, neutropenia, diarrhea, and nausea. One potentially dangerous side effect that may occur during Venclexta use is tumor lysis syndrome, in which Venclexta kills so many tumor cells that the contents of the dead cells clog the kidneys, leading to kidney failure. Because of the risk of side effects, people taking Venclexta may need to stay in the hospital when beginning to take the drug or when increasing the dose.

Genetic Mutations and Oral Therapies

Certain genetic mutations can make CLL/SLL more difficult to treat. Oral targeted therapies can be especially useful for people who have CLL/SLL with del(17p) or TP53 mutations, as cancers with these mutations do not respond well to traditional chemotherapy. A clinical trial is still the best option for people with del(17p) or TP53 mutation CLL/SLL, but if a clinical trial is unavailable, Imbruvica is the preferred first-line treatment. If a second round of treatment is needed, Imbruvica, Venclexta with Rituxan, Zydelig, and Copiktra are the preferred treatments. Read Watchful Waiting With CLL/SLL for more information about genetic testing of cancer cells for CLL/SLL.

Speaking With Your Doctor

Although oral therapies may be the newest preferred treatment for CLL/SLL, several different types of treatment — including traditional chemotherapy — are still options for treating the condition in many people. As medical technology progresses and newer drugs, like oral therapies, are further studied, researchers learn more and more about which treatments best combat specific types of CLL/SLL with the fewest side effects. For more information about speaking with your health care providers about CLL/SLL treatment options, including whether oral therapies are right for you, read Oral Therapies for CLL/SLL: Your Doctor Discussion Guide.

A MyLeukemiaTeam Member said:

Took venclexta and was sick every time I took it. Would rather have chemo treatments

posted about 1 month ago

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Mark Levin, M.D. is a hematology and oncology specialist with over 37 years of experience in internal medicine. Review provided by VeriMed Healthcare Network. Learn more about him here.
Jessica Wolpert works to empower patients through the creation of content that illuminates treatments' effects on the everyday lives of people with chronic conditions. Learn more about her here.

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