Targeted therapies treat chronic lymphocytic leukemia at the molecular level. BTK inhibitors, P13K inhibitors, monoclonal antibodies, and BCL2 agonists are types of targeted therapy for CLL that can help manage this disease.

Chronic lymphocytic leukemia (CLL) is a type of blood cancer that affects immune cells known as lymphocytes.

In CLL, normal processes that regulate the growth and turnover of lymphocytes get interrupted. As a result, lymphocytes can build up in the bone marrow, blood, lymph nodes, and spleen. They can then crowd out healthy cells and prevent them from carrying out their usual functions.

Lymphocytes that are changed because of cancer are sometimes called CLL cells or cancer cells.

As scientists learn more about the underlying biology leading to CLL, new treatment options have emerged that target the disease at the molecular level. These forms of medication are known as targeted therapies.

In this article, we look at some of the types of targeted therapy that doctors use for CLL, including how they work, how they are given, and potential side effects.

What are targeted therapies?

Targeted therapy is a type of cancer treatment that targets the proteins that control how cancer cells grow and spread. The two primary types of targeted therapies include:

  • Small molecule drugs: These drugs are designed to enter cells and target the proteins inside the cells.
  • Monoclonal antibodies: These proteins are produced in a lab. They are designed to attach to targets located on the surface of cancer cells. Some mark cancers cells so they can be easily found and destroyed by the body’s immune system. Others stop the cancer cells from growing, or deliver toxins that cause them to die.

Read more about targeted therapy for cancer here.

BTK is a protein that helps relay signals within CLL cells that promote cancer cell growth and division. BTK inhibitors work by binding to the protein and blocking its activity. This cuts off the signals the cancer cells need to survive.

There are four types of BTK inhibitors currently used to treat CLL:

How BTK inhibitors are taken

All four BTK inhibitors are taken orally as a pill or capsule, once or twice a day, depending on the drug.

BTK inhibitors may be used alone or in combination with other types of CLL treatments. Research from 2019 suggests that BTK inhibitors may help make cancer cells more susceptible to certain types of chemotherapy.

Some cancers become resistant to BTK inhibitors, especially to older drugs like ibrutinib, acalabrutinib, or zanubrutinib. This means the drug stops working. If this happens, a doctor might suggest a newer BTK inhibitor like pirtobrutinib.

You can use ibrutinib, acalabrutinib, or zanubrutinib early in CLL treatment, including as starting therapy. You may also use them after you have tried other forms of treatment.

Pirtobrutinib is typically considered after you have tried other treatments first.

Possible side effects of BTK inhibitors

Most side effects of BTK inhibitors are mild, although some are more serious. Side effects can include:

  • gastrointestinal symptoms like nausea, diarrhea, or constipation
  • fatigue
  • muscle and joint pain or body aches
  • rash
  • swelling of the hands and feet
  • bleeding
  • increased risk of infection
  • cytopenia, or a low number of blood cells
  • headaches (with acalabrutinib)

Changes in blood cell counts are common, but these are often treatable.

More serious complications of BTK inhibitors

You could also experience other, more severe effects that you should discuss with your doctor.

Because these medications target signaling in immune system cells, they may also increase your likelihood of developing severe infections. Although these infections are rare, it’s important to discuss any symptoms with your doctor.

Other rare but serious side effects may include:

Research from 2021 suggests that the likelihood of having these complications is lower with acalabrutinib than with ibrutinib. In the 2021 study, participants had already received some kind of CLL treatment before either acalabrutinib or ibrutinib.

Some people taking BTK inhibitors have developed skin cancer or other cancers. Doctors recommend protecting your skin while on these medications to lower this risk.

PI3K is another protein involved in signaling pathways that control the growth of CLL cells. Different PI3K inhibitors target different forms of the protein to prevent CLL cells from multiplying.

There are currently two types of PI3K inhibitors typically used in CLL treatment:

Idelasinib blocks one form of PI3K (delta), whereas duvelisib blocks two forms (delta and gamma).

Because of new research into the potential safety risks of PI3K inhibitors, these therapies are recommended less often than other treatments for CLL.

Toxicities of PI3K inhibitors are associated more with their use as first-line therapy than in cases of refractory/relapse CLL.

How PI3K inhibitors are taken

Both idelalisib and duvelisib are taken as pills twice per day. You will take idelalisib in combination with intravenous therapy (Rituxan).

These medications are used when other treatment options for CLL have already been tried and have stopped working.

Possible side effects of PI3K inhibitors

Common side effects of PI3K inhibitors are similar to BTK inhibitors. Additional side effects that may occur include:

  • pneumonia
  • belly pain
  • chills

More serious complications of PI3K inhibitors

Rare but potentially serious complications are also possible, including:

  • lung inflammation
  • liver or intestinal damage
  • severe skin concerns
  • allergic reactions

In some people, dormant infections such as hepatitis may become activated again during the use of idelalisib. Your oncologist may recommend antiviral treatment to prevent this from happening.

Safety update about duvelisib

In June 2022, the FDA published a safety update about duvelisib. A clinical trial showed a potential increased risk of death and serious complications in people with CLL taking duvelisib compared with other medications.

Have a conversation with your doctor about whether duvelisib is the best and safest option for you.

Monoclonal antibodies are proteins designed to recognize specific targets found on the surface of cancer cells.

Similar to how the body naturally makes antibodies to help guide the immune system to attack foreign invaders, treatment with monoclonal antibodies can help the immune system recognize and destroy CLL cells.

Monoclonal antibodies used to treat CLL target one of two markers found on lymphocytes:

CD52 is found on CLL cells and many T lymphocytes. CD20 is found on B lymphocytes, which are the cells where CLL starts.

How monoclonal antibodies are taken

You typically get monoclonal antibodies by infusion into a vein. The frequency and length of the infusions vary based on the type of medication you are taking.

One form of rituximab can be given as a shot under the skin.

Depending on the severity of CLL and the stage of the disease, monoclonal antibodies may be used alone or in combination with other medications.

Typically, healthcare professionals recommend them for people whose symptoms are too severe for chemotherapy or whose CLL doesn’t respond to other forms of treatment.

Possible side effects of monoclonal antibodies

Side effects of monoclonal antibodies can happen during infusion or several hours after. They are usually mild and may include:

  • nausea
  • fever
  • rash
  • chills
  • itching
  • headaches

More serious complications of monoclonal antibodies

More serious reactions can also occur, which can lead to:

  • chest pain or a racing heart
  • swelling of the face and tongue
  • trouble breathing
  • lightheadedness or dizziness

You may take other medications before infusions to prevent these side effects.

As with PI3K inhibitors, previous viral infections may reactivate if you are using monoclonal antibodies. During treatment, your doctor may monitor your blood to make sure these infections stay inactive.

Rarely, monoclonal antibodies (especially obinutuzumab) can cause tumor lysis syndrome in people with very high white blood cell counts. Tumor lysis syndrome is when the contents of dead CLL cells overwhelm the kidneys. Doctors can take steps to reduce this risk if you are on monoclonal antibody treatment.

BCL2 is a protein that prevents cell death. It does this by blocking the activity of other proteins that promote cell turnover.

In CLL cells, though, the activity of BCL2 isn’t regulated. This leads to the uncontrolled growth and survival of cancer cells.

Venetoclax (Venclexta) is a medication that binds to BCL2 in place of its usual targets. This keeps the proteins free to send the signals that help kill cancer cells.

How BCL2 antagonists are taken

Venetoclax is taken orally as a pill once per day. You may take it alone or combined with monoclonal antibodies like rituximab.

Possible side effects of BCL2 antagonists

Low blood counts are a common side effect of venetoclax treatment. If blood counts get too low, this can lead to:

  • anemia (low red blood cells)
  • neutropenia (low white blood cells)
  • thrombocytopenia (low platelets)

Other possible side effects include fatigue, diarrhea, and nausea. Mild infections, such as colds, are common.

More serious complications of BCL2 antagonists

Serious infections can also occur from BCL2 antagonists. Similar to monoclonal antibodies, venetoclax can also cause tumor lysis syndrome.

If you begin taking venetoclax, your oncologist will start you with a low dose and increase the amount given slowly over several weeks to prevent rapid cell death.

An improved understanding of the science behind CLL has led to the development of several targeted therapies that can be used alone or in combination with other forms of treatment.

These targeted therapies can be used across the many stages of CLL. Your healthcare team will work with you to help choose the right treatment option based on your individual needs and health status.

Most side effects of targeted therapy are mild, but serious complications can occur. Before starting any therapy, discuss your options with your doctor or oncologist so you will be aware of the potential risks and benefits of treatment.