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

When the typical processes that regulate the growth and turnover of these cells are interrupted, the lymphocytes can build up uncontrollably 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.

As scientists have discovered more about the underlying biology that leads to CLL, many treatment options have become available 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 medications that can be used for targeted therapy in CLL, including how they work, how they are used, and potential side effects.

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 two types of BTK inhibitors commonly used to treat CLL:

  • ibrutinib (Imbruvica)
  • acalabrutinib (Calquence)

How they are taken

Both BTK inhibitors are taken orally as a pill or capsule.

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.

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

Possible side effects

Most side effects of BTK inhibitors are mild. These include:

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

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

Because these medications target signaling in immune system cells, they may also increase the 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 bleeding and irregular heartbeat, or atrial fibrillation. Research from 2021 suggests that the likelihood of having these complications is lower with acalabrutinib than with ibrutinib.

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 two types of PI3K inhibitors typically used in CLL treatment:

  • idelalisib (Zydelig)
  • duvelisib (Copiktra)

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

How they 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

Common side effects of PI3K inhibitors are similar to those of BTK inhibitors. Some other possible side effects to be aware of include:

  • pneumonia
  • belly pain
  • chills

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.

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. Speak 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:

  • Rituximab (Rituxan), obinutuzumab (Gazya), and ofatumumab (Azerra) target CD20.
  • Alemtuzumab (Campath) targets CD52.

How they are taken

You typically get monoclonal antibodies by infusion into a vein. The frequency and length of time 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 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

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 reactions can also occur, which can lead to:

  • chest pain or heart racing
  • 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.

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 it is 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

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. Serious infections can also occur.

Venetoclax can also cause a side effect known as tumor lysis syndrome. This happens when too many cells die at once. When the cancer cells die, they release their contents into the bloodstream, which can overwhelm the kidneys and cause kidney failure. Tumor lysis syndrome is most common in people with large numbers of cancer cells.

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 therapies, it is important to discuss your options with a healthcare professional so you will be aware of the potential risks and benefits of treatment.