How is chronic lymphocytic leukemia (CLL) treated?

Medically reviewed by Archana Sharma, DO

Key Takeaways

• Active surveillance, or watchful waiting, is often recommended for people with slow-growing CLL who do not have symptoms.
• Targeted therapies, such as BTK and BCL-2 inhibitors, are common treatments for CLL and often cause fewer side effects than chemotherapy.

Treatment for chronic lymphocytic leukemia (CLL) depends on more than just the stage of the disease. Your symptoms, overall health, and certain genetic changes help determine whether treatment is needed and which option is most likely to work.

Active Surveillance

Many people with CLL have slow-growing disease and do not have symptoms when they are first diagnosed. If this is the case, your healthcare provider may recommend active surveillance, also called watchful waiting.

During active surveillance, you will have regular:

• Physical exams
• Blood tests
• Checkups to monitor symptoms

This approach does not make CLL worse or shorten survival. Instead, it helps you avoid treatment side effects until treatment is truly needed. Your healthcare provider will watch for signs that the leukemia is becoming more active or starting to affect your health.

Treatment is usually recommended if you develop:

• Increasing fatigue that affects daily life
• Frequent infections
• Enlarging lymph nodes or spleen
• Unexplained weight loss
• Night sweats
• Fever without an infection
• Low red blood cell or platelet counts caused by CLL
• Rapidly increasing white blood cell counts, along with other signs that the disease is progressing

Targeted Therapy

Targeted therapy is a common treatment for CLL. Unlike chemotherapy, which attacks many fast-growing cells throughout the body, targeted therapies focus on specific proteins that leukemia cells need to grow and survive. Because they are more selective, they often cause fewer side effects than chemotherapy.

BTK Inhibitors

BTK inhibitors block a protein called Bruton’s tyrosine kinase (BTK). Healthy and cancerous B cells use BTK to receive signals that tell them to grow, divide, and stay alive. By blocking this protein, BTK inhibitors interrupt those signals, making it harder for leukemia cells to survive and multiply.

Common BTK inhibitors include:

• Imbruvica (ibrutinib)
• Calquence (acalabrutinib)
• Brukinsa (zanubrutinib)

These medications are taken by mouth, usually once or twice a day. Many people continue taking them as long as they are working and side effects remain manageable. BTK inhibitors are often recommended as a first treatment and can also be used if CLL returns after previous treatment. 

Common side effects may include:

• Bruising or bleeding
• High blood pressure
• Diarrhea
• Headache
• Joint or muscle aches
• Irregular heartbeat (atrial fibrillation), particularly with older BTK inhibitors

BCL-2 Inhibitors

BCL-2 inhibitors work differently. They block a protein called BCL-2, which keeps leukemia cells from dying. Normally, damaged or old cells go through a natural process called apoptosis, or programmed cell death. CLL cells produce large amounts of BCL-2, allowing them to live much longer than they should.

Venclexta (venetoclax) blocks BCL-2 so the leukemia cells can die naturally. Because venetoclax can destroy large numbers of leukemia cells very quickly, treatment begins with a low dose that is slowly increased over several weeks. This helps reduce the risk of tumor lysis syndrome, a serious condition that can occur when many cancer cells break down at once.

Venetoclax is commonly combined with a monoclonal antibody, such as:

• Gazyva (obinutuzumab) for newly diagnosed CLL
• Rituxan (rituximab) for some people whose CLL has returned

Monoclonal Antibody Therapy

Monoclonal antibodies are laboratory-made immune proteins that help the immune system recognize and destroy leukemia cells. Those used to treat CLL are designed to attach to a protein called CD20, which is found on the surface of B cells, including CLL cells.

Once attached, these medications can:

• Mark leukemia cells so the immune system can find and destroy them
• Trigger the immune system to attack the cancer
• Directly cause leukemia cells to die

Common monoclonal antibodies include:

• Gazyva (obinutuzumab)
• Rituxan (rituximab)

These medications are administered via intravenous (IV) infusion. They are most often combined with targeted therapies because the combination is usually more effective than either treatment alone.

Possible side effects include:

• Infusion reactions
• Low blood cell counts
• Increased risk of infections

Chemotherapy

Chemotherapy uses medicines that kill rapidly dividing cells, including leukemia cells. Before targeted therapies became available, chemotherapy was the main treatment for CLL.

Today, chemotherapy is used much less often because targeted therapies generally work better and are easier for many people to tolerate. However, it may still be an option for younger, healthy adults whose leukemia has favorable genetic features or for people who cannot take newer medications.

Chemotherapy is often combined with a monoclonal antibody and called chemoimmunotherapy. This combination attacks leukemia cells in different ways and may improve treatment results in some people.

Because chemotherapy also affects healthy fast-growing cells, it is more likely to cause side effects such as:

• Hair loss
• Fatigue
• Nausea
• Mouth sores
• Increased risk of infection
• Low blood cell counts

Stem Cell Transplant

An allogeneic stem cell transplant is not a routine treatment for CLL, but it may be considered for people whose leukemia has stopped responding to multiple treatments or has aggressive, high-risk features.

The procedure begins with high-dose chemotherapy to destroy as many leukemia cells as possible. Healthy blood-forming stem cells from a donor are then infused into the bloodstream, where they travel to the bone marrow and begin producing new blood cells.

Because stem cell transplantation carries serious risks, including severe infections and graft-versus-host disease, it is generally reserved for younger, healthier people who are able to tolerate the procedure.

CAR T-Cell Therapy And Clinical Trials

Researchers continue to develop new treatments for CLL, including CAR T-cell therapy, a type of immunotherapy.

With CAR T-cell therapy, doctors collect a person’s own T cells, a type of immune cell, and genetically modify them in a laboratory. The modified T cells are designed to recognize a specific protein on leukemia cells. After they are returned to the body through an IV infusion, they can find and destroy the cancer cells more effectively.

CAR T-cell therapy is currently used mainly for people whose CLL has returned after several other treatments or has become resistant to standard therapies.

Clinical trials are also evaluating new targeted drugs, immunotherapies, and treatment combinations that may improve outcomes for people with CLL. Your healthcare provider can help determine whether a clinical trial is a good option for you.

Supportive Care

Treating CLL involves more than controlling the leukemia itself. Supportive care helps manage symptoms, reduce complications, prevent infections, and improve quality of life during treatment.

Supportive care may include:

• Vaccinations to help lower the risk of infections
• Antibiotics, antiviral medications, or antifungal medications when needed
• Immunoglobulin (IVIG) therapy for people with frequent infections caused by low antibody levels
• Blood transfusions to treat severe anemia or low platelet counts
• Medications to help manage treatment side effects, such as nausea or pain
• Growth factors that stimulate the bone marrow to produce more blood cells in certain situations

Your healthcare provider may also recommend healthy lifestyle habits, including eating a balanced diet, staying physically active, getting enough sleep, and avoiding tobacco. These steps cannot treat CLL, but they may help support your overall health during treatment.

Choosing The Right Treatment

There is no single best treatment for everyone with CLL. Your healthcare provider will consider several factors before recommending a treatment plan, including:

• Your age and overall health
• Whether you have symptoms
• How quickly the leukemia is growing
• Genetic changes in the leukemia cells, such as TP53 mutations or 17p deletion
• Whether this is your first treatment or the CLL has returned after previous therapy
• Your personal preferences and treatment goals

Many people with CLL live for years or even decades after diagnosis. Advances in targeted therapies have greatly improved treatment options, allowing many people to control their disease while maintaining a good quality of life.

Working closely with your healthcare team can help you choose the treatment approach that best fits your needs and adjust it as new therapies become available.

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