Chronic Lymphocytic Leukemia (CLL)

Chronic lymphocytic leukemia (CLL) is a blood cancer that often progresses slowly. It’s the most common type of leukemia in adults. About 1 out of 100 new cancers each year is CLL. Most people diagnosed are 65 or older.

It happens when healthy white blood cells called lymphocytes, or B cells, change into cancer (CLL cells). These cells don’t act like healthy white blood cells, whose job is to protect you from infections. The CLL cells can also crowd out healthy ones. This can lead to low red blood cells (anemia) and low platelets (thrombocytopenia).

There aren’t standard treatments that can cure it. But over the past decade or so, experts have found treatments that can put CLL into remission. Remission means you don’t have signs or symptoms of disease. These treatments are helping people with chronic lymphocytic leukemia live longer, better lives.

Symptoms of chronic lymphocytic leukemia

You can have this condition for months or even years before having symptoms. Some people never develop problems. But if symptoms start, they usually happen slowly. Chronic lymphocytic leukemia symptoms include:

• Fatigue
• Fever
• Drenching night sweats
• Unexplained weight loss
• Bruising or bleeding easily
• Swollen lymph nodes in your neck, armpit, groin or stomach
• Pain or a sense of fullness under your ribs (signs of an enlarged liver or spleen)

CLL causes

This condition happens when genes or chromosomes change (mutate). These changes cause normal B cells to become CLL cells. The abnormal cells build up in your blood and bone marrow. Your bone marrow is where blood cells get made. The CLL cells can also grow in your lymph nodes and/or in your spleen. Sometimes, they grow in your liver.

As with most cancers, experts don’t know what causes the changes in your cells’ genes that lead to CLL. But people with chronic lymphocytic leukemia often have the same gene mutations. Knowing about these changes helps healthcare providers know which treatments to use. It helps them predict how aggressive the disease might be.

Risk factors

Factors that may increase your risk of developing this condition include:

• Age: The risk increases with age. Most people diagnosed are in their early 70s.
• Sex: CLL is more common in males.
• Ethnicity: It’s more common in people of European descent.
• Family history: You’re not born with it. But the genes you inherit may increase your risk. Having a biological parent, sibling or child with CLL or another B-cell cancer (like lymphoma) makes you more likely to have CLL.
• Exposure to certain substances: Studies show links between CLL and Agent Orange, a chemical used during the Vietnam War. Extensive or prolonged exposure to a pesticide called glyphosate may increase the risk of developing CLL. But there’s no way to know whether someone would have developed CLL even without the exposure.
• Monoclonal B-cell lymphocytosis (MBL): In this condition, you have high levels of identical B cells in your blood. It comes before CLL. But frequently, people who have it aren’t diagnosed.

​Complications of this condition

Chronic lymphocytic leukemia affects your red blood cells, white blood cells and platelets. Red blood cells carry oxygen throughout your body. White blood cells protect you from infection. Platelets help your blood to clot. CLL can prevent them from doing these jobs. This can lead to complications like:

• Anemia, including autoimmune hemolytic anemia
• Thrombocytopenia, including immune thrombocytopenia 
• Frequent infections, including a condition linked to a weak immune system resulting from hypogammaglobulinemia
• Developing an aggressive cancer, like large B-cell lymphoma

When CLL changes into an aggressive cancer, it’s called Richter transformation. This can impact your life expectancy.

How doctors diagnose this condition

About 7 in 10 people diagnosed with CLL don’t have symptoms. Most people learn they have it after having blood tests as part of a routine physical exam.

Tests providers use to diagnose it include:

• Complete blood count (CBC) with differential: This test measures the number of red blood cells, white blood cells and platelets in your blood.
• Peripheral blood smear: A provider examines your blood cells under a microscope to look for abnormal ones.
• Flow cytometry: Providers use this lab test to see if the abnormal cells are CLL.
• DNA tests: These tests can find the gene and chromosome changes that led to chronic lymphocytic leukemia. This info helps providers choose treatments. It also helps them learn more about your prognosis (outlook).

Stages of chronic lymphocytic leukemia

Cancer staging systems help healthcare providers know how advanced cancer is. It helps them predict how quickly it will progress. This helps them come up with treatment plans and determine your prognosis.

There are three different systems your provider may use for staging. They’re the Rai, Binet and CLL-IPI systems. They help providers recognize signs of more serious disease, like:

• High lymphocyte levels
• Abnormal white blood cells in your bone marrow or blood
• Enlarged lymph nodes, spleen or liver
• A low red blood cell count
• A low platelet count
• Certain gene errors

Your healthcare provider will explain how these factors apply to you and what this means for your diagnosis.

How is chronic lymphocytic leukemia treated?

Treatment varies based on your symptoms and test results.

If the disease isn’t impacting day-to-day living, your healthcare provider will probably opt for watchful waiting (active surveillance). This means that your provider will hold off on treatment. They’ll monitor your health by doing regular exams and blood tests. If you’re in good health, it may not be worth it to risk treatments that can cause side effects. There’s no downside to waiting until you need treatment.

But if you have symptoms or test results that show signs of serious disease, your provider will recommend treatments.

Targeted therapy

Within the past decade or so, targeted therapy has become the main treatment for CLL. These are medications that are systemic (go everywhere in the body). They target specific signals in CLL cells. These treatments can kill the CLL cells and/or keep them from growing. Most targeted therapies destroy the cancer cells with minimal harm to healthy cells or tissue. This means fewer side effects. Treatments include:

• BTK inhibitors: This treatment blocks an enzyme (BTK) that causes CLL cells to grow. Examples include ibrutinib (Imbruvica^®), acalabrutinib (Calquence^®) zanubrutinib (Brukinsa^®) and pirtobrtuinib (Jaypirca^®).
• BCL2 inhibitors: Venetoclax (Venclexta^®) blocks BCL2, a protein found on CLL cells. This treatment can destroy CLL cells and make them more sensitive to other cancer drugs.
• Monoclonal antibodies: These are lab-made antibodies that block cancer cell growth or destroy CLL cells. Examples include rituximab (Rituxan^®) and obinutuzumab (Gazyva^®).

Often, providers use a combination of these drugs, like obinutuzumab with venetoclax and/or BTK inhibitors.

Chemoimmunotherapy

Before targeted therapy became the standard, providers often used combination chemotherapy and immunotherapy. Chemotherapy destroys fast-growing cells (like CLL cells). Immunotherapy helps your immune system fight cancer. 

Providers still use it to treat some forms of CLL. In some cases, it can send the condition into long-term remission. It may be an option if targeted therapies aren’t helping enough.

This treatment can cause side effects and complications. Your provider will review any risks with you before starting treatment.

Other treatments

Other treatments you may need include:

• Stem cell transplant: This treatment can send cancer into long-term remission. It isn’t common, though, because it’s an intensive treatment that carries high risks. Your provider will help you weigh the pros and cons if it’s an option.
• Immunotherapy: BiTe therapy and CAR T-cell therapy treat CLL that hasn’t responded to standard treatment. In 2024, the Food and Drug Administration (FDA) approved the CAR T-cell therapy drug lisocabtagene maraleucel (Breyanzi®) for this use.
• Chemotherapy: Once a common CLL treatment, chemotherapy on its own has largely been replaced by targeted therapies. Still, it may help relieve symptoms in advanced disease.
• Radiation therapy: This treatment directs high-powered X-rays to cancer cells to destroy them. It can help relieve symptoms.

Your healthcare provider may recommend you take part in a clinical trial to access new treatments.

When should I see my healthcare provider?

You’ll see your healthcare provider regularly. CLL is a chronic (long-term) condition. Even if the cancer goes into remission, it eventually comes back. Your provider will keep a close watch on your health so you can get the treatment you need if this happens.

What is the life expectancy of a person with CLL?

While CLL was once hard to treat, new targeted therapy treatments have changed the outlook for this disease. Now, more than 9 in 10 people diagnosed with CLL are alive 10 years later. Experts have found that the new treatments extend a person’s life expectancy compared to traditional chemotherapy medications. 

At the very least, they know that new treatments often put the cancer into remission. Remission can last for years. If signs of the disease come back, you may need the same treatments that worked before. Or you may get new treatments.

Still, every diagnosis is different. Lots of factors shape your prognosis. Your provider will explain them to you, so you know what to expect.