Chronic Lymphocytic Leukemia

Medically Reviewed By William C. Lloyd III, MD, FACS
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What is chronic lymphocytic leukemia?

Chronic lymphocytic leukemia (CLL) is a type of blood and bone marrow cancer. “Chronic” means that it usually grows and progresses slowly. The term “lymphocytic” refers to lymphocytes, which are the cells it affects. Lymphocytes are one of the main types of white blood cells. They can develop into B cells and T cells, which help fight infections.

In CLL, your bone marrow makes abnormal lymphocytes. These cells multiply faster than they should and live longer than normal lymphocytes. They build up in the bone marrow over time and crowd out normal white blood cells, red blood cells, and platelets. Eventually, the bone marrow pushes them out into the blood. The abnormal lymphocytes can accumulate in other areas of the body, such as the lymph nodes and spleen. A similar cancer—small lymphocytic lymphoma—also affects lymphocytes and acts like CLL, but it starts in these other areas of the body instead of the bone marrow.

CLL cells often look like normal lymphocytes. However, they are not fully mature and cannot function like normal lymphocytes. They usually cannot fight infections as effectively as normal lymphocytes. This, along with crowding out other normal blood cells, leads to the symptoms of CLL. Common symptoms include anemia, frequent infections, swollen lymph nodes, and easy bruising or bleeding.

CLL is not a common cancer. About 21,000 Americans will be diagnosed with CLL this year. This equates to about 1% of all U.S. cancer cases. However, it accounts for about one-third of all leukemia cases and is the most common leukemia in adults. The average age at diagnosis is 70 years. It is rare in people younger than 40 and is extremely rare in children. The risk of developing CLL is higher in males, Caucasians, and people with a family history or certain chemical exposures. However, the exact cause is unclear.

It is possible to have CLL for years and not know it. It is also possible to live for many years with the disease. CLL is generally difficult to cure, but current CLL treatments can help manage the cancer and its symptoms. For people with few or no symptoms, watchful waiting is the usual recommendation. When symptoms or lab tests suggest it is time for treatment, chemotherapy and a monoclonal antibody has been the main approach. Sometimes, doctors add a targeted therapy drug or use only targeted therapy.

Like other leukemias, signs of CLL can be nonspecific. People may notice flu-like symptoms that persist instead of going away with time. Make an appointment with your doctor if you have lingering symptoms or symptoms that concern you.

What are the symptoms of chronic lymphocytic leukemia?

Chronic lymphocytic leukemia symptoms can take years to develop. In fact, it is common to not have any symptoms at diagnosis. Instead, doctors often find leukemia during lab tests for another health problem or a routine checkup. When symptoms occur, they tend to be vague and nonspecific.

Common symptoms of chronic lymphocytic leukemia

Common symptoms of CLL include:

Because the symptoms of CLL are nonspecific, they can also occur with other diseases and conditions. Many of them are much more common than CLL and are not cancerous. Getting a diagnosis from your doctor is the only way to know for sure what is causing these symptoms. If you have symptoms that persist or worsen, see your doctor.

What are the stages of chronic lymphocytic leukemia?

Staging is an important part of the diagnostic process for cancer. It tells doctors how far the cancer has spread and guides treatment decisions and prognosis. For solid cancers—ones that form tumors, staging usually looks at the size of the tumor, lymph node involvement, and metastasis or spread to other areas. Leukemias do not form tumors, so this type of staging does not work for them. But there are ways to describe CLL that relate to treatment and prognosis.

In the United States, doctors use the Rai system for CLL:

  • Stage 0: Lymphocytosis (high lymphocyte count) alone with no other signs of leukemia

  • Stage I: Lymphocytosis with enlarged lymph nodes, but no other physical signs

  • Stage II: Lymphocytosis with an enlarged spleen and/or an enlarged liver, with or without enlarged lymph nodes

  • Stage III: Lymphocytosis and anemia (low red blood cell counts), with or without enlarged lymph nodes and an enlarged spleen or liver

  • Stage IV: lymphocytosis and thrombocytopenia (low platelet counts), with or without enlarged lymph nodes, an enlarged spleen or liver, or anemia

Stage 0 is low risk for disease progression. Stages I and II are intermediate risk. Stages III and IV are at high risk for disease progression.

Doctors may also describe CLL as asymptomatic, symptomatic or progressive, refractory, or recurrent. In addition, European doctors use a different system called the Binet staging system.

What causes chronic lymphocytic leukemia?

Cancer occurs when DNA mutations change cells in ways that let them grow and replicate in an uncontrolled way. Sometimes, people inherit DNA mutations that make certain cancers more likely. This is rarely the case for CLL. Instead, people with CLL usually accumulate errors in their DNA over the course of their lifetime. This is why CLL is generally a disease of older adults.

Researchers have uncovered certain changes that are almost always present in CLL. The changes occur in one of the 23 pairs of chromosomes each of us has. Chromosomes are highly-compressed strands of DNA. When cells divide, they must make a copy of their chromosomes. Copying errors can occur during the process, such as accidently deleting DNA or inserting extra DNA.

In CLL, the most common DNA mutation is a deletion in chromosome 13 [del(13q)]. About half of CLL patients have this change. Other common CLL changes include deletions in chromosomes 11 and 17 [del(11q) and del(17q)], and trisomy 12, which is an extra copy of chromosome 12.

Researchers do not yet understand how these changes lead to CLL. One theory is that CLL begins after lymphocytes react to certain antigens. Antigens are particles that the immune system sees as foreign, such as bacteria or pollen. Lymphocytes activate and reproduce when they encounter antigens. The genetic mutations may turn on CLL with certain antigens. But again, it is unclear how or why this happens.

What are the risk factors for chronic lymphocytic leukemia?

A number of factors increase the risk of developing CLL. However, risk factors do not explain why some people get cancer and others do not. It is possible to have several risk factors and not ever get CLL. It is also possible to get CLL and have no risk factors for it. Known risk factors for CLL include:

  • Age: The risk of CLL increases with older age. The average age at diagnosis is 70 and about 90% of people with CLL are older than 50 years. It is rare in younger people.

  • Exposure to certain chemicals: Studies have suggested exposure to herbicides, particularly Agent Orange, and pesticides increase the risk of CLL.

  • Family history: The risk of CLL is 2 to 4 times higher for people who have a first-degree relative (parent, sibling or child) with CLL. The risk is also higher for people who have more than one relative with CLL or another lymph-related cancer.

  • Monoclonal B-cell lymphocytosis: In this blood disorder, people have high levels of B-cell lymphocytes, but not as high as in CLL. Sometimes, it turns into CLL.

  • Race: Caucasians are more likely to get CLL than other races. 

  • Sex: CLL affects more males than females.

Reducing your risk of chronic lymphocytic leukemia

Strategies to prevent cancer focus on modifying risk factors. Unfortunately, the few known risk factors for CLL are beyond your control. And most people seem to get CLL for random reasons since they do not have risk factors. So currently, there is no clear way to avoid or prevent CLL.

If you work in farming or have regular exposure to herbicides or pesticides, follow safety protocols when handling these chemicals.

How do doctors diagnose chronic lymphocytic leukemia?

Many times, doctors find CLL when reviewing lab results for an unrelated problem or on a routine checkup. Other times, people go to the doctor with symptoms. Either way, your doctor will need to take a careful medical history to diagnose the underlying cause. This will likely involve asking several questions including:

  • What symptoms are you experiencing?
  • How long have you had these symptoms?
  • Are your symptoms constant or do they come and go?
  • What, if anything, seems to make your symptoms better or worse?
  • Have you ever been diagnosed or treated for another type of cancer?
  • Do you have a family history of any type of cancer, including leukemia?
  • What other medical conditions do you have?

Your doctor will also perform a physical exam and check for enlarged lymph nodes, especially in your neck, under your arms, and in your groin. Your doctor will also feel your abdomen to check for any enlargement of the spleen or liver. Based on the results, your doctor may order testing including:

  • Complete blood count to measure the number of each type of white blood cell, red blood cells, and platelets. High lymphocyte levels may suggest leukemia.
  • Flow cytometry to look for specific markers present on CLL cells. This is the most important test for diagnosing CLL because it can tell the difference between CLL cells and normal lymphocytes. It can also give doctors information about prognosis and how aggressive the CLL is likely to be. Immunophenotyping is another name for this test.
  • Genomic and molecular testing to look for gene and chromosome mutations that can affect treatment and prognosis. Tests include FISH (fluorescence in situ hybridization), PCR (polymerase chain reaction), and others. 
  • Bone marrow aspiration or biopsy to examine it for the presence of leukemia cells. Doctors can usually diagnose CLL using blood tests alone, but bone marrow sampling can help show how advanced it is. 
  • Imaging exams to check for cancer spread, including X-ray, ultrasound, CT (computerized tomography) scan, or PET (positron emission tomography) scan 

Other less common testing for CLL may include lumbar puncture and lymph node biopsy.

What are the treatments for chronic lymphocytic leukemia?

CLL is very hard to cure, but people can live with it for many years. Research has shown that early treatment—before disease progression or symptoms develop—does not help people live longer. And treatment can cause significant side effects. This means treatment early in the disease carries risk, but no potential benefit. Because of this, doctors usually recommend watchful waiting in early stages. Regular checkups and lab monitoring will help your doctor decide when treatment becomes beneficial. In general, doctors wait until bothersome symptoms develop or lab results are problematic.

Once treatment starts, the standard regimen is chemotherapy (chemo) plus a monoclonal antibody. Monoclonal antibodies are a form of immunotherapy. They are man-made versions of immune system proteins that recognize and attach to specific targets on cells. Other types of targeted therapy, such as kinase inhibitors, are often part of first-line CLL treatment as well.

Less common treatments for CLL include radiation therapy and surgery for enlarged lymph nodes or spleen, and stem cell transplant for people with very high-risk disease.

Recently, a CLL treatment breakthrough now offers a chemo-free option for previously untreated patients. Research suggests people using a combination of targeted therapies as initial treatment may do better than the standard chemo plus a monoclonal antibody, with less toxicity. Currently, there are several targeted therapy-only options for first-line treatment including:

  • Acalabrutinib (Calquence) with obinutuzumab (Gazyva)
  • Alemtuzumab (Campath) with rituximab (Rituxan)
  • Ibrutinib (Imbruvica) with rituximab 
  • Ibrutinib with obinutuzumab
  • Venetoclax with rituximab
  • Venetoclax (Venclexta) with obinutuzumab

These CLL treatments may replace standard care of chemo plus a monoclonal antibody.

Alternative treatments for chronic lymphocytic leukemia

Alternative treatments can supplement traditional treatment to ease side effects during cancer therapy. They should not replace traditional treatments. Treatments that may help improve your comfort include:

  • Acupuncture
  • Exercise and regular physical activity
  • Massage therapy
  • Relaxation techniques, including meditation, guided imagery, and mind-body activities like yoga and tai chi

In addition, some research suggests green tea extract may be beneficial for people with very early CLL. A Mayo Clinic study looked at green tea extract use in CLL patients who did not need treatment yet. More than half of patients showed a beneficial effect in their blood cell counts. However, this research is not conclusive. More study is necessary to know for sure if green tea extract helps people with CLL.

Talk with your doctor before trying alternative treatments to make sure they will not interfere with your traditional treatments.

How does chronic lymphocytic leukemia affect quality of life?

Cancer of any kind tends to affect quality of life. For CLL patients, the top issues include anxiety, fatigue, physical functioning, social functioning, depression, and sleep disturbance. The level of anxiety seems to be higher for people in active treatment. However, watchful waiting carries its own burdens.

Research shows that people in watchful waiting still have an impaired quality of life compared to the general population. In fact, one study found younger patients in watchful waiting had more depression and worse social and emotional quality of life than older patients with more advanced disease. This suggests a need to connect people in watchful waiting with the resources to support their mental, emotional and social well-being.

Cancer centers offer patients a wide variety of coping and support resources. These include counselors, therapists, chaplains, and medical social workers, among others. Support groups are another resource to help people cope with CLL and its treatment. Connecting with others who are in the same process or who have been through it already can be extremely beneficial.

What are the potential complications of chronic lymphocytic leukemia?

It is possible to live for many years with CLL. During that time, complications are possible including:

  • Autoimmune reactions due to a faulty immune system. CLL can cause the body to mistakenly make antibodies that attack normal blood cells, causing low counts. Most often, red blood cells are the target, causing a disorder called autoimmune hemolytic anemia. Sometimes, platelets are the target. Rarely, the immune system attacks normal white blood cells. 

  • Frequent infections due to poorly functioning lymphocytes. Serious infections can also occur as a side effect of chemotherapy treatment.

  • Other cancers are more common in people with CLL, including melanoma, lung cancer, and cancers of the digestive tract.

  • Richter’s syndrome or Richter’s transformation can occur in a small number of people. It happens when CLL turns into a more aggressive cancer called diffuse large B-cell lymphoma.

What is the survival rate and prognosis for chronic lymphocytic leukemia?

The 5-year survival rate for adults with CLL is high at 86%. Staging is one factor that helps determine prognosis, but there are others. Some of these factors have a favorable influence on prognosis and others are unfavorable.

Adverse or unfavorable factors include:

  • CLL cells that do not have the TP53 gene or that have an unmutated gene for IGHV (immunoglobulin heavy chain variable region)

  • Deletions on chromosomes 11 [del (11q)] or 17 [del(17q)], or trisomy 12 in CLL cells

  • Diffuse or widespread replacement of normal bone marrow with leukemia cells

  • High percentage of CLL cells with ZAP-70 (20% or more) or CD38 (30% or more) or high blood levels of certain substances, such as beta-2-microglobulin

  • High fraction of an early form of lymphocytes, called prolymphocytes, in the blood

  • Lymphocyte count doubling time of less than a year

  • Older age

Factors that have a favorable influence include:

  • CLL cells with a mutated gene for IGHV

  • Deletion in chromosome 13 [del(13q)] with no other chromosome abnormalities

  • Low percentage of CLL cells with ZAP-70 (less than 20%) or CD38 (less than 30%)

  • Nodular or interstitial pattern of bone marrow replacement instead of being widespread

There are other things that influence your individual prognosis and life expectancy, including the overall state of your health. Your doctor is the best source for understanding your prognosis and future outlook.

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Medical Reviewer: William C. Lloyd III, MD, FACS
Last Review Date: 2021 Jun 18
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