Overview of Chronic Lymphocytic Leukemia

chronic lymphocytes leukemia (CLL) is a classic slow-growing cancer that starts in the bone marrow and spreads into the blood. Often, it is first suspected in people who are asymptomatic during routine blood tests. Additional tests help confirm the diagnosis and classify CLL from low to high risk. Usually, CLL does not cause any symptoms for at least a few years and does not require immediate treatment. Once treatment is needed, there are many options to help manage the disease.

This cancer develops in a type of white blood cell called a B cell or B lymphocyte. In fact, some of the therapies used to treat different types of B-cell lymphomas are also used for CLL.


An unexplained high white blood cell (lymphocyte) count is the most common clue that a health care provider considers a CLL diagnosis. Often, a person has no symptoms associated with CLL at the time of diagnosis.

People with more aggressive types of CLL and people with more advanced disease may show any number of signs and symptoms, including any or a combination of the following:

  • Fatigue, feeling exhausted, decreased exercise capacity
  • swollen lymph nodes
  • frequent infections
  • abdominal pain, pressure, or fullness
  • bleeding problems

Systemic symptoms may also occur, including what are sometimes called “B symptoms”:

  • fever/chills
  • night sweats
  • lose weight

However, none of the above symptoms are specific to CLL.


The diagnostic process begins with an appointment with your healthcare provider. You may have symptoms, or signs of CLL may show up on your routine blood work and need further testing.

History and Physical Examination

During a complete medical history, your doctor will ask about symptoms, possible risk factors, family history, and your general health.

During the physical exam, your healthcare provider will look for possible signs of CLL and other health problems, especially swollen lymph nodes, any abdominal findings that may indicate an enlarged spleen, and other areas that may be affected.

Blood tests and lab work

A complete blood count (CBC) measures different cells in the blood, such as red blood cells, white blood cells, and platelets. More than 10,000 lymphocytes per cubic millimeter of blood suggest CLL, but other tests are needed to determine it.

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If your blood counts suggest CLL, you may be referred to a hematologist (specialist in blood disorders) for additional tests to confirm the diagnosis and determine the risk group for CLL.

CLL is usually diagnosed by a blood test rather than a bone marrow test because cancer cells are easily found in the blood.

Flow cytometry uses machines that can differentiate between different types of cells to help determine the types of cells in a sample and the number of specific types of cells. Flow cytometry can be done using blood samples, bone marrow samples, or other fluids.

Bone marrow biopsy is usually not required to diagnose CLL, but is done in certain circumstances, such as before starting CLL treatment, or when the disease has progressed or some other condition has changed significantly.

Your healthcare team may use other blood tests to help find liver or kidney problems that may affect treatment options. They can also test your blood immune globulin (antibody) levels to help determine your ability to fight infections, especially if frequent infections are part of your medical history. They may do other blood tests to identify the characteristics of CLL.

Genetic and Molecular Testing

Each of our cells typically has 46 chromosomes, 23 of which are from both parents, which contain many genes. Each chromosome has a number, and the genes within each chromosome are named. Many different chromosomes and genes are important in CLL, including chromosomes 13, 11, and 17, as well as genes such as TP53 and IGHV.

Sometimes CLL cells have chromosomal changes due to partial chromosomal deletions or deletions. Partial deletions of chromosomes 13, 11, or 17 are associated with CLL. The deletion of part of chromosome 17 is associated with poor outlook. Other less common chromosomal changes include an extra copy of chromosome 12 (trisomy 12) or a DNA translocation (crossover) between chromosomes 11 and 14.

Some studies look at chromosomal changes, while others look at changes in specific genes. Some tests that look for chromosomal changes require cancer cells to start dividing in the lab, so the whole process can take quite a while to get results.

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Fluorescence in situ hybridization (FISH) tests use fluorescent dyes that attach to specific chromosomes to look for changes. It’s faster than methods that require cells to be grown in the lab.

Other markers important in CLL include IGHV and TP53 mutation status:

  • Immunoglobulins are antibodies that your immune system produces to help your body fight infection. Leukemia cells use the immunoglobulin heavy chain variable (IGHV) gene, and the unmutated IGHV gene has a poorer prognosis than the mutated IGHV gene.
  • Abnormalities in the TP53 gene, a tumor suppressor, are also important for guiding treatment decisions. People with TP53 mutations are less likely to do well with standard chemotherapy than with non-chemotherapy treatments.

This information from genetic and molecular testing may help determine a person’s outlook, but needs to be considered along with other factors in making treatment decisions.

Staging refers to the degree of CLL progression, or the number of CLL cells in the body and the impact of this burden. Staging is used in CLL (eg, the Rai and Binet systems), but outcomes in patients with CLL also depend on other information, such as the results of laboratory tests and imaging tests.


The choice of treatment will depend on many factors and the stage of CLL.

watch and wait

CLL is a slow-growing cancer, and there is insufficient evidence to support treatment for people with early-stage CLL who are asymptomatic and not at high risk. For these people, a period of no treatment — called watch and wait, watchful waiting, active surveillance, or active surveillance — is considered the best option. Watchful waiting is not synonymous with the above treatments and does not worsen the outcome.

Instead, regular blood cell counts are performed, if systemic symptoms (fever, night sweats, fatigue, weight loss greater than 10% of body weight), progressive fatigue, progressive bone marrow failure (decreased red blood cells or platelet count), swollen and painful lymph nodes, liver and/or significantly enlarged spleen, or very high white blood cell count.

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Traditionally, a selected group of patients (young, healthy, IGHV-mutated, without TP53 mutations or chromosome 11 or 17 deletions) benefited most from a defined course of fludarabine, cyclophosphamide, and rituximab , the combination is known as an FCR, which achieves durable remissions for many patients.

In some cases, biologics such as ibrutinib, acalabrutinib, or venetoclax (rather than chemotherapy) are also optional in regimens with or without monoclonal antibodies such as rituximab or obinutuzumab.

Novel agents and combinations

For healthy older adults (over 65 years of age) with CLL, the most effective initial treatment has not been established. In frail older adults, ibrutinib alone is usually considered when no other medical conditions preclude or raise concerns about its use.

Approved options now include new drugs such as ibrutinib and combinations of new drugs with anti-CD20-directed monoclonal antibodies. Both ibrutinib and venetoclax can be used in combination with anti-CD20-directed monoclonal antibodies.

The efficacy and safety of ibrutinib alone have been demonstrated in previously untreated patients with CLL 65 years of age or older, and data support continued ibrutinib use in the absence of progression or toxicity. Continue to explore the role of adding a monoclonal antibody (targeting the CD20 marker on CLL cells) to ibrutinib.

VigorTip words

The introduction of novel targeted therapies that inhibit important pathways in the disease process of CLL has changed the outlook for the treatment of this disease. Biologics such as ibrutinib, idelalisib, and venetoclax have shown excellent efficacy, including in patients with high-risk disease such as TP53 mutations or chromosome 17 deletions.

However, the problems of residual disease, acquired resistance and lack of good, long-term responses in patients with high-risk disease remain a concern. Furthermore, despite considerable progress, much remains unknown about the optimal treatment options and sequence of treatment for different populations. In conclusion, great progress has been made in recent years, but there is still room for improvement.