An Overview of Chronic Lymphocytic Leukemia

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Chronic lymphocytic leukemia (CLL) is a typically slow-growing cancer that begins in the bone marrow and extends into the blood. Often, it is first suspected in a person who has no symptoms, during routine blood work. Additional testing helps to confirm the diagnosis and classify CLL into groups by low-risk to high-risk. Often, 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 control the disease.

In more than 95% of people with CLL, the cancer develops in a line of white blood cells called B-lymphocytes. In fact, some of the therapies used in the treatment of different types of B-cell lymphoma are also used in CLL.

Symptoms

An unexplained high white blood cell (lymphocyte) count is the most common clue that leads a doctor to consider a CLL diagnosis. Often, a person has no symptoms related to CLL at the time of diagnosis. 

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

  • Fatigue, feeling run down, less able to exercise
  • Swollen lymph nodes
  • Frequent infections
  • Pain, pressure or fullness in the abdomen
  • Bleeding problems

So-called systemic symptoms are also possible, including the following, which are referred to as “B symptoms:"

  • Fever/chills
  • Night sweats
  • Weight loss

None of the above symptoms is specific to CLL, however.

Diagnosis

The diagnostic process begins with an appointment with your doctor. You may be having symptoms, or signs of CLL may appear in your routine bloodwork and warrant further work-up.

Medical History and Physical Exam

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

During the physical exam, your doctor will look for possible signs of CLL and other health problems, especially enlarged lymph nodes, any findings that might suggest an enlarged spleen in the abdomen, and other areas that might be affected.

Blood Tests and Laboratory Work

The complete blood count or CBC measures the different cells in your blood, such as the red blood cells, the white blood cells, and the platelets.  Having more than 10,000 lymphocytes/mm³ (per cubic millimeter) of blood is suggestive of CLL, but other tests are needed to know for certain.

If your blood count is suggestive of CLL, you may be referred to a hematologist for additional testing to confirm the diagnosis and determine the risk group of your CLL.

CLL is usually diagnosed with blood tests, rather than bone marrow tests, because the cancerous cells are easily found in the blood.

Flow cytometry uses a machine that looks for certain markers on or in cells that help determine what types of cells they are. Flow cytometry can be done using blood samples, samples from the bone marrow, or other fluids.

A bone marrow biopsy is usually not needed to diagnose CLL, but it is done in certain instances, such as before starting CLL treatment, or when there has been a major change in the progression of the disease, or certain other instances.

Other blood tests might be done to help find liver or kidney problems that might help steer your medical team toward one treatment or another. Your blood immunoglobulin (antibody) levels might be tested to see if you have enough antibodies to fight infections, especially if frequent infections are part of your history. Still other blood tests might be done as part of trying to determine the risk characteristics of your CLL. 

Genetic and Molecular Testing

Each of our cells normally has 46 chromosomes, 23 from each parent, that contain many genes. Each chromosome has a number, and the genes within each chromosome are named. For CLL, many different chromosomes and genes are important, including chromosomes 13, 11, or 17, and genes such as p53 and IGHV.

Sometimes CLL cells have chromosome changes as a result of part of the chromosome being missing or deleted. Deletions in parts of chromosomes 13, 11, or 17 are associated with CLL. Deletion of part of chromosome 17 is linked to a poor outlook. Other, less common chromosome changes include an extra copy of chromosome 12 (trisomy 12) or a translocation or swapping of DNA between chromosomes 11 and 14, which is noted as t(11;14).

Some studies look at chromosomal changes, whereas others look for changes in specific genes. Certain tests that look for chromosomal changes require that the cancer cells start dividing in the laboratory, so the whole process can take quite some time before you get results.

Fluorescent in situ hybridization (FISH) testing is great for CLL because it can be used to look at the CLL cells’ chromosomes and DNA without having to grow the cells in the lab and can yield results more quickly than cytogenetics.

Additional markers of importance in CLL include IGHV and P53 mutation status:

  • Immunoglobulins are the antibodies that help your body fight infections, and they are made up of light chains and heavy chains. Whether the gene for the immunoglobulin heavy chain variable region (IGHV or IgVH) is mutated or not can be an important detail in planning which treatments are likely to be worth your while.
  • Abnormalities in the TP53 gene, which is considered a tumor suppressor, are also important in guiding treatment decisions. For instance, people with p53 mutations may be less likely to do well on a fludarabine-based chemoimmunotherapy (eg, FCR, discussed below) than with a novel agent. P53 mutation often goes together with a deletion in chromosome 17 (17p deletion).

This information from genetic and molecular testing may be helpful to determine a person’s outlook, but it needs to be looked at along with other factors in the shared decisionmaking that happens leading to treatment.

Staging refers to the extent to which the CLL has progressed, or the amount of CLL cells in the body and the impact of that burden. Staging is used in CLL (eg, the Rai and Binet systems), however the outcome for a person with CLL depends on other information, such as the results of lab test and imaging tests.

Treatment

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

Watch and Wait

In the early stages of CLL, a period of no treatment, referred to a watchful waiting, or watch and wait, is considered the best option. Up to 40% of people managed initially by watch and wait will not receive any anti-CLL therapy during their lifetime.

Watchful waiting is not synonymous with foregoing treatment and does not worsen outcomes; thus far, treatment before a person meets established criteria for treatment has not been shown to lead to longer remissions or better outcomes.

Instead, blood counts are done fairly regularly, and treatment is initiated if constitutional symptoms (fever, night sweats, fatigue, weight loss greater than 10 percent of body mass), progressive fatigue, progressive bone marrow failure (with a low red blood cell or platelet count), painfully enlarged lymph nodes, a significantly enlarged liver and/or spleen, or a very high white blood cell count arise.

Chemoimmunotherapy

A select group of patients (young, fit, with mutated IGHV, without del(17p)/TP53 or del(11q)) has traditionally been viewed to benefit the most from a defined course of therapy with fludarabine, cyclophosphamide, and rituximab, the combination known as FCR, which achieves durable remissions for many patients.

More and more, use of novel agents such as ibrutinib or venetoclax (rather than chemotherapy) in regimens with monoclonal antibodies (such as rituximab or obinutuzumab) is being considered among the options in appropriate scenarios.

Novel Agents and Combinations

The most effective initial therapy for fit, older adults (age over 65 years) with CLL has not been established definitively. For frail older adults, ibrutinib alone is often considered when there are no other health conditions that would preclude or cause concerns about its use.

Approved options now include novel agents such as ibrutinib and novel agent combinations 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 has been established in previously untreated patients age 65 years or older with CLL, and data support continuous ibrutinib use in the absence of progression or toxicity. The role of the addition of a monoclonal antibody (that targets the CD20 marker on CLL cells) to ibrutinib continues to be explored.

A Word from Verywell

The introduction of novel targeted therapies that inhibit important pathways in the CLL disease process has changed the landscape of the treatment of the disease. Newer agents include ibrutinib, idelalisib, and venetoclax, and these agents have reported excellent outcomes, including in patients with high-risk disease such as 17p deletion or TP53 deletion. 

However, issues of residual disease, acquired resistance, and lack of a nice, long response in patients with high-risk disease remain concerns. Additionally, despite this considerable progress, much is unknown regarding best treatment selection and sequence of therapies for different groups of people. In short, tremendous progress has been made in recent years, but there is still room for improvement.

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