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About CLL

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About chronic lymphocytic leukaemia (CLL)

What is Chronic Lymphocytic Leukaemia (CLL)?

Chronic Lymphocytic Leukaemia (CLL) is one of the most common types of leukaemia among adults. It is usually a slow-growing cancer of the blood and bone marrow that occurs when the bone marrow, the spongy material inside bones, produces too many lymphocytes, a certain type of white blood cell, that are not fully developed and don’t function properly.2 CLL is sometimes used as an overarching term that includes Small Lymphocytic Lymphoma (SLL), a nearly identical disease, where cancerous cells are found more commonly in the lymph nodes.3

Under normal conditions, lymphocytes produce antibodies that help the body fight infection and disease. In people with CLL, the abnormal lymphocytes being produced can build up over time in the bone marrow. This leaves less space for normal white blood cells, red blood cells and platelets to develop, which is what causes many of the symptoms that patients experience.24

As with other types of cancer, CLL is categorised in different stages to indicate the severity of the disease and how far it has spread. For CLL, there are two clinical staging systems:5

  • Rai system: used more often in the United States. This system is based on lymphocytosis, a condition in which there is an increase in white blood cells, called lymphocytes, in the blood stream.6 The patient must have a high number of lymphocytes in their blood and bone marrow that isn't linked to any other cause (like infection). Rai stages range from 0 to IV.37

  • Binet system: used more widely in Europe.38 In this system, CLL is classified by the number of affected lymphoid tissue groups (neck lymph nodes, groin lymph nodes, underarm lymph nodes, spleen, and liver) and by whether or not the patient has anaemia (too few red blood cells) or thrombocytopenia (too few blood platelets). The Binet stages are A, B and C.

CLL is different from other types of leukaemia, including acute myeloid leukaemia, acute lymphoblastic leukaemia, and acute myeloid leukaemia, in that it grows and spreads more slowly.3

CLL is known to have a genetic basis and be hereditary (run in families), being known as familial CLL.5

What causes CLL?

The exact cause of CLL is still not known; however, scientists have learned a great deal about the disease.67

What is known is that something happens to cause mutations (changes) in the DNA of white blood cells, resulting in the bone marrow making too many abnormal and ineffective lymphocytes (B-cells).38

It is the build-up of these B-cells over time that lead to changes in your blood, which may cause:8

Anaemia

Caused by a lower red blood cell count which can increase fatigue

Low platelet counts (thrombocytopenia)

Causing an increased tendency to bleed

Low count of certain white blood cells (neutropenia)

Increasing risk of infection

Diagnosis


In most cases the diagnosis of CLL is random and is often discovered by chance after a routine blood test.3

If you do have symptoms, your doctor will examine you and do a blood test to check your full blood count (the number of the different types of blood cells). If they think you have CLL, they will refer you to a haematologist (a doctor who specialises in diagnosing and treating blood abnormalities). The haematologist will arrange further tests for you.3

Testing


There are several tests that you may encounter during diagnosis and throughout the progression of your CLL.

You will undergo regular blood testing throughout your treatment to check up on your general health as well as being asked about any symptoms you may be having. These blood tests will look at your:

  • lymphocyte count – which will indicate the status or level of your CLL
  • haemoglobin and/or red blood cell count – a low level can result in you being tired or feeling out of breath
  • platelet levels – a low level can mean you bleed and bruise more easily

Sometimes, you may be required to undergo a bone marrow aspiration (removing fluid) or biopsy (removing bone and marrow) to determine prognosis and whether a treatment is working. These will generally be done at a hospital appointment.

In flow cytometry testing, a machine is used to check for markers on or in the cells that can help in identifying their type.

In diagnosing CLL, it is used to see if the lymphocytes in a blood sample contain abnormal B-cells. It can also be used to see if there are CLL cells present in bone marrow or other fluids.

For diagnosis, blood testing is usually sufficient, however testing the bone marrow can help determine how advanced your CLL is. This can be done through a bone marrow aspiration or a bone marrow biopsy and is performed when clinically indicated.

Genetic Testing


The presence of certain chromosomal changes (aberrations) found within leukaemia cells can help inform doctors about the most appropriate treatment pathway for you.10 They may run a series of genetic tests before making a final decision on which treatment recommendations to give.11 The tests will evaluate some of the biological characteristics found within leukaemia cells. These tests are:

The fluorescence in situ hybridisation (FISH) test uses blood or bone marrow to find missing parts of chromosomes (deletions, often written as “del”) or duplications of chromosomes. These changes can help determine whether your CLL is high or low risk.

A karyotype gives a picture of a cell and all your chromosomes within it. Karyotyping is a test that shows if there is a change to the number, size or shape of chromosomes.

DNA sequencing looks at blood or bone marrow cells to detect changes or mutations. In CLL, it is used to test for mutations in the immunoglobin heavy chain variable (IGHV).

The IGHV gene, in immune cells, contains instructions for making a specific part of antibodies – a protein that helps your body fight off infections. In CLL, these genes are either mutated or unmutated. Mutated IGHV is often associated with a favourable outlook, whereas unmutated IGHV genes can mean that your CLL is higher risk and certain treatments will be better suited to patients with high-risk disease.510

When part of a chromosome (a critical structure within the cell) is missing, it’s called a deletion. One type of deletion that occurs in chromosome 17 is called del(17p), which is common in CLL. This deletion may affect how cancer grows. It is considered a risk factor that may suggest that the disease will progress more quickly.510

Some people with del(17p) may not respond to certain treatments.

The TP53 gene signals whether damaged cells should be repaired or destroyed. If this gene is mutated in someone with CLL, it may mean that CLL is higher risk. Mutated TP53 is often detected in people who also have del(17p) which means part of the short arm of chromosome 17 are missing.10

Another deletion is del(11q), which means parts of chromosome 11 are missing. When this occurs, it may affect how DNA repairs itself, which means cancer can continue to grow. Del(11q) is considered a risk factor that can suggest that the CLL may progress more quickly.51211

When there are three copies of a chromosome in a cell, it is called trisomy ("tri" because there are 3 chromosomes instead of the usual 2).
People who have trisomy 12, or +12, as their sole abnormality are considered as having medium-risk CLL. But people with +12 and other abnormalities may be at a higher risk for the disease to progress.510

Chromosome 13 contains the gene that helps control cell growth. Del(13q) means that part of chromosome 13 is missing. When that happens, it can affect cancer growth. Del(13q) is the most common deletion. When it’s the only genetic marker, it suggests a favourable outlook, which means your CLL may be at a lower risk for progression.510

Stages


A staging system is a way a cancer care team describes cancer and helps them to determine how and when it needs to be treated. There are two different systems for staging CLL, which are both built on clinical observations:

  • Binet System – used more widely in Europe

  • Rai System – used predominately in the United States

    CLL is the only form of leukaemia where a staging system is used.13

In this system, CLL is classified by the number of affected lymphoid tissue groups (lymph nodes in neck, groin and underarm, as well as spleen and liver) and by whether the patient has anaemia (too few red blood cells) or thrombocytopenia (too few blood platelets).

The Binet stages are:

  • Stage A – you have enlarged lymph nodes in fewer than 3 areas (such as your neck, armpit or groin) and a high white blood cell count
  • Stage B – you have enlarged lymph nodes in 3 or more areas and a high white blood cell count
  • Stage C – you have enlarged lymph nodes or an enlarged spleen, a high white blood cell count, and a low red blood cell or platelet count

Stage B and C CLL are usually treated straight away. Stage A is generally only treated if it's getting worse quickly or starting to cause symptoms.

This system is based on lymphocytosis, a condition in which there is an increase in white blood cells, called lymphocytes, in the blood stream.4 The patient must have a high number of lymphocytes in their blood and bone marrow that isn't linked to any other cause (like infection). Rai stages range from 0 to IV and is a system mostly used for clinically assessing CLL in the USA.2

References

[1]
Méjécase C et al. Ther Adv Ophthalmol. 2020; 12:1S28.