What is chronic lymphocytic leukaemia?

Chronic lymphocytic leukaemia (CLL) is a type of lymphoma. Although CLL has the word leukaemia in its name, the World Health Organisation (WHO) classifies it as a subtype of lymphoma because it is a cancer of B-cell lymphocytes, which are blood cells.

CLL occurs due to changes in our DNA inside our cells. DNA makes up genes and genes control how our cells function. In CLL, there are often many different genetic changes. These can vary from person to person. Some of the most affected genes in CLL are:

• Tumour protein 53 (TP53)
• Ataxia telangiectasia mutated (ATM)
• Neurogenic locus notch homolog protein 1 (NOTCH1)
• Splicing factor 3B subunit 1 (SF3B1)

Different gene mutations carry different risks. Some mutations mean the disease is harder to treat or more aggressive. Some mutations mean the disease is likely to have a poorer prognosis.

The genetic changes in CLL means that the bone marrow produces too many abnormal white blood cells. In CLL the abnormal white cells are mainly found in the bone marrow and the bloodstream. If the abnormal white cells are mainly found in the lymph nodes this is diagnosed as small lymphocytic lymphoma (SLL). CLL and SLL are considered the same disease and are treated in the same way. When this webpage refers to CLL it is inclusive of SLL.

Usually, lymphocytes help protect against infection. In CLL the abnormal white blood cells called lymphocytes do not work properly. The abnormal cells build up in the bone marrow limiting space to make enough healthy blood cells. Healthy blood cells include red cells, white blood cells, and platelets. They are very important for body function. The abnormal lymphocytes can build up in organs including the lymph nodes (glands), liver, spleen, and other parts of the body.

Causes of CLL

In most cases, there is no specific cause of CLL. There are some risk factors that increase your likelihood of developing CLL. Such as:

• Age – more common in older people
• Gender – more common in men than women
• Ethnicity – more common in people of European origin
• Family history – people who have a parent, sibling or child with CLL
• Exposure to high-risk chemicals like pesticides, benzene and heavy solvents

Symptoms of CLL

Many people don’t have any symptoms of CLL when they are diagnosed. It is often found by doing a routine blood test which may show a high number of lymphocytes. This is called lymphocytosis.

Common symptoms of CLL can include:

• Tiredness
• Weakness
• Dizziness
• Weight loss
• Fevers
• Infections
• Night sweats
• Easy bruising
• Swollen lymph nodes
• Abdominal discomfort/swelling

Enlarged spleen

An enlarged spleen is a symptom of CLL. Your spleen is an organ located in the top left of your abdomen (stomach), near your rib cage. It acts like a sponge for blood cells. It stores blood cells but can also make them. If your spleen starts making too many blood cells, it may swell up. When the spleen is swollen (enlarged), it is called splenomegaly. Symptoms of splenomegaly are:

• Feeling of fullness in your abdomen
• Discomfort or pain in the left upper side of your abdomen
• Feeling full quickly when eating

Swollen lymph nodes

If the CLL has spread to your lymph nodes, you may have small, hard lumps. These are swollen lymph nodes, they may be in your armpits, on either side of your neck, and/or in your groin. They’re usually painless. There are also lymph nodes in your chest and abdomen. They might swell but can only be seen with scans. Swollen lymph nodes are called lymphadenopathy.

Diagnosis of CLL

CLL is diagnosed with a number of tests. It is possible that CLL will be picked up on a routine blood test. The tests can include:

• Medical history and physical exam
• Blood tests – full blood count (FBC), kidney and liver function, electrolytes
• Genetic tests

These tests help your treatment team work out how far the disease has spread. These tests include:

• Bone marrow biopsy
• Lymph node biopsy
• Computed tomography (CT) scan
• Positron emission tomography (PET) scan
• Ultrasound

You can read more about these tests in the CLL booklet

Staging CLL

Staging CLL helps your haematologist prescribe the right treatment for your disease. There are two staging systems for CLL. In Australia the Binet system is typically used. This divides CLL into three stages. Your haematologist will look at:

• The number of red blood cells and platelets in your blood
• How many areas of swollen lymph nodes you have

Comparison of CLL stage and symptoms.

Stage	Symptoms
Stage A/0	Unlikely to have symptoms but you may feel a swollen lymph node in your neck, armpit or groin.
Stage B/I-III	You may feel tired, with low energy.
Stage C/III-IV	You will likely feel tired due to the low red blood cells. You get noose bleeds, bruising or heavy periods. You could get frequent colds, lose weight without trying and have night sweats.

Prognosis of CLL

A prognosis is an estimate your haematologist will make of the likely course and outcome of your disease. Your haematologist will let you know your stage and prognosis. They will also consider many factors, some of these are:

• Your lymphocyte count (and how long it takes to double)
• Which chromosomes or genes are affected
• Stage of CLL
• Your overall health
• Your age

Your prognosis might change if your CLL comes back after treatment or changes to a different type of cancer.

Genetic changes can be an indicator of prognosis and treatment response. Some genetic changes lead to a poorer prognosis, are predicted to have a poorer response to treatment and a higher risk of disease progression.

Transformed CLL – Richter’s syndrome

Richter’s syndrome, also called Richter’s transformation, is a rare complication of CLL. It is when CLL transforms into a more aggressive form of non-Hodgkin lymphoma (NHL) called diffuse large B-cell lymphoma (DLBCL) or into Hodgkin lymphoma (HL). This can affect up to 7% of people with CLL.

Prolymphocytic leukaemia

Prolymphocytic leukaemia is a rare complication of CLL. It can occur in up to 2% of people with CLL. It is aggressive, has a poorer prognosis, and can be difficult to treat.

Treatments for CLL

There is currently no cure for CLL. For many people with CLL, no treatment is required, and it has minimal impact on their quality of life. For those that CLL treatment is recommended it can be very effective at managing CLL. Allowing people to live long and healthy lives.

Treatment for CLL is based on:

• The stage of CLL
• Whether you have symptoms of CLL
• Your blood count
• Your genetic changes
• Whether your lymph nodes or spleen are larger than normal
• Your age and general health
• Your decisions

Your treatment plan could include one or more of the following:

• Watch and wait (active observation) with regular checkups but no treatment
• Supportive care to control symptoms of CLL like thrombocytopenia
• Targeted therapy, immunotherapy or chemotherapy
• Involvement in a clinical trial
• Stem cell transplant

Watch and wait

Many people with CLL do not need to start treatment due to minimal blood count changes and no symptoms. This approach is watch and wait. It involves regular check-ups and monitoring by your haematologist and/or general practitioner (GP). Studies show that watch and wait offers no disadvantages compared to early treatment for low-risk CLL. In some cases, CLL can be managed with this approach for years before it progresses.

Many people with CLL on watch and wait feel like they should be doing something. There are some actions people can take:

Supportive care

Supportive care prevents and treats symptoms and side effects. It includes emotional and social support too. The goal is to improve symptoms of your CLL, but it doesn’t treat the disease itself. People with stage B and C (intermediate-high risk) CLL may have supportive care alongside treatment.

Get more information on:

• Supportive care
• Emotional support services

Targeted therapy and CLL

Cancer growth inhibitors

Cancer growth inhibitors are a type of targeted therapy. They block signals to cancer cells to stop them from growing or surviving. There are a few types of cancer growth inhibitors used to treat CLL:

B-cell leukaemia/lymphoma-2 (BCL2) inhibitors:

Venetoclax is an example of a BCL2 inhibitor

• BCL2 is a type of protein that some cancer cells make
• BCL2 inhibitors block the protein, and the cancer cells die
• Taken as a tablet.

Bruton’s tyrosine kinase inhibitors (BTKi’s):

Some BTKI’s are ibrutinib, acalabrutinib, zanubrutinib

• Bruton’s tyrosine kinase (BTK) protein is essential to the growth of B-cells
• BTKi’s block the B-cell receptor (BCR) on cancer cells
• When this receptor is blocked the cancer cells die
• Taken as a tablet

Monoclonal antibodies

Monoclonal antibodies attach to a specific target on a cancer cell and stop it from growing. They can also slow down cancer cell growth. They can be referred to as immunotherapy or targeted therapy. There are a few types of monoclonal antibodies that can be used to treat CLL:

Monoclonal anti-CD20 antibody:

Rituximab and Obinutuzumab are examples of monoclonal anti-CD20 antibodies.

• CD20 is a protein located on the surface of B-cells, and it is present in some individuals with CLL
• This is termed CD20 positive
• The monoclonal anti-CD20 antibody connects to this protein on the blood cancer cell
• It destroys the cell by damaging the antibody, causing the cell to die

Chemotherapy and CLL

Chemotherapy is a less common treatment for CLL. However, depending on your type of CLL and genetic mutations, chemotherapy might be the best treatment option. Chemotherapy drugs for CLL are often given in combination with immunotherapy drugs.

Some common treatments for CLL

Venetoclax and Obinutuzumab

• Combination treatment with Venetoclax, a BCL-2 inhibitor and Obinutuzumab, a monoclonal anti-CD20 antibody
• Treatment is introduced slowly due to the risk of tumour lysis syndrome
• Venetoclax is taken continuously
• Obinutuzumab is given over 1-2 days, every 4 weeks
• Requires close blood test monitoring at treatment commencement

Fludarabine, Cyclophosphamide and Rituximab (FCR)

• Fludarabine and cyclophosphamide are chemo drugs
• Rituximab is a monoclonal anti-CD20 antibody
• Given intravenously over 3 days, every 4 weeks

Bendamustine and Rituximab

• Bendamustine is a chemo drug
• Rituximab is a monoclonal anti-CD20 antibody
• Given intravenously over 2 days, every 4 weeks

Treatment side effects can vary. Read more about the general chemotherapy side effects.

Follow-up

Ongoing follow up, including frequent blood tests is important to monitor CLL. This includes all people with CLL – watch and wait, during treatment, after treatment.

Living with CLL

How CLL affects your everyday life will depend on many factors. It could be that you are returning or managing work, your emotional health or managing fatigue. There are some helpful resources and information to guide you – Living well with blood cancer. The Online Blood Cancer Support Service has learn modules on cancer related fatigue, transition to the new normal, emotional resilience and more.