What is chronic lymphocytic leukaemia (CLL)?

Also known as:

chronic lymphoid leukaemia
CLL
Small lymphocytic lymphoma (SLL)

A note on naming and spelling.

SLL – or small lymphocytic lymphoma is the same disease as CLL. In the past, different names were used depending on which parts of the body were affected. SLL was associated with the lymph nodes and spleen, CLL was used when the blood and bone marrow were affected.

You will see two different versions of leukaemia – one with an a (leukaemia) and one without (leukemia). These are just different spellings of the same thing. Leukaemia is the English spelling, leukemia is the American version. Either is fine, but if you’re searching for more information your choice of spelling will affect whether you find more US or UK based resources.

What it is not:

There are several other types of leukaemia with similar sounding names that can be easily confused. CML (chronic myeloid leukaemia), ALL (acute lymphocytic leukaemia) and AML (acute myelogenous leukaemia) which will be described elsewhere. CLL is a very different condition from the acute forms that are more common in children.

CLL is now considered to be a separate disease from T-cell prolymphocytic leukaemia which used to be known as T-cell CLL.

How rare is chronic lymphocytic leukaemia?

In the UK and Europe the usual definition of a rare cancer is one that occurs in less than 6 people out of every 100,00 each year. Because there are around 200 rare cancers, this means that they make up about 24% (nearly a quarter) of all cancers.

Although rare, CLL is the commonest type of blood cancer. The incidence rate in the UK is around 5.6 cases per 100,000 people. It is more common in men, typically twice as many men develop CLL as women. CLL is never seen in children and is exceptionally rare in adults under 40. Over the age of 40, the incidence increases with age to over 30 cases per 100,000 people in their late 80s.

What is CLL?

CLL or chronic lymphocytic leukaemia is a type of leukaemia, a blood cancer affecting the white blood cells of the blood and bone marrow. It is described as chronic as it develops slowly and can remain undetected for many years.

A family of blood cells.

When we are in the early stages of growth as an embryo, we are just a ball of cells of no particular type. These are called stem cells that can change to become all of the different cells that make up a human being. Once we are born only a very few cells keep the ability to do this. The most important of these are found in our bone marrow where a single type of stem cell is responsible for producing all the cells that are found in our blood. The oxygen carrying red blood cells, the many types of white blood cells that fight infections and the platelets that help our blood to clot.

The picture below shows the family tree of these blood cells. All of them come from the haematopoietic stem cells (haematopoietic means blood forming). The stem cells will multiply and become more specialised as they develop down the branches of the tree.

Image from Wikimedia Commons.

There are two big families within the blood cells. The myeloid cells on the left and the lymphoid cells on the right. These may sound familiar if you have met the different leukaemias.

CML (chronic myeloid leukaemia) and AML (acute myeloid leukaemia) affect white blood cells that form from the myeloid side of the family – the granulocytes (also known as neutrophils) and the monocytes.

Notice their “cousin” the erythrocyte or red blood cell. These can also develop a rare cancer called polycythaemia vera. On the other side of the family tree are the lymphoid cells that produce the B and T lymphocytes or white blood cells. When these develop into cancer they are called lymphocytic leukaemia. CLL (chronic lymphocytic leukaemia) comes from the B-cells and ALL (acute lymphocytic leukaemia) from either T or B cells. There are different types of ALL depending on whether B or T cells are affected.

Chronic lymphocytic leukaemia biology.

CLL is a cancer where your bone marrow, the spongy part in the middle of the long bones, makes too many of one type of white blood cell, called a B-lymphocyte. These excess white blood cells make it harder for your bone marrow to make other types of white and red blood cells and platelets. These B-cells are also not quite mature, so they can’t do their job properly. This is what causes most of the symptoms of CLL.

If you don’t produce enough red blood cells you will feel tired, breathless, lacking in energy as not enough oxygen is being delivered to your tissues. A shortage of platelets will make it harder for blood to clot, so there may be bruising or bleeding that doesn’t stop easily.

The affected lymphocytes or leukaemia cells fill up the bone marrow so it is harder for your body to make normal infection fighting white blood cells. This means you are more likely to get an infection and find it harder to recover. Patients typically will have a low grade fever/slightly raised temperature and ongoing skin, chest or sinus infections.
The leukaemic B-cells that are made when someone has CLL are made more quickly than normal and don’t mature enough to do their job properly. B-cells normally make antibodies that stick to invading organisms and mark them for destruction. The antibodies leukaemic cells produce are not as good at doing their job and also interfere with the action of antibodies from unaffected cells. This further affects a person’s ability to fight infections.

If the disease had become very advanced there may be bone pain from the large numbers of cells occupying the bone marrow.

Are there any known risks for developing CLL?

We don’t know what causes these changes but there are a few factors that increase the risk of developing CLL. The clearest is getting older, and this is true for many cancers. Many things we are exposed to in life, sunlight, radiation, certain chemicals and the normal things that happen in cells cause damage to our DNA. Our cells have the ability to repair much of this damage, but over time damage can build up and cause changes that lead to cancer developing.

Being exposed to certain chemicals is known to increase the risk. The main one is benzene, a chemical used in manufacturing plastics, detergents, paints, pesticides as well as being in petrol and petroleum products. As it is a known carcinogen (cancer causing chemical) there are now rules limiting how much benzene you can be exposed to at work.

There is also a genetic link to CLL. Around 1 in 10 people who develop CLL will have a family member who either had CLL or one of a number of other conditions which affect the white blood cells. We don’t know what genes are involved in this inherited tendency, so there are no tests available to confirm whether someone is at higher risk of developing CLL.

What happens genetically?

Researchers studying what genes are affected in CLL have seen many different mutations or changes in the DNA of affected cells. There is no single change that is associated with CLL, some are more common than others. This is very common in cancer. Cells that have escaped the normal controls on their behaviour are more likely to add further mutations that help them survive.

The gene and chromosome mutations in CLL can be used to make a prognosis, the most likely path the disease will take. Having particular changes to genes or chromosomes can be associated with the CLL being more or less aggressive and can be used to decide on the most effective treatments.

Chromosomal changes involve large amounts of DNA being deleted (missing) or present as extra copies. There are four chromosomal changes to chromosomes that are associated with CLL. These are:

Del(13q) a deletion on chromosome number 13 found in over half of patients and is associated with a slow growing disease.
Del(11q) a deletion on chromosome 11 found in 10% of newly diagnosed patients but over 20% of patients who develop more aggressive disease.
Del(17p) a deletion in chromosome 17 that includes the important TP53 gene. This gene produces the p53 protein which has been called the “guardian of the genome” because of its role in repairing damage that occurs to our DNA. This mutation is associated with poorer outcomes.
Trisomy 12 has three copies of chromosome 12. This is seen in 10-20 % of patients and is linked to medium to poor outcomes depending on other factors.

Doctors will test for these changes using a technique called FISH where special dyes show up changes under the microscope..

Other genetic changes are smaller and can be found either by DNA sequencing (reading the sequence of letters in your DNA) or looking for the changes in particular proteins they produce.

TP53 may be mutated without the larger deletion on chromosome 17
Notch1 mutations are found in 10–15% and are linked with a greater chance of CLL developing into a diffuse large B-cell lymphoma (Richters transformation)
IGHV mutations affect the antibodies produced by the B-cells. These mutations are linked to less aggressive disease.
SF3B1 mutations affect how cells make certain proteins. Mutations here are linked to faster disease progression.
ZAP70 is a protein that sends messages within cells. Mutations that increase the amount of ZAP are associated with worse disease.

What are the current treatment options for CLL?

CLL is considered to be Incurable, the aim of treatment is to achieve remission, where there is no sign of active disease, or to manage symptoms such as breathlessness or pain.

The choice of treatment will depend on the stage of disease, your overall health and the results of genetic tests that will help to identify the most appropriate treatment for your condition.

Wait and watch:

If CLL is at an early stage, there are no symptoms and there is a low risk of the disease progressing, doctors will advise that no treatment is needed. Instead there will be a period of “wait and watch”, sometimes called active surveillance. This means that patients will be checked regularly, looking for changes in the size of their spleen or lymph nodes. Blood will be checked for changes in the numbers of lymphocytes, red blood cells and platelets.

Studies have found that there is no benefit to patients in treating early CLL, but there will still be the side effects of treatment to consider. Some people may never need treatment as their CLL never gets worse and doesn’t cause any symptoms.

This has the potential to be an anxious time when most people with cancer begin treatment immediately. The various support sites and groups (links below) have video and written resources as well as patient communities to help maintain physical and emotional wellbeing as well as further information about CLL.

Surgery:

This is not the first choice of treatment for CLL. Very occasionally the spleen may be removed if it has become very enlarged and is causing problems.

If the symptoms or clinical tests suggest that it is necessary to start treating CLL, the exact choice will depend on which mutations have been found in your cancer. The most important of these is TP53. If TP53 has a mutation, conventional chemotherapy won’t work as well so targeted therapy will be used in preference. Immunotherapy can still be used alongside targeted therapy.

Chemotherapy/chemoimmunotherapy:

Chemotherapy is often given with immunotherapy drugs at the same time, although the combination depends on how well a patient is.

Fludarabine, cyclophosphamide, chlorambucil and bendamustine are the main chemotherapy drugs used for CLL. They act by interfering with the DNA in the cells so that they can’t divide properly and will eventually die.

There are several types of immunotherapy that are used in cancer. For CLL there are two drugs, obinutuzumab and rituximab that work in the same way. They are both monoclonal antibodies. Antibodies are molecules made by your immune system that normally stick to the surface of invading cells like bacteria to mark them out for destruction by the rest of the immune system. Monoclonal simply means that they are identical. These antibodies have been changed in a lab so they stick to a molecule called CD20 on the surface of B-cells. This is not something that your normal antibodies would do. Once they stick they mark the B-cells for destruction. These drugs will affect any B-cells, including healthy ones so treatment won’t start until any infections are under control. As there are fewer white blood cells there is also a risk of getting an infection afterwards.

Targeted (biological) therapy:

By studying cancer cells and comparing them with normal cells we have discovered many differences that can be used to create new drugs that exploit these differences.
Because B-cells are only needed in large numbers when you have an infection the ones that are always present need to be activated to become fully mature and make copies of themselves. To do this, messages are received by the cells and sent to the nucleus to start the activation process. In CLL the messaging system gets stuck at “on”. Drugs such as acalabrutinib, ibrutinib and idelalisib act by binding to important parts of the messaging system (called Btk and PI3K) and stopping the activation message.

Venetoclax works differently. Normal cells will respond to dangerous changes that could lead to cancer by activating a self-destruct mechanism called apoptosis. This obviously needs to be carefully controlled so cells have a mechanism to stop it happening. In CLL this gets ramped up so the cancer cells ignore the self-destruct signal. Venetoclax switches it off so the cancer cells are more likely to die.

Management of symptoms (supportive therapy):

These treatments are for the consequences of CLL. Because the immune system is less effective due to both the CLL and many of the treatments given, patients are more likely to get infections and are less likely to be able to get rid of them without help. Any infections can be treated with antibiotics (for bacteria) antivirals (for virus infections) or antifungals for (fungal infections). Vaccines will protect against getting, or having a serious infection of flu, COVID or pneumonia.

Other treatments help reduce the impact of CLL on the production of blood cells. Blood transfusions will reduce anaemia and platelet transfusions will allow blood to clot normally. It is not usually possible to give someone extra white cells, but chemicals called growth factors can be given that stimulate your bone marrow to make more neutrophils (the other “family” of white blood cells). Finally, you can be given antibodies from donated blood to boost the ability to fight infection.

What are the current clinical trials for CLL?

Current clinical trials in the UK are focussed on new combinations and dosing regimes for the currently available drugs as well as a few relatively new drugs that target either the Btk or PI3k messaging systems. Although it might not seem sensible to develop more drugs that do the same thing as ibrutinib and idelalisib, similar alternatives can have different side effects, or be better tolerated by different people. They can also be more effective or sometimes get round problems caused by drug resistance.

These newer drugs are LOXO-305(Pirtobrutinib), Umbralisib, KRT-232 (Navtemadlin) and TL895.

There are also trials of further antibody medicines.

NVG-11: NVG-111 is a bispecific antibody drug, having two “arms”, one arm attaches to a substance on cancer cells called ROR1, the other arm attaches to the body’s immune cells directing them to kill the cancer cells.

JNJ-75348780: Is another antibody drug which also has two “arms” , but these attach to different parts of the cancer cells and other immune system cells.

CD19CAT-41BBZ CAR T-cells: This is a trial of new form of CAR-T cell therapy.