Chronic Lymphocytic Leukaemia (CLL)

Chronic Lymphocytic Leukaemia (CLL) is a type of blood cancer that occurs when your body makes too many abnormal white blood cells.

Blood cells are formed in the bone marrow, which is the spongy tissue found inside bones. Blood-forming stem cells divide to produce either more stem cells or immature cells that become mature blood cells over time. A blood stem cell may become a myeloid stem cell or a lymphoid stem cell. In CLL it affects the lymphoid stem cells.

A lymphoid stem cell becomes a lymphoblast cell and then one of three types of lymphocytes (white blood cells):

  • B lymphocytes that make antibodies to help fight infection.
  • T lymphocytes that help B lymphocytes make the antibodies that help fight infection.
  • Natural killer cells that attack cancer cells and viruses.

In CLL the bone marrow produces too many B lymphocytes which are not fully developed (immature). These cells fill up the bone marrow, preventing it from producing normal, healthy cells.

CLL progresses slowly but, although it can be treated, it is not usually possible to cure chronic leukaemia with standard treatments.

Watch: Professor Chris Fegan explains what CLL is. Thank you to VJHemOnc for the footage.

What causes CLL?

In most cases of CLL there is no obvious cause but it is important to understand that:

  • It is not a condition which can be caught from someone else (contagious)
  • It is not passed on from a parent to a child (inherited)

Risk factors:

  • Age – like most forms of cancer, CLL is more common in older people
  • Being male – CLL affects more males more than females
  • Genes – CLL is not an inherited disease but it is slightly more common in close relatives of patients. The risk is very small and this is not a cause for concern. There is no screening test for CLL
  • Environment – It is generally thought that radiation does not increase the risk of developing CLL. There is some evidence that exposure to agricultural chemicals may increase the risk of CLL but this is not a definite cause
  • Monoclonal B lymphocytosis (MBL) – Many older people have a condition called MBL in which they have increased numbers of identical (clonal) lymphocytes in their blood. Although most people with MBL will never become ill, it is thought that everyone who develops CLL has previously had MBL

Signs and symptoms of CLL

Many patients with CLL have no symptoms at the time they are diagnosed. Their CLL is discovered following a blood test as part of a routine check-up or for another condition. There are no specific signs or symptoms which would allow a diagnosis of CLL to be made. The most common signs and symptoms are caused by the bone marrow being unable to produce enough normal blood cells.

Other signs and symptoms which may occur include:

  • Swollen liver, spleen or lymph nodes (glands)
  • Some patients with CLL develop autoimmune conditions, in which the body produces antibodies against its own tissues. This may include rheumatoid conditions or autoimmune destruction of red cells or platelets


CLL is often a chance finding during when a blood sample has been taken for another condition or as part of a routine check-up. Most patients with CLL will have bone marrow samples taken to confirm the diagnosis and to help to determine exactly what type of leukaemia a patient has. A bone marrow sample may not be necessary if treatment is not being started, but it is often valuable to have an initial sample to compare with later samples. More specialised tests are often done at the same time. Usually, a chest x-ray will be taken and also scans, to look for swollen lymph nodes, or other affected sites. Blood samples will be taken to test for any problems with the liver, kidneys or other organs. Some blood tests and scans will be repeated to check for the response to treatment and any complications. Other tests are usually only done at diagnosis. Other tests which may be done include:

  • X-rays, ultrasound or scans (CT or MRI) – To monitor impact on organs of the body

Blood tests and bone marrow samples may be repeated during treatment to monitor response. Occasionally, it may not be clear whether the diagnosis is CLL or another condition called small lymphocytic leukaemia (SLL) as they are very similar in presentation and the diagnosis may even change. This is not a cause for concern because the two diseases are treated in the same way.


CLL is the only form of leukaemia in which staging is routinely used. There are two staging systems called the Rai and Binet systems. In the Rai system (mainly used in America) there are five stages from I to IV, with IV being the most advanced. The Binet system is most common in Europe; it runs from A to C, with C being the most advanced stage. The staging systems may be used in treatment planning.

Watch and Wait

Watch and wait refers to the time when you have no active treatment following a blood cancer diagnosis.
You will be actively monitored; how often will depend on how stable your condition is. You will attend regular hospital visits or see your GP where you will have regular blood tests which will be reviewed by your GP, consultant haematologist or specialist. They will also ask how you are feeling, monitor any symptoms you may be experiencing and check for any changes or developments in your cancer. Some patients may never need treatment for their blood cancer because it does not progress to a stage where treatment is required. It is important to know that even though you are on a watch and wait policy, you will still be receiving all the support you need. This form of management is chosen because the condition is either progressing very slowly and remains stable or you may feel well and have no symptoms from your cancer. Treating it would only make you feel more unwell as a result of the cancer drugs.

Leukaemia Care has produced a booklet on information about watch and wait which can be found here. There is also a new document about Living well with Watch and Wait, which can be found here.

Treatment of CLL

Chemotherapy Chemotherapy is the use of anti-cancer (cytotoxic) drugs to destroy cancer cells. It has a very high success rate in the treatment of CLL. It does not cure the disease but it gives good control for most patients. Chemotherapy will also damage some normal cells as it is toxic to all living cells, which means that there are side effects. Examples of chemotherapy agents include: Purine analogues Fludarabine and Bendamustine are types of drugs called purine analogue. Purine analogues affect your body’s immune system and may reduce your blood counts by affecting the bone marrow’s production of normal blood cells. While you are being treated with Fludarabine or Bendamustine, you will be carefully watched for any sign of infection. You may be given drugs to prevent some virus and fungal infections if your lymphocyte count is very low. If this applies to you then you will be given detailed information. Your haematologist or clinical nurse specialist will explain any special precautions you may need to take and will answer all your questions. Fludarabine may cause nausea and/or vomiting but this can usually be controlled by taking drugs called anti-emetics at the same time. Alkylating agents Alkylating agents include cyclophosphamide or Chlorambucil. They are a group of anti-cancer drugs which damage DNA and kill CLL cells. For some patients, who are less fit or who have poor kidney function, alkylating agents may be given alone but most patients have the addition of a monoclonal antibody such as Rituximab, Ofatumumab or Obinutuzumab as the combination works better than Chloranbucil therapy alone.

Targeted Therapy

Treatments have been developed that target leukaemia cells more precisely than does chemotherapy, which reduces the effect of treatment on healthy cells and hence side effects. The main types of targeted therapies include: Immunotherapy Immunotherapy is used to ‘wake up’ your own immune system to fight the cancer. One immunotherapy technique uses monoclonal antibodies to attack and destroy CLL cells. Monoclonal antibodies are drugs that recognise, target and stick to particular proteins on the surface of cancer cells. They can stimulate the body’s immune system to destroy these cells. The most common target for immunotherapy is a protein called CD20, which is found on nearly all CLL cells. A drug called rituximab is the most commonly used anti-CD20 treatment. Other more recently available anti-CD20 drugs include Ofatumumab and Obinutuzumab.

Small molecule Inhibitors

B-cell receptor inhibitors Like normal B-lymphocytes, CLL cells have proteins on the outside called B-cell receptors (BCRs). When a protein binds to a BCR it sends the cell a signal to divide. Unfortunately, CLL cells are particularly sensitive to BCR signals, which means they divide and produce more CLL cells. One way to stop this is to design a BCR inhibitor, which is a drug which blocks, or inhibits, the BCR signal. There are two oral (taken by mouth) drugs currently being used which inhibit the BCR pathway:

  • Ibrutinib, which blocks a protein called Bruton’s Tyrosine Kinase (BTK)
  • Idelalisib, which blocks a different protein called phosphatidylinositol 3-kinase (PI3K)CLL cells are more dependent on these proteins than normal cells so they are vulnerable to Ibrutinib and to idelalisib. Because of the way they work, these drugs are just as effective when a patient has a 17p deletion or a TP53 mutation. This is an important option for patients with TP53 deficient CLL because normal chemotherapy is not successful in this form of the disease and immunotherapy by itself is not very effective.Both Ibrutinib and Idelalisib interfere with BCR signalling by triggering apoptosis in the  CLL cells. Apoptosis is a natural process in which cells which are worn-out, or no longer needed by the body trigger a ‘suicide’ pathway. Many anti-cancer drugs work by triggering apoptosis but cancer cells, including CLL cells, find ways to block apoptosis. These two drugs target anti- apoptosis pathways and, despite the name, are designed to switch apoptosis back on. This means that anti-cancer drugs such as Ibrutinib and idelalisib are more able to kill CLL cells at lower doses, which means fewer side effects.

BCL-2 inhibitors

Cancer cells accumulate by switching off the process which enables cells to die- so called apoptosis. CLL cells have a very complex process for switching off apoptosis including high levels of proteins including BCL-2 and MCL-1. Venetoclax is a first in class BCL-2 inhibitor and has been shown to be effective often when other treatments fail and possibly even more effective when used in combination with chemotherapy, immunotherapy and other small molecule inhibitors. So potent is Venetoclax that you may be required to be admitted overnight to start treatment.

Immunomodulatory drugs

Also known as IMiDs, immunomodulatory drugs modify, or modulate, the way in which the immune system behaves. They have been widely used for treatment of other forms of blood cancer, and are now being studied for use in treatment of CLL. One of the advantages of IMiDs is that they do not kill all dividing cells, which means that, although they do have side effects, they are not the same as other anti- cancer drugs. This is called non-overlapping toxicity and, for patients, it means better cancer killing without more severe side effects.

Chimeric antigen receptor T cells (CAR-T cells)

Our immune system is able to kill cancer cells. However, to have developed CLL the immune system must have failed. In CAR-T cell therapy a CLL patients own T cells are removed and then manipulated in a laboratory to make them better able to kill CLL cells. They are then infused back into the patient. At present CAR-T cell therapy is not widely available and just how effective it will be in CLL is still being assessed.

Stem cell transplant

A stem cell transplant involves the use of high-dose treatment to kill as many as possible of the leukaemia cells. This also destroys the bone marrow’s ability to make new blood cells, so the patient is given healthy stem cells from a donor. With an allogeneic transplant, there is a chance of life-threatening side- effects because donor cells can attack your healthy tissues in a graft-versus-host effect. This option is therefore only suitable for a small number of patients, with very aggressive disease who are fit enough to be able to tolerate the treatment, because the risks associated with a stem cell transplant aren’t justified for patients with a slowly progressing disease like CLL. If this might be an option for you, then your haematologist will discuss it with you and give you a chance to ask questions. However, for most patients the risk of a transplant is greater than the benefit. There are now many alternatives to stem cell transplantation and the use of this approach is decreasing with the introduction of all the new agents.


This treatment uses high-energy rays, usually x-rays, to destroy the cancer cells. Radiotherapy is a usually given using a large external machine that directs beams of radiation at the cancer. Most patients with CLL don’t get treated with radiotherapy. However, if your spleen or specific groups of lymph nodes are particularly swollen or symptomatic, radiation may help shrink them. The procedure itself is painless, but common side effects of radiation therapy may include redness in the treated area, fatigue, nausea, and vomiting.


On very rare occasions, selected patients have an operation to remove the spleen (splenectomy). CLL can cause the spleen to become very large, so that it presses on nearby organs and causes discomfort or pain. Surgery to remove the spleen may be an option if radiotherapy and chemotherapy fail to reduce its size. Your spleen may be removed by keyhole (laparoscopic) surgery or by a cut made just under your ribs in the middle or left side of your abdomen (open surgery). People tend to live a full life without a spleen, however, risk of infection increases. Splenectomy may also be required if the standard treatments for Auto- Immune Haemolytic Anaemia are inadequate.

Treatment pathways

Initial treatment

If you begin to suffer from symptoms, or if your lymph glands cause problems or the normal blood counts start to fall, you may need to start treatment. The very first treatment you have is called initial, or first-line, treatment.

There are many different first- line treatment options for CLL patients. The choice of treatment will depend on the stage of your disease, your age and general fitness, as well as on whether you carry prognostic genetic mutations, del17p or TP53. The most common first-line options are:


Currently, the first-line treatments for CLL are the combinations of chemotherapies. These are:

  • Fludarabine, cyclophosphamide and rituximab (often abbreviated to FCR)
  • Bendamustine and rituximab (often abbreviated to BR)

Over 90% of patients respond to FCR treatment; however, it is best given to young (aged 65 years or under), fit patients with previously-untreated CLL, as FCR is an intensive chemoimmunotherapy which carries the potential for more severe side effects.

BR is established as the treatment of choice for elderly patients and patients with kidney disease who cannot tolerate FCR.

Alternative first-line options for more elderly or less fit patients include:

  • Chlorambucil with obinutuzumab or ofatumumab
  • B-cell receptor inhibitors such as idelalisib or ibrutinib (ibrutinib has shown efficacy in patients with relapsed CLL and as first-line therapy for previously untreated CLL patients with 17p deletion or TP53 mutation)
  • Clinical trials with some of the newly developed treatments may be available. These include cyclin-dependent kinase inhibitors, histone deacetylase inhibitors and chimeric antigen receptor (CAR) T-cell therapy

Targeted therapy

BCR and BCL-2 inhibitors are also initial treatment options for adult patients with a 17p deletion or TP53 mutation as chemoimmunotherapy is not suitable for this group of patients. Options include:

  • Ibrutinib
  • Idelalisib in combination with rituximab 
  • Venetoclax

Second-line Treatment

Some patients may be refractory to initial treatment or experience a relapse.

Refractory CLL occurs when the cancer has not responded to first-line treatment. A relapse is when a patient initially responds to leukaemia therapy but, after six months or more, response stops. This is also sometimes called

a recurrence. The majority of treatment-responsive patients do eventually relapse. Most patients with relapsed or refractory CLL will need second-line therapy (treatment other than the type used the first time around).

Second-line drug regimens may include:

  • FCR
  • Chlorambucil with a monoclonal antibody (if the patient only received chlorambucil on its own as first line therapy)
  • Ibrutinib
  • Venetoclax
  • Venetoclax with rituximab for patients who have had at least one previous line of treatment
  • Idelalisib in combination with rituximab or ofatumumab

Questions to ask your doctor about CLL

We understand going through a blood cancer through journey can be difficult. It may help to talk to a close friend or relative about how you are feeling. Here are some questions that may be useful to ask your doctor.

  • How would I know if I had CLL?
  • What tests will I need to have?
  • What will the tests show?
  • How long will the results take?
  • How rare is CLL?
  • What sort of treatment will I need?
  • How long will my treatment last?
  • What will the side effects be?
  • Is there anything I should or shouldn’t eat?
  • Will I be able to go back to work?
  • Where can I get help with claiming benefits and grants?
  • Where can I get help dealing with my feelings?

Further downloads

We have free patient information available for CLL patients. You can download the booklets on our information pages here. Alternatively, you can have the information delivered free of charge by requesting it through our resources page. 

Patient stories You can watch Mike’s CLL story above

Further support for CLL

Online support There is also a busy CLL forum which is moderated by CLLSA. You can find it on HealthUnlocked. There is also a general leukaemia support group on Facebook which is ran by Leukaemia Care. To request to join, click here. Other CLL charities The CLLSA is a dedicated support charity for CLL patients. You can find out more information on CLLSA on their website   Facebook Group Leukaemia Care is trialling a closed Facebook group for anybody affected by CLL. You can request to join here. Buddy support Leukaemia Care also have a buddy support scheme where you can be matched with another person who has a similar diagnosis and you can gain support from one another by phone, email or meeting at support groups. Find out more about our buddy scheme on its dedicated page. 

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  • Published: October 2019
  • Review date: October 2022