Chronic myeloid leukaemia (CML) is a blood cancer which affects the white blood cells known as myeloid cells.
People with CML produce too many granulocytes which is why CML used to be referred to as chronic granulocytic leukaemia (CGL). In the early stages of the disease, too many mature granulocytes are produced. If left untreated, more immature cells (blast cells) are produced and populate the blood and bone marrow. The granulocytes may not be fully developed, immature and poor functioning. Over time, these abnormal cells will accumulate and begin to fill up the bone marrow, preventing it from producing healthy blood cells.
Stages of CML
CML typically has three stages:
- Chronic phase – Many patients are diagnosed in this stage and it is where the body produces too many granulocytes. Symptoms, if any are noticed at all, may be mild and vague and may include tiredness, weight loss and a slightly enlarged spleen. The number of platelets and white blood cells may increase.
- Accelerated phase – If left untreated, CML will progress to the accelerated phase. Symptoms will be more noticeable, and you may experience increased fatigue and further weight loss as well as painful feelings under your ribs from an enlarged spleen.
- Blast phase – In the blast phase, the leukaemia will become more aggressive and develop quicker. Symptoms may be more troublesome and cause you to feel quite unwell.
The Philadelphia chromosome
In almost all cases, CML cells have an abnormality called the Philadelphia chromosome. This is something that has developed in your bone marrow after birth and you cannot inherit this chromosome or pass it onto your children.
All of the chromosomes in the body are made up of DNA. The DNA is arranged in sections called genes and there are 23 pairs of chromosomes in each cell in your body.
The Philadelphia chromosome is formed when the ABL gene on chromosome 9 and the BCR gene on chromosome 22 swap part of their DNA. The swap-over, or translocation, forms an abnormal ‘fusion’ gene called BCR-ABL. The BCR-ABL gene produces a new enzyme called a tyrosine kinase, which means the body’s normal signals to the bone marrow to stop producing white blood cells is ignored by the bone marrow, leading to too many cells.
The BCR-ABL gene is the target for the newest forms of treatment called tyrosine kinase inhibitors (TKIs). Only about 1 in 20 CML patients do not have the BCR-ABL gene – this is called atypical CML. If you have atypical CML, then your specialist will explain what this means and discuss treatment options with you.
Almost all patients who are diagnosed with CML will be treated with a type of drug called a tyrosine kinase inhibitor (TKI). These drugs block the harmful effect of BCR-ABL and stop CML from progressing.
Kris is a CML patient. You can watch his story above.
Causes of CML
In most cases, there is no obvious cause of CML but there are certain things which are known to be linked to a high chance of developing this disease.
- Exposure to radiation – this is the only clearly established risk factor.
- Smoking – This is not a definite risk factor, but some studies suggest a weak link.
- Age – CML is more common in older people, aged 60 and above.
- Gender – CML is slightly more common in men than women.
Studies have shown no increased risk of CML in relatives of patients, so it isn’t deemed to be hereditary and it cannot be passed onto your children.
Some patients blame themselves, or someone else, for their diagnosis. However, it is not likely that anything you have done, or not done, has caused your CML.
Signs and symptoms of CML
Many patients with CML have no symptoms at the time they are diagnosed. Their CML 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 CML to be made. The most common signs and symptoms are caused by the bone marrow being unable to produce enough normal blood cells.
- Anaemia – due to lack of red blood cells
- Weakness, tiredness, shortness of breath, light-headedness, palpitations
- Infections – due to lack of normal white blood cells
- Infections are more frequent, more severe and last longer
- Fever, malaise (general feeling of illness) and sweats
- Purpura (small bruises in skin), nosebleeds, bleeding gums
- Bleeding and bruising – due to lack of platelets
Other signs and symptoms which may occur include:
- Swollen spleen (in about half of all patients) or less commonly, swollen liver.
If CML is suspected, you will have a set of tests to confirm the diagnosis. If you are diagnosed with CML, you will also have further tests to determine the right treatment for your cancer.
Tests to confirm the diagnosis of CML may include:
- Full Blood Count (FBC) – this is a simple blood test which measures the number of red cells, white cells and platelets in the blood. In CML, you’ll have more white cells than normal, and your platelets may be higher, too.
- Polymerase chain reaction (PCR) test – An important test in the diagnosis of CML is the PCR test which measures the amount of CML in the blood. The PCR test will be done throughout your treatment to monitor your response to treatment and whether the treatment needs to be changed.
- Cytogenetics – Cytogenetics is the study of gene changes and investigates the genetic differences between ALL cells and normal cells. Cytogenetic results are important for the WHO classification of ALL and for risk classification.
- Bone marrow samples – Some patients will have a bone marrow sample taken, where a small amount of bone marrow is taken from the hip bone using a fine needle (an aspirate), to look at the cells. You may also have a sample of bone marrow taken from the core using a larger needle (a trephine) to look at the structure of the bone marrow. This is normally done under local anaesthetic.
Many of the tests will be repeated throughout your treatment to check for the response to treatment and any complications, while some may only be done at diagnosis.
Staging and classification
Following the diagnosis of CML, your doctor will do some tests to stage your cancer which will help them to determine the best treatment option for you. Your doctor will want to find out if your CML is in either the chronic, accelerated or blast phase (or blast crisis). The stage of your CML will also be able to better predict your prognosis (outlook).
Most patients are diagnosed at the chronic phase and, with revolutionary treatments available now, a very high proportion of patients do not progress beyond that phase and their CML does not affect their overall life expectancy. A small number of patients are at accelerated or blast phase CML when they are diagnosed. The phase is defined on the basis of signs and symptoms and on the results of blood and bone marrow tests.
There are three risk score systems used in classifying CML, called the Sokal, Hasford and EUTOS systems. These look at your age, the size of your spleen and your blood count results. Risk scores are much less important with modern treatment, regardless of risk score.
What happens next?
As with all cancers, the treatment choice of CML will depend on your general health, your age, level of fitness and the phase of the illness.
Almost all patients with CML start treatment soon after diagnosis. The exceptions would be very elderly or frail patients who may be too unfit to tolerate treatment.
You can refuse treatment at any time, but it is important that you clearly understand what might happen in this case. However, you can’t start treatment if your haematologist doesn’t think you need to, but this is rare for CML. If you do not agree with them, you can ask for a second opinion at any time. As far as possible, all decisions about treatment will take your wishes in to account.
Treatment of CML
CML is not a curable disease, but a new class of drugs called tyrosine kinase inhibitors (TKI), has transformed the treatment of CML, meaning many patients will have a normal life span with a good quality of life after diagnosis. Without treatment, CML will always be fatal.
A stem cell transplant can cure the disease in a small number of younger and/or fitter patients but with TKIs having a good success rate, bone marrow or stem cell transplants to treat CML are fairly rare.
Treatment options for CML
Once your diagnosis is confirmed, you will be given the chance to discuss treatment options and detailed information on your treatment plan before it starts. The side effects of treatment vary between different types of treatment and different patients.
The aim of treatment for CML is to:
- Reduce the amount of leukaemia in the blood to a level where it does not cause any symptoms
- Achieve normal levels of blood cells
- Reduce the risk of it progressing to a more aggressive form
The three main ways in which CML is treated are:
- Targeted therapy – Treatments which target the abnormal protein (tyrosine kinase) produced by the BCR-ABL gene. Targeted therapy using tyrosine kinase inhibitors (TKIs) is the usual first choice of treatment for CML.
- Chemotherapy – the use of anti-cancer (cytotoxic) drugs to destroy or damage leukaemia cells. It‘s most likely to be used if the TKIs aren’t effective or they cause severe side effects. The chemotherapy drug is that is used is called hydroxycarbamide and comes in a tablet form. Chemotherapy is not currently widely used in treatment of CML.
- Stem cell transplant – A stem cell transplant involves the use of high dose chemotherapy to kill as many leukaemia cells as possible. This option is only suitable for a small number of CML patients who are fit enough and have a very well-matched donor. Stem cell transplants are rarely performed for CML patients and normally only done if a patient hasn’t responded to TKIs.
If a stem cell transplant is an option for you, then your haematologist will discuss it with you and give you a chance to ask questions. This is generally considered the only potential cure for CML, but for most patients, the risk of a transplant is greater than the benefit. This is especially true given the very good results of treatment with TKIs.
Tyrosine kinase inhibitors (TKIs)
Targeted therapy using TKIs is now the most widely used treatment for CML. This treatment has transformed the outlook for CML patients. Before TKIs were introduced, the average survival after diagnosis was about seven years. Now, it is expected that many, probably most, CML patients will have a good quality of life and a normal or near-normal life expectancy. All of the currently available TKIs are taken by mouth (orally), which most patients prefer to any type of injection.
There are five TKIs used in the UK:
- First generation – imatinib (Glivec™)
- Second generation – nilotinib (Tasigna™), dasatinib (Sprycel™) and bosutinib (Bosulif™)
- Third generation – ponatinib (Iclusig™)
The decision about what TKI is suitable depends on the effectiveness of the drug in certain situations, likely side effects, personal preference over how the drug is taken and what the drug is licensed and funded for. You should discuss this with your specialist when considering your treatment options.
Imatinib is called a first generation TKI because it was the first BCR-ABL TKI to be used in the treatment of CML. It is taken orally, once a day, after eating. Although imatinib works well for most patients, and is still the most popular first choice, some patients either do not have good response, or their response does not last, and some cannot tolerate the side effects of imatinib. For these reasons, other similar drugs were developed, which are referred to as either second or third generation.
Two of the second generation TKIs, called nilotinib and dasatinib are licensed for use in the UK for treatment of newly diagnosed CML patients and those that have tried another TKI and either it wasn’t tolerated or didn’t work. Bosutinib has been licensed for use in the UK when previously treated with one or more of the other TKIs and for whom imatinib, nilotinib and dasatinib are not considered appropriate treatment options.
The main reasons the older drug, imatinib, remains the most popular for initial treatment are due to the extensive experience in using this drug and the fact that in more than 14 years of use, no severe or unexpected side effects have been seen.
Fortunately, it is usually clear within three to six months of starting treatment if a TKI is going to be successful and, if not, patients can switch to another TKI which is usually effective. The choice of which of the three second generation TKIs to use is based on testing for changes (mutations) in the BCR-ABL protein and on the known side effects of the different drugs. Certain mutations are known to respond better to some drugs than others and, if a patient has been troubled by side effects, it is possible to choose another TKI which is unlikely to cause the same side effects.
There is evidence that some patients may be able to stop taking TKIs, or at least reduce the amount of TKI they are taking, without their CML returning. In patients who do stop treatment under medical advice, and whose CML does return, this usually responds well to re-treatment. At present, there is not enough evidence to know which patients can safely stop treatment and you should never stop or reduce your treatment unless your doctor has advised you to. Your doctor may discuss stopping your TKI if you have been having problems with it or if you are offered a clinical trial.
Side effects of TKIs
All treatments can cause side effects, however, because TKIs are much more targeted, unlike other cancer treatments such as chemotherapy, the side effects are much less severe.
However, you may notice some side effects which may be connected to the TKI you are taking. Some side effects are common to all TKIs, others are more specific to a particular type.
Common side effects include:
- Muscle/joint pain
- Abdominal pain
- Oedema (fluid retention, such as swollen ankles)
- Pleural effusion liquid (fluid around the lungs)
- Blocked arteries
- Abnormal liver function test results
- Raised glucose levels
- Neutropenia (low white blood cells)
- Low platelets/abnormal platelet function
Remember to mention any side effects you’re experiencing to your healthcare team as they will be able to help manage them.
Nilotinib and food
Nilotinib should be taken on an empty stomach with a large glass of water. It’s important you don’t eat for two hours before or for one hour after taking nilotinib, as this affects the absorption rate of the drug and may increase the side effects. Nilotinib is usually taken twice a day, with 12 hours between each dose.
It’s also important that you don’t drink grapefruit juice or eat grapefruit while you’re taking nilotinib as this can increase the side effects.
Response to treatment
It is really important that you attend appointments with your consultant as they will be measuring your response to your treatment, usually by measuring the amount of CML in the blood or marrow. When you first start treatment with a TKI you will have regular blood tests to make sure that the level of CML is reducing fast enough. Once you are settled on the treatment, you only need to have your blood monitored every three to six months. If the level of the CML doesn’t fall quickly enough or starts to rise, then you may need to change to another one of the TKIs. The important thing to remember is that the majority of people respond well to the first TKI and never need it changed.
The level of CML is usually measured with blood tests but occasionally require bone marrow tests. The amount of CML in the blood may be described as how easy it is to spot it (how detailed a test you need to detect it), the percentage of white cells in the blood which is caused by the CML or the decrease in the amount of CML from the start of treatment.
Complete haematological response (CHR)
- This means that the blood count has become normal.
- If treatment is stopped, it is likely the white cells count would increase and the CML will soon return.
- This is usually the first improvement that is seen during treatment and the easiest to measure as it only requires a full blood count.
- This involves a test to measure the number of cells which contain the Philadelphia chromosome.
- Fewer than 35% of cells with the Philadelphia chromosome is called a partial cytogenetic response (PCyR). Ideally, this should happen by three months of treatment.
- No Philadelphia chromosome detected is a complete cytogenetic response (CCyR), ideally, this should happen by six months of treatment.
- The next aim of treatment after a cytogenetic response is to see the levels of CML fall even further. This requires a polymerase chain reaction (PCR) test which is an even more sensitive test that is able to detect one leukaemia cell in up to one million normal blood cells. This test measures the percentage of cells in the blood which are due to the CML.
- Major molecular response is where less than 0.1% of the white cells are due to the CML, this currently is the aim of treatment and should ideally be achieved by 12 months.
- Complete molecular response is where no detectable CML by the PCR test.
A log reduction score has been developed to determine how far the level of CML has fallen since the start of treatment from a standardised baseline value of 100%. Log reduction is a mathematical term used to show the relative number of cells reduced ‘on’ something. When the term log reduction is used in CML, it refers to the reduction of CML, or specifically BCR-ABL. The numbers are produced by a PCR test.
A 1 log reduction means the number of CML cells is 10 times smaller (since start of treatment); a 2-log reduction means the number of CML cells is 100 times smaller and a 3-log reduction means the number of CML cells is 1000 times smaller.
This will hopefully make it easier to compare results between different laboratories.
The response to treatment is defined as ‘Optimal’ where no change to treatment is required, ‘Warning’ where close monitoring is required, but most people eventually respond, and ‘Failure’ where a different TKI should be considered.
If the levels of a patient’s CML starts to rise, then t is described as ‘loss of response’.
New treatments and treatments on the horizon
The main options being considered for new approaches to CML, involve new ways of using older drugs:
- Interferon alpha – Interferons are proteins that occur naturally in our bodies and help us fight infection. Interferon alpha was one drug used for CML before TKIs were developed. The main disadvantages of interferon alpha were that it was given as an injection under the skin and came with unpleasant side effects. One key use of interferon alpha is in women who have CML and are pregnant. There is evidence that TKIs can cause harm to the developing baby if given to a pregnant woman, but it is considered safe to use interferon alpha in the later stages of pregnancy (the second and third trimesters).
- Re-use of older drugs – A number of drugs, which were used to treat CML before the introduction of TKIs, may offer benefit in treating patients who do not respond to TKI treatment, or who have problems with the side effects of TKIs. At present it is not clear which, if any, of these drugs will enter routine use for treatment of CML. If any are re-introduced, they are likely to be used only for selected patients. The response to TKI treatment is so good that it is very unlikely these will ever be replaced in treatment of CML.
Questions to ask your doctor about CML
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 CML?
- What tests will I need to have?
- What will the tests show?
- How long will the results take?
- How rare is CML?
- 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?
We have free patient information available for CML 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.
Support for CML patients
A Facebook group exists called CML UK, for CML patients and carers to chat on an informal basis, ask questions and support each other.
The group has been set up by Nigel Deekes, a CML patients and patient advocate, who found there to be very little support online for CML patients.
The group is a closed group, so content can only be seen by members.
If you would like to join, visit the page and request to join.
There is also a general leukaemia support group on Facebook which is ran by Leukaemia Care. To request to join, click here.
Offline support groups
There area number of CML specific support groups in the UK. Find out more on our support groups page.
CML advocates network
The Chronic Myeloid Leukaemia (CML) Advocates Network is a worldwide network of more than 80 non-profit organisations supporting patients with chronic myeloid leukaemia. It was set up to enable the sharing of best practice and up-to-date information amongst patient advocates across the world.
Other CML charities
CML Support are the UK’s only charity with an exclusive focus on people diagnosed with Ph+ Chronic Myeloid Leukaemia. You can find out more on their website cmlsupport.org.uk
Published date: November 2016
Review date: December 2018