Chronic Myeloid Leukaemia (CML)

Chronic myeloid leukaemia (CML) is a form of blood cancer, which affects the white blood cells known as myeloid cells. It is a slowly progressing form of leukaemia. Approximately 750 people are diagnosed with leukaemia every year in the UK and CML makes up about 15 out of every 100 cases.

Chronic myeloid leukaemia (CML) is a myeloproliferative neoplasm (MPN) in which the myeloid cells in the bone marrow multiply uncontrollably leading to large numbers of abnormal, immature myeloid cells. Neoplasm is the medical term for cancer and it can be benign or malignant. MPNs are chronic disorders where the myeloid stem cells in the bone marrow make too many white blood cells which do not function properly.

In CML, any of the myeloid white blood cells may multiply; however, granulocytes are the most likely to do so. In the early stages of CML, too many abnormal leukaemia cells are produced. Over time, these leukaemia cells become poorly developed and do not function properly. As they accumulate and begin to fill up the bone marrow, they prevent it from producing healthy blood cells.

The production of new blood cells is very closely controlled so that it is balanced with the loss of worn-out cells or cells lost by bleeding or damage. Tyrosine kinases are enzymes (substance produced by the body to help bring about a specific biochemical reactions) that switch ‘on’ and ‘off’ many of the functions of the body’s cells. The role of one of these tyrosine kinases is to control how white blood cells grow and multiply. It is thought that a mutation in the gene for this tyrosine kinase enzyme results in the overproduction of granulocytes in CML.

Stages of CML

CML typically has three stages:

  1. 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.
  2. 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.
  3. 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.

Kris is a CML patient. You can watch his story above.

What causes of CML?

The exact cause of CML is not known, but it has been found that exposure to radiation can be linked to a higher chance of developing CML. No firm association between CML and industrial chemicals or alkylating agents has been found. Additionally, no hereditary link has been shown for CML.

Genetic studies, however, have shown that around 95% of CML patients have a specific chromosome called the Philadelphia chromosome. The Philadelphia chromosome is the name given to a shortened abnormal chromosome formed when the BCR (Breakpoint Cluster Region) gene on chromosome 22 and the ABL (Abelson) gene on chromosome 9 swap part of their DNA, resulting in an abnormal fusion gene called BCR-ABL1. The Philadelphia chromosome t(9;22)(q34;q11) is produced in your bone marrow by chance, meaning you cannot inherit this chromosome or pass it onto your children. The BCR-ABL1 fusion gene produces an abnormal version of the tyrosine kinase enzyme which allows the overproduction of myeloid cells.

Only about 5% of patients with CML do not have the Philadelphia chromosome or the BCR-ABL1 gene; this is called atypical CML and is a different condition. In this booklet, we only discuss CML where the BCR-ABL1 gene is present.

Signs and symptoms

The signs and symptoms of CML tend to be related to the phase of the disease in which patients are in. The three phases of CML are chronic, accelerated and blast phases. Blasts are immature cells found in the bone marrow which are not fully developed. Normally, only up to 5% of the cells found in the bone marrow are blast cells. In patients with CML, particularly in the blast phase, there are a much higher number of leukaemia blast cells in the bone marrow.

Symptoms generally associated with the three phases of CML are:

  • Chronic phase: Generally, there are less symptoms present and they tend to be vague. In this stage, CML is often detected through a blood test for something else, or through a health check. Patients can remain in this phase for years before proceeding to the accelerated phase.
  • Accelerated phase: The symptoms described below become apparent as the number of blast cells in the blood and bone marrow start to increase. Commonest symptoms are feeling tired or unwell, night sweats, weight loss and frequent infections. The accelerated phase normally lasts between three to nine months.
  • Blast phase: This is the final phase of CML, also called the blast crisis. The blast phase is when the leukaemia has become more aggressive and patients in this phase may experience more noticeable and extreme symptoms. The disease is similar to acute myeloid leukaemia (AML) during this stage, with more than 30% of bone marrow and blood cells being blast cells. Unless it is treated, death will generally occur.

Many patients with CML usually present in the chronic phase in which there is only a clonal increase of mature myeloid cells, but no symptoms at the time of diagnosis.

Clonal means that all the cells are genetically identical and have a single common ancestor cell. Typically, these patients are identified following abnormal results from a routine full blood test for something else. If left untreated, patients with CML will eventually progress to the accelerated and blast phases.

Other patients with CML may be diagnosed at a more advanced stage. As the abnormal white blood cells build up, they can eventually take over the bone marrow making the production of enough normal blood cells difficult. This is usually the cause of the symptoms of CML:

  • Anaemia (low levels of red blood cells as the bone marrow cannot produce enough red blood cells)
  • Fatigue (may be caused by anaemia)
  • Unexplained weight loss
  • Night sweats
  • Bloating, feelings of fullness after eating or pain in the abdomen due to an enlarged spleen. The spleen usually returns to its normal size with treatment
  • Unusual bleeding e.g. from gums and frequent bruising (low levels of platelets)
  • Infections (low levels of white blood cells)
  • Bone pain


Your haematologist may suspect you have a type of leukaemia, either following the results of a blood test or symptoms that you have experienced. Further tests are required to reach and confirm a diagnosis. These test results can take a little while, which may be a worrying time for you, but it is worth remembering that they are essential so your haematologist can reach the correct diagnosis.

Tests used to make a diagnosis

CML is diagnosed by the use of blood tests, bone marrow aspiration/ biopsy, and analysis of chromosomes and gene mutations. The tests that you may have include:

  • Full blood count: This is a routine blood test which measures the number of red cells, the different types of white cells, and the platelets in the blood. The blood is smeared onto a microscope slide, allowing the blood cells to be examined under the microscope.
  • Bone marrow aspiration/biopsy: The bone marrow sample is generally taken from the hip bone under local anaesthetic, using special biopsy needles: liquid bone marrow (aspirate) and/or a tiny core of bone marrow tissue (trephine).
  • Chromosome abnormalities or gene mutations tests: Blood or bone marrow may be tested to check for chromosome abnormalities or gene mutations in the leukaemia cells.
  • Polymerase chain reaction (PCR) test: A PCR test is used to detect genetic information. It can be performed using a regular blood sample. It is an important test in the diagnosis and management of CML as it measures the amount of the BCR-ABL1 gene which is characteristic of CML. As well as helping establish the diagnosis, PCR tests will be done throughout your treatment to monitor your response and to find out whether treatment needs to be changed.
  • Immunophenotyping: This process analyses the types of antigens or markers on the surface of the leukaemia cells, based on antibodies that are present in the patient’s blood. According to which antibodies are present, it is possible to identify the type of leukaemia.
  • Minimal residual disease (MRD) testing: This test measures the presence of leukaemia at a molecular level rather than at a cell level. Biomarkers linked to the leukaemia cells are measured using. molecular techniques such as flow cytometry to determine the very small level of leukaemia cells which are still remaining in the bone marrow of patients. MRD testing is important in planning the next phase of your treatment.
  • Imaging investigations: X-rays, ultrasounds or scans, including computer tomography (CT) and magnetic resonance imaging (MRI) can be done to assess the impact of your CML such as the increase in the size of your spleen.

Blood tests, bone marrow samples and scans will be repeated throughout treatment to monitor your response to treatment. If you want to know more about your test results, you can ask your doctor or your clinical nurse specialist.

Diagnosis of CML

To establish a diagnosis of typical CML, there are two main conditions that need to be met:

  • Persistent unexplained increase in the number of white blood cells (white cell count above 11.0×109/l)
  • Identification of the Philadelphia chromosome t(9;22) or the BCR-ABL1 fusion gene, in the peripheral blood or bone marrow cells. This is achieved with the PCR test.

Approximately 95% of CML patients have the typical Philadelphia chromosome t(9;22).

Around 5% of patients have different chromosome abnormalities to the normal Philadelphia chromosome t(9;22). These variations may be simple, involving chromosome 22 and another chromosome other than chromosome 9, or complex, involving one or more other chromosomes in addition to chromosomes 9 and 22. The diagnosis in these patients depends on being able to see the BCR–ABL1 fusion gene. These patients should receive the same treatment as patients with a Philadelphia chromosome t(9;22) as they respond to treatment in the same way.

For some patients, neither the Philadelphia chromosome nor BCR–ABL1 gene is seen when testing. These patients are said to have atypical CML which is classified as a separate disease.

Staging of CML

The phase of your CML is defined on the basis of your signs and symptoms and the results from blood and bone marrow tests. Putting CML into stages helps with defining the best treatments for you and will also be able to better predict your prognosis.

  • Chronic phase: Myeloid blast cells can be seen in the blood and bone marrow.
  • Accelerated phase: The increased numbers of blast cells in the blood and bone marrow account for 10-30% of white blood cells.
  • Blast phase: In the blast phase, more than 30% of bone marrow and blood cells are blast cells. The disease is similar to AML during this stage.

Most patients are diagnosed at the chronic phase of CML, and with the arrival of a class of drugs called the tyrosine kinase inhibitors (TKIs), a very high proportion of these patients do not experience disease progression to the accelerated or blast phases. Patients who remain in the chronic phase of CML have a similar life expectancy as the general population.

Up to 10% of patients are diagnosed when they are in the accelerated or blast phases of CML which lowers their prognosis.


Despite CML not being considered to be a curable disease, the TKIs have transformed its treatment enabling a ‘practical’ cure. Many patients will have a normal life span and good quality of life. Without treatment, CML can be life-threatening. A stem cell transplant may achieve a ‘cure’ for some patients. It is an important treatment option for some patients in the chronic phase for whom at least two TKIs have been unsuccessful, and for all patients in accelerated phase.

By staging your CML, your haematologist can determine the best treatment regimen for you.

Treatment options

The three main options for treating CML are:

  • Targeted therapy: The main targeted therapy for CML is the TKIs used to find and remove the abnormal protein (tyrosine kinase) produced by the BCR-ABL1 gene that encourages overproduction of the white blood cells in CML.
  • Chemotherapy to destroy or damage leukaemia cells. Chemotherapy is generally used when the TKIs are not effective or they cause severe side effects. The chemotherapy drug most frequently used is called hydroxycarbamide as it can reduce the very high number of blast or leukaemia cells in the blood.
  • Allogeneic stem cell transplant (Allo-SCT) which involves donation of healthy stem cells, from a well-matched donor. This option is only suitable for patients who are fit enough to undergo it.

Treatment regimens for the phases of CML

Treatment regimens for patients in the different phases of CML can include targeted therapy, which consists mainly of the TKIs, chemotherapy, Allo-SCTs or a combination of these three treatments.

  • Patients in the chronic phase of CML should receive any of the TKIs approved by the EMA and recommended by NICE for use in newly diagnosed patients such as imatinib, nilotinib, dasatinib and bosutinib.
  • Patients in the accelerated phase of CML may receive initial therapy with one of the newer generation TKIs such as dasatinib or ponatinib (EMA-approved and NICE recommended) to reduce the symptoms of CML, and then be considered for early Allo- SCT.
  • Patients in the blast phase of CML are generally treated with the third generation TKI, ponatinib, combined with chemotherapy, followed by an Allo-SCT as soon as a complete response is achieved. Despite no evidence of the superiority of a TKI and chemotherapy over a TKI alone, treatment with FLAG-Ida (fludarabine, idarubicin, granulocyte-colony stimulating factor [GCSF] and high-dose cytarabine), with or without a TKI, has become the most common approach in the UK, especially if there is significant delay in arranging an Allo-SCT. Subsequently these patients receive maintenance treatment with a TKI.

Nilotinib, bosutinib and ponatinib have been recommended by NICE as treatment options for chronic, accelerated and blast phase Philadelphia chromosome-positive CML, who have previously had one or more TKIs and imatinib, nilotinib and dasatinib are not appropriate.

Targeted therapy

There are five TKIs approved for use in the UK, and all are recommended by NICE:

First generation (first developed):

  • Imatinib (Glivec, Novartis Pharmaceuticals UK Ltd)

The 10-year patent for imatinib expired in December 2016, after which the generic version (non-branded) of imatinib could be manufactured by any pharmaceutical company. Novartis Pharmaceuticals UK Ltd are still producing Glivec as a generic drug but at a much lower price.

Second generation:

  • Nilotinib (Tasigna, Novartis Pharmaceuticals UK Ltd)
  • Dasatinib (Sprycel, Bristol Myers Squibb Pharma)
  • Bosutinib (Bosulif, Pfizer Europe)

Third generation:

  • Ponatinib (Iclusig, Incyte Biosciences Distribution BV)

The decision about which TKI will be suitable for you will depend on the mutations in the BCR-ABL gene, the known side effects of the different drugs, and your haematologist’s experience of your personal situation such as your age and other illnesses. Certain mutations are known to respond better to some TKIs than others and, if a patient has been troubled by side effects, it is possible to choose a different TKI that is unlikely to cause the same side effects.

All of the currently available TKIs are taken by mouth, which patients prefer to intravenous infusion or injection administration.

Allogeneic stem cell transplantation (Allo-SCT)

An Allo-SCT can potentially provide a cure for some patients with CML; however, it is only an option for patients with good health status and organ functions. Your haematologist will let you know if an Allo-SCT is an option for you, and will discuss it with you giving you a chance to questions. While an Allo-SCT is generally considered as the only potential cure for CML, the risk of a transplant may be greater than the benefit for most patients.

During an Allo-SCT, healthy bone marrow stem cells from a matched relative or a matched unrelated donor are infused intravenously into your blood. These healthy stem cells migrate to the bone marrow to restore it and start forming new blood cells. The procedure requires a hospital stay for four to six weeks, while the stem cells multiply and make new blood cells, a process which is called ‘engraftment’. After the Allo-SCT, you will receive drugs to help prevent rejection of the donated stem cells.

To prepare your bone marrow to receive the healthy donor stem cells, you will receive high dose chemotherapy to kill the leukaemia cells in the bone marrow. This process is called ‘conditioning’ of the bone marrow to prevent the donor’s immune system rejecting the newly donated stem cells. This is why an Allo-SCT is only an option for fit patients as the high dose chemotherapy is difficult to withstand.

Other treatment options

If TKIs are not successful for the treatment of your CML and an Allo-SCT is not an option, there are a number of other drugs that were used with relative degrees of success before the arrival of the TKIs. These include interferon alpha, hydroxycarbamide, hypomethylating agents (such as azacitidine and decitabine), and chemotherapies such as busulfan, 6 mercaptopurine and low dose cytarabine.

Interferons are proteins that occur naturally in the body and help fight infection. Interferon alpha can lead to regression of the CML and increase survival but its effect is modest and it has several troublesome side effects. One benefit of interferon-alpha is it can be used in women with CML who are in the second and third trimesters of pregnancy.

The combination of interferon-alpha with TKIs can achieve higher rates of response than TKIs alone; however, the dose of interferon-alpha is limited by the occurrence of side effects. Pegylated forms of interferon, where a polyethylene glycol is attached to the interferon drug, have less side effects and are better tolerated. Combinations of TKIs and hydroxycarbamide or TKIs and low dose cytarabine have not shown satisfactory results.

Side effects

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:

  • Fatigue
  • Headaches
  • Muscle/joint pain
  • Diarrhoea
  • Nausea/vomiting
  • 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
  • Anaemia
  • 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.

Cytogenetic response

  • 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.

Molecular response

  • 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 medical team 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?

Further downloads

We have free patient information available for CML patients.

View our free CML resources by clicking the button below.

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Patient stories

Support for CML patients

Facebook group

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

Published: November 2020

Review date: November 2023