Chronic Myeloid Leukaemia

Chronic Myeloid Leukaemia (CML)

Leukaemia is a cancer of the white blood cells. There are different types of leukaemias and these are classified based on the type of white blood cells that transform into a leukaemia and also whether the cancer grows quickly(acute) or slowly(chronic).

Chronic myeloid leukaemia (CML) is type of leukaemia that develops when a section of the white blood cells increase without control.
Most cells in the body consist of 23 pairs of chromosomes which are named as chromosome 1 to 23.

These chromosomes contain a number of genes on them. Majority of chronic myeloid leukaemias develop when there is a translocation (interchange) of genes between chromosome 9 and chromosome 22. A gene, ABL1 present on chromosome 9 gets attached to BCR gene on chromosome 22 and this creates a BRC-ABL1 gene. This then leads to production of more white blood cells in the blood which become a chronic myeloid leukaemia.

A Philadelphia chromosome (Ph) is the chromosome 22 that contains the BCR-ABL1 gene and can be seen under the microscope and helps in the diagnosis of CML.

Chronic Myeloid Leukaemia can produce a variety of symptoms. Most of the symptoms are due to excess number of white blood cells in the blood. A number of patients may not have any symptoms and may only be diagnosed accidentally on routine blood tests. Other may have the following symptoms.

Tiredness and weakness

The high number of WCC in the blood impede the function and growth of other blood cells such as red blood cells. This leads to development of anaemia which causes symptoms such as tiredness and weakness.


High WCC causes a reduction in platelets in the blood leading to symptoms of bleeding. This bleeding can be from the gums, motions or as bruising on the skin or rash on the skin.

Abdominal Pain or distension

The spleen is an organ in the body and present on the left side of the abdomen. Spleen can be enlarged in CML and sometimes enlarged to a big size. This causes symptoms such as a dragging sensation, distension or heaviness, fullness or pain in the abdomen.


Even though there are high WCC in this condition, the function of those cells is not good enough. Therefore, there is an increased risk of frequent infections.

Fever and night sweats

These symptoms can be present in some patients with CML

Other symptoms

Other symptoms in CML include joint and bone pains, enlargement of lymph nodes or weight loss.

Once a CML is suspected the following tests are done to establish the diagnosis.

CBP and Blood film

A complete blood picture or blood count usually gives a strong clue to the presence of CML. The blood test shows an increase of white blood cells of about 100,000 (normal level 4000-11000). Not all patients with CML have a count of 100,000 but may have any level from 12000 to 100,000 or above. It has to be remembered that a raised white cell count very commonly occurs due to other causes not related to cancer such as infections. When looked under the microscope, these increased cells are types of white blood cells called myelocytes. Other blood cells such as platelets, Haemoglobin and other white blood cells may be low or high.

Bone Marrow biopsy

The bone marrow is the place where new blood cells are born. When a cancer of the blood cells is suspected, a bone marrow biopsy is done to look at the cells in the marrow and to confirm the diagnosis.

Genetic Tests

Genetic testing looking for the BCR-ABL1 protein is done. This is done by FISH or RT-PCR testing. The test shows the abnormal translocation in about more than 90% of patients with CML. These are called as Ph chromosome positive and the remainder or Ph negative patients.
The diagnosis of CML is confirmed by the presence of high white blood cell count, the presence of BCR-ABL1 fusion gene or mRNA and the demonstration of Ph chromosome.

Chronic myeloid leukaemia is divided into 3 phases depending on the number of blast cells. Blast cells are immature white blood cells. Myelocytes are also immature white blood cells but are more mature than blast cells. The three phases are

Chronic Phase

Most patients with CML, up to 80-85% of them are in the chronic phase of the disease. Here, the percentage of blast cells in the bone marrow is less than 5%. The disease in this phase is slow growing and well controlled with treatment.

Accelerated Phase

In this phase, the number of blast cells make up between 10% and 19% in the bone marrow or blood.

Blast Phase

In the blast phase, blast cells make up more than 20% of cells in the blood or bone marrow.

A patient with CML can change from one phase to another phase over time or may be diagnosed with CML in the blast phase. As the blast phase has more blast cells, it is more difficult to treat as compared to other phases.

Chronic myeloid leukaemia is a very treatable disease in majority of patients. The treatment options depend on the phase of the disease, the symptoms and fitness of the patient.

For majority of patients who are in the chronic phase and for patients in the accelerated and blast phase, the initial treatment is in form of drugs (targeted therapy) called tyrosine kinase inhibitors or TKI’s. For patients with chronic phase disease, this can be the only initial treatment and good and prolonged responses can be expected. For patients with accelerated phase or blast phase, TKI’s are used as initial treatment to enable patients to go into a remission or into the chronic phase. Following that, these patients could proceed to a stem cell transplant.

Tyrosine Kinase Inhibitors

The drugs that come under this category that are used in the treatment of CML include Imatinib, Dasatinib, Nilotinib, Bosutinib and Ponatinib. Of these, Imatinib is most commonly used and cost effective in the Indian setting. These drugs are taken as tablets, some with and others without food. They are well tolerated with few side effects. Common side effects with these drugs include nausea, loose motions, skin rash, swelling of face and legs, fluid retention. The side effects of these different TKI’s vary and dependent on which one is taken. It is essential that the tablets are taken regularly without interruptions to get the maximum benefit from them.

Response Evaluation and monitoring of treatment

For patients who start on TKI’s, the response of the disease to treatment is assessed by a series of blood and genetic tests. CBP is done to look at the total white cell count and a reduction of that is an indication of response to treatment. A normal complete blood count (WCC less than 10000) is a sign of complete haematological response. This usually happens within 3 months of treatment. A blood test to check for level of Philadelphia positive cells is done after CHR and if this is sufficiently low, a complete cytogenetic response (no Ph+ cells) is said to have been achieved. Minimal, minor or major responses are said to have happened depending on the number of Ph+ cells present if seen. A major molecular response (MMR) is achieved when BCL-ABL1 test is done and the level drops to a certain level (three log reduction).

Duration of TKI therapy

For patients who respond to a TKI and is tolerating the treatment well, the drugs are continued for as long as the treatment works. For patients where there is increase of CML again while on TKI, an alternative TKI is considered. If Imatinib has been used first, other drugs such as Dasatinib, Nilotinib or Bosutinib are used. A haematopoietic cell transplant is considered in such patients.

Haematopoietic cell transplantation or stem cell transplantation

This is an option of treatment for patients who have accelerated phase or blast phase of chronic myeloid leukaemia. It is an option of treatment also for patients with chronic phase who have not responded to TKI’s or have disease that has increased again after TKI treatment.
Factors that are considered before selecting a patient for stem cell transplant include age of the patient, the presence of other medical illnesses and the fitness of the patient.

For this transplant, a donor is required from whom the stem cells are taken. This donor could be an identical twin if present, a relative like a parent or sibling (brother or sister) or a donor who is not related to the patient.

There is also assessment about how well the donor’s cells match the patient’s (HLA match). This could be a full match where there is full match in the HLA between the donor and the patient, mismatch where there is no match and haploidentical where there is a half match between the donor and the patient.

The stem cells are collected from the blood, bone marrow or cord blood if one is available. Whether to collect from the blood or bone marrow will depend on the condition of the patient, donor and the type of CML present.

Conditioning Treatment

Prior to having a stem cell transplant in chronic myeloid leukaemia, conditioning chemotherapy is given to ablate all the blood cells in the blood and marrow. This is to help kill off all the leukaemia cells prior to giving cells from the donor. The treatment drugs commonly used can include Busulfan and Cyclofosfamide or in some situations Cyclofosfamide and total body irradiation. In patients who are aged over 60 and felt to be not able to tolerate above treatment are given a less intensive chemotherapy treatment.

Collection of Stem Cells

Stem cells are a type of blood cells that have the capacity to develop into any kind of blood cell such as red blood, white blood cell or platelets. These stem cells are present in the blood stream and bone marrow and are initially collected from the patient before the patient receives high dose chemotherapy.
If the stem cells are from another person(donor), then it is called an Allogenic stem cell transplant. The donor can be related, usually a brother or a sister, or unrelated but matched donor. An unmatched or partially matched donor can also be used.

Before collection of stem cells, the patient may have chemotherapy and injections with G-CSF which will increase the number of stem cells in the blood to achieve a successful collection.

On the day of collection of stem cells, the donor is connected to a machine and the blood is taken out from one vein and it passes through the machine to collect the stem cells present in the blood. The blood then passes back into the donor through another vein. This process is done over a few hours.
Once the stem cells are collected, the patient receives the high dose chemotherapy. After the chemotherapy, the stem cells from the donor are infused into the patient. These cells go into the bone marrow and start making blood cells again.

Collection of bone marrow

Bone marrow is the spongy material that is present inside the bones. For a bone marrow transplant, the marrow needs to be collected prior to giving high dose chemotherapy. The procedure to collect the marrow is done under general anaesthesia usually in an operation theatre. The marrow may be taken out from different places in the bones and about 1 litre of it may be taken out at the procedure. Once taken out, it is stored and infused into the patient when needed.

Risks and side effects of Stem cell and Bone marrow Transplant

Having a stem cell or bone marrow transplant is a complex process and is associated with side effects. This procedure usually involves staying in hospital for a few weeks for the blood cells in the marrow and blood to recover to normal levels after the transplant is done. Common side effects associated with this procedure include

Nausea, Vomiting, Hair loss, altered function of the liver are potential side effects of this treatment.

Risk of Infection as white blood cells are low and the patient to prone to get an infection. The infections could be bacterial, viral or fungal and will usually need antibiotics to control them.

Mucositis is due to effect of chemotherapy on the inside lining of the mouth and digestive tract. This can limit the amount of food taken by the patient and other methods of feeding may be used in that instance.

Bleeding is a risk associated with this procedure due to low platelet count, but platelet transfusion can be given to keep the platelet counts up.
Graft versus host disease This is a reaction of the body to the transfused cells from a donor.


Chemotherapy is used as a treatment in CML in patients who relapse after TKI treatment or in whom where TKI treatment is not effective. The drugs commonly used are cytarabine, Busulfan and Hydroxyurea.