Chronic myeloid leukemia (CML)

Chronic myeloid leukemia (CML) is a rare form of leukemia where certain white corpuscles in the bone marrow, blood, spleen and liver multiply uncontrollably.  

CML is caused by a genetic mutation in a blood stem cell in the bone marrow: chromosomal mutations are found in the leukemia cells of almost all patients with CML. The medical term for them is Philadelphia chromosomes. 

Onset of the disease is slow for most patients. Chronic myeloid leukemia (CML) is frequently detected inadvertently following a blood test. Many patients have no symptoms, or no definitive symptoms at this point.  

Symptoms that may be an indication of CML are: 

• fatigue, weakness, deterioration in performance, lassitude 
• loss of appetite, involuntary weight loss 
• upper abdominal discomfort due to enlarged spleen 
• (slight) high temperature, night sweats 
• bone pain 

However, these symptoms are not exclusive to CML but occur in many other conditions. Anyone who feels unwell and debilitated, involuntarily loses weight, experiences severe night-time sweats and has a slightly high temperature over a prolonged period should consult their doctor. This way doctors can start narrowing down what is causing the symptoms and if necessary initiate further diagnostic steps by specialists. 

In chronic myeloid leukemia (CML) there is a genetic mutation in a hematopoietic stem cell in the bone marrow: a shortened chromosome 22 is found in the genetic material of the leukemia cells of almost all patients with CML. This mutated chromosome was first described by researchers in the USA and named after the site of its discovery as the Philadelphia chromosome. 

How does the Philadelphia chromosome develop? 

There are 23 pairs of chromosomes in the nucleus of human cells. They carry the genetic material (genes). When the cell divides the genetic material is first duplicated and then divided between the two daughter cells in two equal parts. Errors may occur each time the cell divides. 

The Philadelphia chromosome is created during cell division when genetic material is swapped (“translocated”) between chromosome 9 and chromosome 22. This means that two parts of human genetic material are combined that do not normally belong together, creating a new gene known as the BCR-ABL fusion gene.  

This mutated gene means the cells form a new protein known as BCR-ABL tyrosine kinase. It prompts the blood stem cell to divide uncontrollably. 

The reason chronic myeloid leukemia (CML) develops is unclear in most patients.  

One risk factor is believed to be exposure to radiation; however, most patients have no history of exposure to radiation.  

CML is recognized as an occupational disease under certain circumstances for people who work with certain chemical substances (1,3 butadiene, benzene, benzene derivatives).  

1,000 to 1,200 people develop chronic myeloid leukemia (CML) every year in Germany. So it is a fairly rare form of cancer. 

The total number of patients with CML is increasing because people with CML are living longer thanks to new therapies. 

The progression of chronic myeloid leukemia (CML) can be divided into three phases: chronic phase, accelerated phase and blast phase. 

Chronic phase

At the chronic phase CML causes no or only a few symptoms. At this phase, CML is detected in most patients inadvertently when they are tested for something else.

The goal is to use drug treatment to maintain the CML at the chronic phase, during which patients’ life expectancy is virtually the same as that of healthy people.

Accelerated phase

The accelerated phase is detected by an increase in symptoms. The white corpuscle count rises and the proportion of immature white blood cells (blasts) in the blood and bone marrow increases. The spleen is also enlarged.

Blast phase

At the blast phase, CML progression is similar to that of acute leukemia. Since the leukemia cells increasingly compromise normal blood formation (hematopoiesis), patients are particularly at risk of infections, hemorrhaging or complications due to anemia.

A blast crisis is a severe condition that can cause death within a few weeks or months if untreated.

Specialist doctors need to carry out careful blood and bone marrow tests to diagnose chronic myeloid leukemia (CML) correctly.
A blood sample is taken from a vein in the patient’s arm for the blood test.  

For the bone marrow test the doctor applies a local anesthetic to a small patch of skin on the lower back. A small amount of bone marrow is aspirated from the top of the pelvic bone with a syringe. The doctor may also use a hollow needle to punch out a small sample.  

Specialists start by examining the blood and bone marrow under a microscope. They also investigate whether there are any mutations to the genetic material in the leukemia cells. 

Tyrosine kinase inhibitors are the drugs of choice for most patients with chronic myeloid leukemia (CML). They are also referred to by the abbreviation TKI. They belong to the group of targeted cancer therapies.

These drugs inhibit BCR-Abl tyrosine kinase which is typically found in CML. This is the enzyme that is formed by the cells because of a genetic mutation. By inhibiting tyrosine kinase, the drug stops the leukemia cells from multiplying uncontrollably and they die.

There are a number of different tyrosine kinase inhibitors available for treatment of CML. Doctors focus on three particular factors when choosing which to use:

• efficacy
• potential side effects
• personal risks and co-morbidities

Experts recommend starting treatment as quickly as possible after diagnosis. The goal of treatment is to mitigate the leukemia as much as possible. Studies have shown that improvement in the prognosis is directly proportional to success at this stage.

If there is a very good response and a good and lasting therapeutic outcome, it may even be possible to discontinue treatment permanently. However it is still not entirely clear whether that also means that patients have made a full recovery.

Regular testing is essential

Doctors carry out regular blood and bone marrow tests to check whether treatment is successful. Remission is the metric used to measure how well the leukemia has responded to treatment:

• Hematologic remission: medical practitioners use the term complete hematologic remission to refer to a response where all blood cell counts and spleen size are normal and patients have no symptoms of CML.
• Cytogenetic remission: complete cytogenetic remission (CCyR) is where no Philadelphia chromosome can be found in the bone marrow.
• Molecular remission: molecular genetic testing is the most accurate. It can even detect single leukemia cells out of several thousand normal blood cells. If the treatment reduces the number of leukemia cells below a specified limit of detection, doctors use the term deep molecular remission. This is the therapeutic goal.

Allogeneic stem cell transplant: an additional treatment option

If the leukemia does not respond or stops responding to the selected treatment, doctors switch to another tyrosine kinase inhibitor as quickly as possible.

If tyrosine kinase inhibitors are not a promising option, or cease to be promising, doctors may also consider the option of a stem cell transplant, where specially treated blood stem cells from a suitable donor are transplanted into the patient.

Stem cell transplantation is an intensive therapy that has some risks associated with it. However it also offers a chance of permanent recovery.

Would you like to find out more about the treatment of chronic myeloid leukemia (CML), what the potential side effects of treatment are and how you can cope with them? You can find detailed information on the German Cancer Research Center’s Cancer Information Service website.

Patients whose leukemia responds well to tyrosine kinase inhibitor therapy largely have a normal life expectancy.  

However it is important to keep taking the tablets regularly. Patients suffering from side effects should discuss with the doctor whether it might be advisable to switch to a different drug.  

Regular check-ups are needed to identify problems at an early stage: if there are any signs that the therapy is not or no longer sufficiently effective, the supervising doctors will rapidly switch treatment. 

Women should not become pregnant whilst receiving tyrosine kinase inhibitor therapy. The drugs are harmful to the fetus and may cause deformities. If you are a woman with CML and want to have a baby you should discuss this with your doctors and consider all the options together.  

Would you like to find out more about how people can make their dream of having a baby come true during and after cancer? And who to contact? You can find a summary of all the relevant information on the German Cancer Research Center’s Cancer Information Service website. 

You can find information about chronic myeloid leukemia (CML), including information for patients, on the Acute and Chronic Leukemia Competence Network website. The German CML Study Group is a member of the Acute and Chronic Leukemia Competence Network.

CML should be treated by a team of experienced doctors from a number of different specialties. Hospitals that are particularly experienced in the treatment of patients with leukemia can become certified as oncology centers specializing in “hematological neoplasms”. The German Cancer Society (DKG), in conjunction with the German Society for Hematology and Medical Oncology (DGHO), regularly checks these hospitals for compliance with certain requirements.

You can find the addresses of centers with this designation on the OncoMAP website. To do this, select “Hematological Neoplasms” in the search panel under “Centre”.