Chronic myeloid leukaemia (CML)

Chronic myeloid leukaemia (CML) is a malignant blood disease with a slow progression. CML is characterised by degeneration of the blood stem cells, which leads to uncontrolled proliferation of certain subgroups of white blood cells (leukocytes). If left untreated, the insidious disease ("chronic phase") changes after a few years into a more threatening and faster progressing form ("accelerated phase") and finally appears like an acute leukaemia ("blast crisis").

CML is a rare blood disorder. In Germany, around 1-2 adults per 100,000 inhabitants develop the disease every year. The risk of developing CML increases with age, but the disease can occur in all age groups.

In most patients, no cause for the development of CML can be identified. Exposure to ionising radiation and chemicals such as benzene promote the degeneration of blood stem cells. Other factors that favour the development of CML are not yet known. In over 90% of cases, the disease is caused by a defined genetic change, the so-called Philadelphia chromosome, which can be detected in the bone marrow. This is caused by an exchange of genetic material between chromosomes 9 and 22, resulting in a fusion of the two genes BCR and ABL1 at the gene level. It is assumed that the Philadelphia chromosome or BCR-ABL1 causes the increased division of blood cells. In later stages of the disease, further gene mutations are added.

As blood tests are frequently carried out nowadays, CML is diagnosed at an early stage in the majority of patients. Many patients are unaware of the disease at the time of diagnosis. It is characterised by an asymptomatic increase in white blood cells (leukocytosis). In some cases, fatigue, reduced performance and night sweats also occur. In more advanced stages in particular, an enlargement of the spleen is regularly present, which can lead to a feeling of pressure in the left upper abdomen.

Patient consultation and physical examination

In a detailed discussion, all complaints and relevant previous illnesses are enquired about. During a physical examination, an enlargement of the spleen can be detected in some patients by palpation of the left upper abdomen.

Laboratory tests

Blood tests provide the most important information for making a diagnosis of CML. In addition to counting the blood cells, microscopic examination of a blood smear is particularly helpful here. Modern molecular genetic tests confirm the suspicion of the disease (so-called BCR-ABL1 PCR from the blood). In addition, a bone marrow examination should be carried out as it allows the detection of the Philadelphia chromosome and is important for the staging of the disease.

Further examinations

An ultrasound examination is carried out in order to be able to assess the abdominal organs and in particular the size of the spleen more precisely. X-ray examinations can usually be dispensed with.

The differentiation of the disease phases of CML (chronic phase, acceleration phase and blast crisis) is carried out on the basis of blood and bone marrow analyses. This makes it possible to advise on the best possible treatment strategy.

It is important that treatment is started immediately after diagnosis, as CML is more difficult to treat in more advanced stages than in the early phase. Thanks to the use of new drugs that follow the principle of molecularly targeted therapy, the treatment of CML has made enormous progress in recent years.

Targeted drugs

Their effect is based on the targeted inhibition of the characteristic changes in the leukaemia cells caused by the Philadelphia chromosome or BCR-ABL1 (so-called tyrosine kinase inhibitors, TKIs). TKIs are taken in tablet form once or twice a day. The longest-proven TKI is imatinib. Side effects such as nausea, muscle cramps and fluid accumulation in the tissue (oedema) can occur. The second-generation TKIs developed in recent years (nilotinib and dasatinib) are even more effective than imatinib according to study results and have therefore also been authorised for the first-line treatment of chronic phase CML since 2010. In addition, two further drugs (also TKIs) are now available for patients with intolerance to the TKIs mentioned or in special situations where TKI resistance or intolerance occurs: Bosutinib and Ponatinib.

In most cases, the white blood cells normalise after just a few weeks of therapy. The success of treatment is determined by regular blood tests (blood count and BCR-ABL1 PCR). In some cases, a new bone marrow examination is also necessary or useful to check the response to treatment. In many patients, the treatment responds so well that after a few months or a few years of therapy, the disease is barely detectable or no longer detectable. Until a few years ago, it was assumed that even in these patients, daily administration of the TKI was necessary on a permanent basis in order to control CML and prevent the disease from progressing. However, more recent studies show that around half of patients with a very good response to therapy can permanently discontinue the medication without the CML becoming detectable again (so-called therapy-free remission, TFR). However, this requires close monitoring of the minimal residual disease (BCR-ABL1 PCR from the blood), especially in the first few months after discontinuation, in order to recognise the need for renewed therapy at an early stage before CML is detectable again in the blood count.

Stem cell transplantation

Due to the very good treatment success of the disease with the above-mentioned tablet therapy, the importance of stem cell transplantation in CML has continuously decreased in recent years and is mainly considered for patients with an inadequate response to TKI therapy (e.g. if so-called resistance to the drugs occurs) or in advanced stages of the disease (e.g. in the blast crisis). Due to the risk of serious complications during transplantation, a particularly careful risk-benefit assessment must be carried out. The transplantation is carried out with blood stem cells from a sibling donor or a third-party donor (so-called allogeneic blood stem cell transplantation).

Chemotherapy

A mild form of chemotherapy with tablets is sometimes necessary for a few days after initial diagnosis if there is a very strong increase in white blood cells. More intensive chemotherapy, which is administered in the form of infusions, is only used if the disease is at a later stage or if a blood stem cell transplant is to be carried out.

Most patients for whom treatment of CML is initiated in good time can lead a largely normal life thanks to the use of TKIs.
If the course of the disease is uncomplicated, patients are usually monitored by a haematology specialist every three to six months.

The prognosis for CML is very good if diagnosed early. In the long-term use of TKIs in the chronic phase, long-term survival rates of over 90% are reported.
The situation is more problematic in the advanced stages (in the acceleration phase and especially in the blast crisis), in which intensive therapeutic measures such as haematopoietic stem cell transplantation often have to be used.
Clinical trials are needed to achieve further progress in the treatment of CML.