Personalised Medicine at a Glance: Chronic Myeloid Leukaemia (CML)
For patients, policy makers and other non-medical professionals
This text was prepared by ESMO for the European Alliance for Personalised Medicine – March 2015
In several cancers, the search for drugs that target the specific molecular abnormalities that cause uncontrolled tumour growth has resulted in encouraging improvements in care. In the case of the blood malignancy chronic myeloid leukaemia (CML), the progress achieved by this approach has been truly dramatic.
We are now able to successfully target not only the molecular abnormality that causes the disease but also the genetic changes that malignant cells evolve when they develop resistance to first-line treatments. Since several different mutations cause resistance, identifying the ones that are relevant to a particular patient – and selecting the right drug in response – is an important and rapidly developing part of personalised medicine for CML.
The disease arises when a specific error occurs during cell division. Using a microscope to look at the nucleus of CML cells shows that genetic material from part of chromosome 9 is missing from its usual position and appears instead attached to chromosome 22. This translocation (known as the Philadelphia chromosome since the researchers who discovered it were working there) causes two genes that would not normally be neighbours to fuse together. The hybrid gene (called BCR-ABL) produces an abnormal protein that transforms normal blood-forming cells into malignant ones.
However, the effects of the gene translocation are not immediately felt. In the early “chronic” phase of CML, the disease is not severe and may first be identified in blood tests carried out for other reasons. But the BCR-ABL gene is unstable. It accumulates mutations over a period of years until CML enters an accelerated phase and then a state called “blast crisis”. At this stage, large numbers of abnormal and immature white cells are produced and overwhelm healthy blood forming cells in the marrow.
The abnormal BCR-ABL protein at the root of the problem is a tyrosine kinase enzyme. Drugs that block its activity are tyrosine kinase inhibitors (TKIs). The first drug designed to inhibit BCR-ABL tyrosine kinase, imatinib, greatly slowed the progression of CML from chronic phase to potentially fatal blast crisis. In the first major trial, almost 90% of CML patients treated with imatinib were alive at five years.
Other BCR-ABL tyrosine kinase inhibitors, notably nilotinib and dasatinib followed. Imatinib, nilotinib and dasatinib differ to some extent in their toxicity profiles and their ability to target specific gene mutations. So there are now several options from which to choose initial treatment and as back-up if the CML develops resistance to the first-line agents.
But the personalisation of CML treatment starts with diagnosis and the tests that follow. Doctors will look at the stage the disease has reached, as shown by a patient’s precise pattern of blood cell abnormalities. This covers the number of different kinds of blood cells detected (the “blood count”), the proportion which have the abnormal Philadelphia chromosome when looked at under the microscope (ie the cytogenetics), and the quantity of abnormal BCR-ABL protein being produced.
Regular monitoring of all of these factors is essential in assessing how well the disease is responding to treatment, and whether there can safely be a period when therapy is discontinued. Levels of the abnormal BCR-ABL molecule are measured using a highly-sensitive technique called polymerase chain reaction, or PCR. This is the most precise way of assessing how well CML is responding to treatment. Doctors are also able to detect the exact mutations that have been developed by the BCR-ABL gene.
Information from all of these tests is important in alerting doctors to CML that is escaping from control, showing that drug therapy should be changed. A decision to change drugs may also be suggested if a patient is having unacceptable side effects with the TKI that was first prescribed.
In the relatively few cases when blast crisis develops, chemotherapy with cytotoxic drugs remains possible. If the disease responds well, this can be followed by a stem-cell transplant. But there is no doubt that developments over the past fifteen years have transformed the prospects for patients with CML – to the extent that it is no longer thought of as an incurable disease.
In patients who are not cured, life expectancy has been dramatically improved. In many respects, this disease – and the way its genetic abnormalities have been targeted by drug therapy tailored to the characteristics of individual patients - are the model which those researching other types of cancer have sought to emulate. That said, even with this disease, further progress is needed.