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10 Facts about CML
Bone marrow, under healthy conditions, makes blood stem cells which over time mature into myeloid stem cells or lymphoid stem cells. A myeloid stem cell further matures and becomes either a red blood cell that carries oxygen around the body, platelets to form blood clots and stop bleeding or white blood cells (called granulocytes) which help combat disease and infection.
With CML, too many of these granulocytes are created and they never mature properly so are not able to carry out their normal functions. These are leukaemia cells. Over time, they can build up in the blood and bone marrow and ‘crowd out’ healthy cells.
For the vast majority of patients CML is not fatal. CML used to be a form of blood cancer that had poor outcomes, including death - but treatment has been revolutionised in recent years.
Before 2001, treatment options for CML were limited and without a successful bone marrow transplant survival chances beyond a handful of years were not good with 3-5 years being the median survival rate. Thankfully, the vast majority of patients now enjoy a normal life-span with good quality of life thanks to a brand-new class of anti-cancer drugs. In 2011 a clinical trial reported that after a follow-up time of 8 years over 95% of patients were still alive, which is similar to what you would expect in the general population. Only about 1% of those in the study died of leukaemia in those 8 years.
A new class of drugs called Tyrosine Kinase Inhibitors (TKI) are responsible for revolutionising treatment for CML.
TKIs have been the most successful targeted therapies ever developed for any cancer. The very first TKI called Imatinib (brand name Glivec/Gleevec) was approved for use in 2001 specifically for CML. Since then, other TKIs have been developed for CML, as well as for other cancers, giving multiple treatment options for CML patients. Unlike traditional chemotherapy, TKIs are tablets taken on a daily basis and don’t require patients to receive treatment in a hospital setting.
The fusion of 2 genes creates a new ‘oncogene’ called BCR-ABL1, located on chromosome 22. It is often referred to as the Philadelphia Chromosome, since it was first discovered in Philadelphia. Because genes carry instructions to create proteins, much like a recipe, the existence of this gene leads to the creation of an abnormal protein that signals for uncontrolled replication of leukaemic blood cells. It is not currently known why some people develop the Philadelphia Chromosome. Exposure to ionising radiation is one known risk factor.
Although CML is genetic at its root, it is not inherited from parents nor is it passed on to children.
Most of us think that the genes we are born with are the genes we have for the rest of our life. But the body’s genes can change over time in small ways. Sometimes this causes no problems but sometimes it can cause more serious things like CML.
An abnormality in a stem cell inside the bone marrow causes CML. This genetic abnormality has no effect on the reproductive system. Because of this, the abnormal gene that causes CML does not pass from one generation to another.
CML is a rare condition in the adult population, very rare in young adults under 19 and ultra-rare in children.
Over their lifetime, approximately 1-2 people in every 100,000 will develop CML. Whilst incidence rates (the number of people each year developing CML) has remained static, the prevalence rate (the number of people living with CML) has increased hugely because patients that were previously dying are now living much longer.
The median age at diagnosis is 56 years old (meaning half of cases are diagnosed in patients older than this; half in younger).
Incidence is pretty even around the world, although there is a slightly younger population diagnosed in Asia Pacific regions.
The earlier CML is diagnosed, the better the treatment options are.
CML that has entered the Blast phase is difficult to manage and acts like an acute leukaemia but treatment can sometimes bring it back to the chronic phase in preparation for a stem cell transplant. If CML in the Blast phase does not respond to this initial treatment, lifespan is usually measured in months.
TKI therapy does not 'cure' CML. However, in a small but significant group who respond very well, it is possible to stop therapy.
In some patients it may be possible to stop taking medication after they achieve a deep molecular response that is stable for at least 3 years. Once medication is stopped, regular blood tests will be needed to monitor for the presence of the fusion gene BCR-ABL1. It seems that, although the genetic marker is still detectable, they remain in treatment free remission (TFR). It is theorised that the patient’s immune system relearns its proper response to the abnormal cells and keeps the disease at very low or undetectable levels.
This is an area of ongoing research and several clinical studies are in place to develop our understanding of which patients could be suitable to stop taking TKIs.
It is important that patients who stop therapy and are successful in maintaining TFR are monitored very regularly to ensure that molecular relapse does not occur.
Some patients can develop other mutations which might cause resistance to a particular TKI.
Mutations can be present at diagnosis or can arise during therapy. Some mutations cause resistance to a particular TKI. When imatinib was introduced, it was the only TKI to treat CML and when some patients became resistant to that drug, a number of mutations causing that resistance were discovered. Second generation TKIs such as dasatinib and nilotinib were developed which can successfully treat most known treatment resistant mutations.
The multidrug resistant mutation known as ‘T315i’ proved to be one of the most complex to treat. However a TKI called ponatinib was developed that can successfully treat CML positive for the T315i mutation.
Though treatment options are better than ever, research for even better patient outcomes continues.
While TKI therapy has transformed CML, research continues to try to find even better treatment options for patients – hopefully leading to a complete remission or ‘cure’. Work is ongoing to understand which drugs or combinations of drugs could work best for individual patients. Research across many disciplines including gene therapy and immunotherapy will help achieve even better results for CML patients in the future.