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10 Facts about CML
Chronic Myeloid Leukaemia is a cancer of the bone marrow which causes it to make too many immature white blood cells.
Bone marrow contains early progenitor cells called stem cells which, over time, mature into myeloid stem cells or lymphoid stem cells. A myeloid stem cell goes on to further matures and become either red blood cells that carries oxygen around the body, platelets need to form blood clots to stop bleeding or white blood cells like lymphocytes, neutrophils, monocytes etc. which are involved in mounting an immune response in order to combat bacterial diseases and viral infections.
With CML, too many of immature white cells are created by the original stem cells. Such cells are incapable of maturing in the right way, so are not able to carry out their normal immune function. These abnormal cells are leukaemia cells. Over time, the numbers increase in the bone marrow crowding out healthy white cells.
For the vast majority of patients diagnosed in chronic phase, CML is no longer fatal. CML used to have a poor outcome for many who were not eligible for Stem Cell Transplantation, but since the advent of TKI therapy treatment has been revolutionised in the last two decades.
Before 2001, treatment options for CML were limited to chemotherapy and for eligible patients with an HLA matched donor, a stem cell transplant. For the majority survival between 3-5 years was the median survival rate. Thankfully, over 90% of chronic phase patients achieve their normal life-span with good quality of life. This is thanks to a class of targeted therapies called TKIs. In 2011 a clinical study of chronic phase CML reported that after a follow-up time of 8 years over 95% of patients treated with TKI therapy had survived, which is similar to what you would expect in the general population. Only about 1% of those in the study died of CML over those 8 years.
A new class of drugs called Tyrosine Kinase Inhibitors (TKI) are responsible for revolutionising the treatment of CML.
TKIs have been the most successful targeted therapies ever developed for any cancer. The very first TKI was called Imatinib (brand name Glivec/Gleevec) and was approved for use in 2001 specifically for CML. Since then, other TKIs have been developed, giving unusually good 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.
CML is caused by the fusion of two genes: BCR and ABL1.
The fusion of 2 genes located on chromosomes 9 and 22 respectively, creates a new ‘oncogene’ called BCR-ABL1. This new 'fusion gene' is located on chromosome 22. It is referred to as the Philadelphia Chromosome, since it was first discovered by two researchers based in Philadelphia USA. Because genes carry the instructions to create cell signalling proteins, much like a very specific recipe, the existence of the Philadelphia chromosome leads to the creation of an abnormal protein that signals for uncontrolled replication of abnormal white blood cells in the marrow. It is not currently known why people might develop the Philadelphia Chromosome. However, possible exposure to ionising radiation is a known risk factor.
Although CML has a genetic abnormality at its root, it is not inherited from parents so it cannot be passed on to children.
Most of us think that the genes we are born with are the genes that we have for the rest of our life. But genes can change over time in small ways. Sometimes this does not cause problems, but sometimes it can be the cause of more serious health problems like CML.
An abnormality in a stem cell inside the bone marrow is known to be the cause of PH+ 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 and babies.
Over a lifetime, approximately 1-2 people in every 100,000 develop CML. Whilst the incidence rates (the number of people each year who develop CML) remains unchanged. Since the advent of TKI therapy, disease prevalence (the number of people living with CML within a given population) continues to increase as patients that previously did not survive are now living out their normal life span, very close to or the same as that of the normal population.
The median age at diagnosis is 56 years old (meaning half the cases diagnosed are older and half are younger).
The incidence rate of PH+cml is pretty even around the world, although there is a slightly younger population are diagnosed in the Asia Pacific regions.
The earlier that CML is diagnosed, the better the treatment options are.
CML has three phases: Chronic Phase, Accelerated Phase and Blast phase, also referred to as Blast Crisis. The majority of patients in western countries are diagnosed during the Chronic Phase.
When CML progresses to the Blast phase it is very difficult to manage and behaves more like an acute leukaemia. However, more intensive treatment can bring it back to a 2nd chronic phase for a short time, in preparation for a stem cell transplant in eligible patients. If CML in the Blast phase does not respond to high dose chemotherapy in preparation for an SCT, survival is usually reduces to a few months.
TKI therapy for the majority is not a 'cure' for CML. However, in a small but significant group who respond well to TKi therapies and achieve stable deep molecular responses, it can be possible for some to stop therapy. The achievement of TFR is only successful in 40% of those who maintain a deep molecular response (DMR) over some years so for the majority of people it is unlikely they will maintain TFR. However, studies like the DESTINY trial in the UK has shown that dose reduction for those who maintain stable molecular responses can successfully control this disease over the long term with a lessening of side effects and an improvement in quality of life.
When trying to see if TFR is an option in those with DMR, once medication is stopped, more regular qPCR tests will be needed to monitor the percentage of the BCR-ABL1 oncogene. Studies have shown that although the genetic marker is still detectable at an extremely low level, some can remain in treatment free remission (TFR). One theory is that the patient’s immune system 'relearns' how to control the abnormal cells and those effectively keeps the disease at very low or undetectable levels without therapy.
This is an area of ongoing research and several clinical studies are in place to identify which patients might be suitable to achieve TFR and stop taking TKI therapy for the long term.
It is important that patients successfully maintaining TFR are monitored regularly by qPCR to effectively guard against a possible molecular relapse. If molecular relapse occurs, studies show that TKI therapy can be re-introduced and such patients regain their previous molecular response levels within 5-6 months.
Some patients can develop other mutations which might cause resistance to a particular TKI.
TKi resistant mutations can be present at diagnosis or arise during TKI therapy. Different mutations cause resistance to particular TKIs. When imatinib was introduced, it was the only TKI available to the wider CML population and when a small number of patients developed resistance to that particular TKI, more mutations with more a less resistance were identified. However, with the advent of the second and third generation (2G and 3G) TKIs namely dasatinib, nilotinib, bosutinib and ponatinib were successful in treating patients who had developed resistance to imatinib.
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 with the T315i mutation. Another drug call aciminib (developed by Novartis) will hopefully be available soon to the small sub-population who do not response optimally to the other 5 TKIs.
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.