Overview 

Chronic Myeloid Leukaemia (CML) is a blood cancer that affects cells within your bone marrow, the key site of blood cell production. When cells replicate, unexpected changes to genes may occur, leading to excessive replication and an increased likelihood of malformed blood cell formation. The increased presence of these malformed blood cells may cause various patient symptoms. For decades, treatments were either too risky or not specific enough. However, the development of Tyrosine Kinase Inhibitors (TKIs) changed this completely, and TKIs are now the key first option of treatment for many patients. 

Summary of chronic myeloid leukaemia 

CML is one of several forms of blood cancer known as leukaemia. This disease affects bone marrow cells on their journey towards becoming fully-formed blood cells, through the process of cell replication.

CML consists of three key phases:¹

• Chronic phase: This is the stage in which most patients receive a diagnosis, as excessive blood cell growth elevates white blood cells and platelets in blood test results 
• Accelerated phase: With cell proliferation remaining uncontrolled, underdeveloped white blood cells called blasts begin to form
• Blast phase: it is in this stage, blasts can escape the bone marrow and invade other tissues and organs within the body

White blood cells help your body fight infections, so when more of these cells are immature, your immunity is compromised as a result. This means that a plethora of symptoms may start to develop, including:

• Fever
• Loss of appetite and weight 
• Joint and bone pain 

Additionally, patients may also have a swollen spleen, as this is a key organ within your body that blasts migrate to.² The spleen is situated underneath the left side of the rib cage; if enlarged, the patient may have subtle discomfort that is amplified when a health provider feels your tummy. 

Patients may remain in the chronic phase for several years, and advancement towards the accelerated and blast phases can happen at any time. This is why it is important for individuals to be placed on treatment as soon as possible, to hinder that progression from occurring. 

What causes chronic myeloid leukaemia 

For decades, it has been challenging for scientists and healthcare professionals to determine the key causes of CML. However, there is one particular underlying theory that gradually emerged to the forefront of consideration, and inspired the development of Tyrosine Kinase Inhibitors (TKIs). The action of TKIs is easier to understand when you explore the science underpinning their purpose. 

Within your cells, some molecules control their function; these are known as genes, and their structure is coded by a transcript known as DNA. DNA is stored within chromosomes, and during the process of cell replication, there may be changes to these chromosomes. 

One type of chromosome change that can take place is known as translocation, where two chromosomes exchange sections to form new chromosomes. In the case of CML, there is one particular chromosome formed by translocation that is regarded as a key instigator of CML progression. 

This is known as the Philadelphia Chromosome, which is formed by an exchange of segments between chromosomes 9 and 22. The Breakpoint Cluster Region (BCR) of chromosome 22 fuses with the Abelson murine leukaemia (ABL1) on chromosome 9, to form the BCR-ABL1 segment of the chromosome. This is the code for the BCR-ABL1 gene, which forms a Tyrosine Kinase (TK) cell receptor.³

As a result, the emergence of the Philadelphia Chromosome was crucial in making CML treatment more specific to the disease.³ The subsequent association with its BCR-ABL1 product is what sparked the development of a breakthrough drug, which is now your initial standard therapy for CML. 

What are tyrosine kinase inhibitors (TKIs)?

TKIs are a category of drugs that prevent activation of the BCR-ABL1 TK. BCR-ABL1 is activated by a molecule known as ATP, so TKIs bind to the ATP binding site on BCR-ABL1 to stop this from occurring.³  

Normally, growth factors bind to TKs to turn them on, so they end up firing off a signalling cascade, causing mass cell division. This process continues up to the point their switch is turned off. With CML, myeloid cell mutation causes the formation of faulty BCR-ABL1 TKs that remain on from the moment the growth factor switches them on. 

Overview of CML treatment goals 

When treating you for CML, your healthcare provider is looking at three key responses: 

• Haematological response (HR): the extent to which the numbers of white blood cells and platelets decrease towards normal levels 
• Cytogenetic Response (CyR): the proportion of cells containing the Philadelphia chromosome
• Molecular Response (MR): the proportion of cells containing the BCR-ABL1 gene

The key goals of treatment over several years are for patients to achieve the following two goals: 

• Complete CyR (CCyR): less than 1% of bone marrow cells contain the Philadelphia chromosome
• Major MR: BCR-ABL1 gene is present in less than or equal to 1 in every 1000 cells 

Ideally, however, healthcare providers would want patients to reach a state of Deep MR (DMR); this means that the BCR-ABL1 gene is present in less than or equal to: (a) 1 in every 10000 cells or (b) 1 in every 100000 cells. 

How monitoring tests are conducted 

For HR, a healthcare provider will need to take a sample of blood from the patients’ veins every 3-6 months. A needle attached to a tube is inserted through their skin and into one of their veins, for blood to then travel through the needle and tube into a sample bottle. This can be a little uncomfortable, but the patient is allowed to look away or do something to take their mind off things. 

For MR, blood will also need to be taken, but a Polymerase Chain Reaction (PCR) test will need to be conducted. This is a very sensitive test in determining how well the patient is responding to therapy, therefore complementing less specific results (like the HR and CCyR) very well. This test is completed every 3 months, followed by every 3-6 months according to their own experience with treatment. 

For the CyR, a sample of cells is usually taken from your bone marrow, but this procedure is rarely needed due to the MR result being strongly specific. If anything, it is more likely to be ordered if the patients’ healthcare provider needs further information (following abnormal HR and a concerning MR), or if there are worries about the patients’ case disease progression.. 

Why treatment response matters 

Using the indicators outlined in the previous section of the article, healthcare providers are able to judge whether the treatment has been effective enough. If they feel the patient would produce a stronger response to a different TKI, they may well choose to move the patient onto that particular drug. 

Many patients are commenced on a first-generation of TKI known as Imatinib, which was approved for use in CML patients in the early 2000s. A key international study demonstrated its effectiveness in driving a significant proportion of patients towards CCyR and MMR over ten years.⁴

However, as years have gone by, it has emerged that some patients may have resistance to Imatinib or produce an insufficient response to the therapy. This is why further generations of TKIs have been developed since. Whilst the side-effects are stronger in these TKIs, they have been shown to provoke deeper treatment responses within the patients using them. 

Second-generation TKIs are up to 50 times more likely to attach themselves to the ATP binding region and inhibit the BCR-ABL1 TK.³ Moreover, in one particular trial, the TIDEL-II study, it was concluded that an earlier switch to Nilotinib (one key second-generation example) from Imatinib was a significantly better approach when handling Imatinib intolerance.⁵

TKI resistance 

One particular cause of TKI resistance that has been spotlighted in recent years is point mutations in the BCR-ABL1 gene; a common mutation of focus has been T315I.³ Gene mutations like T315I alter the code for the protein formed, which changes their shape and thus, their ability to bind to other molecules (including medications).³

Third-generation and newer-generation TKIs have therefore been produced to overcome this resistance issue. Whilst third-generation TKIs are more likely to result in vascular issues than first and second-generation TKIs, newer-generation TKIs (such as Asciminib) currently have a better side-effect profile.⁶

Side effects of TKIs

Even though your health provider will assist with managing your experiences with medication, these are some key examples of symptoms to keep track of. 

• Fluid retention 
• Diarrhoea, nausea and vomiting 
• Blood in your stool or vomiting of blood (due to gastrointestinal bleeding) 
• Cardiovascular symptoms: slowing of your heart rate, chest pain, raised blood pressure 
• High blood sugar 
• Kidney disease (which may present as having trouble urinating or producing sufficient urine) 

FAQs 

How will I be taking TKIs?

TKIs are usually issued as a liquid or pill. 

How often will I need to take them per day? 

This will depend on your cancer type and the stage you are at, progression-wise. The common frequency of pill and liquid consumption is 1-2 times a day. 

Will I need to be on TKIs forever? 

With CML, you will likely be on medication for a long while, or the rest of your life. This is to ensure that Treatment Free Remission (TFR) is achieved; TFR can be very challenging to pinpoint. 

Summary 

We hope this article has provided a balanced picture of how TKIs help CML patients and the signs to be aware of. It is important to know that nerves over blood cancer treatment are completely normal, as there is a lot of information to get your head around.