Chronic Myeloid Leukemia (CML) is a cancer of the blood and bone marrow characterized by the overproduction of white blood cells. The development of Tyrosine Kinase Inhibitors (TKIs) has transformed treatment, turning a once life-threatening disease into a manageable chronic condition. These targeted therapy drugs alter the outlook for patients by directly addressing the molecular cause of the cancer.
The Molecular Basis of CML
The origin of CML lies in a specific genetic translocation where a piece of chromosome 9 swaps places with a piece of chromosome 22. This exchange creates a new, shorter chromosome 22, known as the Philadelphia chromosome. The presence of this altered chromosome is a hallmark of CML.
The Philadelphia chromosome creates an abnormal fusion gene called BCR-ABL1, not found in healthy cells. It contains instructions for producing an abnormal protein, a type of enzyme called a tyrosine kinase. Unlike normal tyrosine kinases that regulate cell growth, the BCR-ABL1 protein is unregulated.
This abnormal protein is permanently stuck in the “on” position, continuously signaling bone marrow stem cells to grow and divide uncontrollably. This leads to the overproduction of immature white blood cells (granulocytes) that define CML. The bone marrow becomes crowded with these leukemia cells, hindering the production of normal blood cells.
How Tyrosine Kinase Inhibitors Work
Tyrosine Kinase Inhibitors are targeted therapy drugs designed with a high degree of specificity to interfere with the abnormal BCR-ABL1 protein. This precision allows the drugs to attack cancer cells while causing less damage to healthy cells.
After being taken orally as a pill, the TKI molecule enters CML cells and seeks out the BCR-ABL1 protein. The drug binds directly to the protein’s ATP-binding site. This is the spot the protein uses to get the energy it needs for its continuous growth signals.
By occupying this site, the TKI acts as a blocker, preventing the BCR-ABL1 protein from using energy. This effectively turns the “on” switch to the “off” position, halting the signals that tell leukemia cells to multiply. Without these instructions, CML cells stop dividing and die.
Generations of TKIs for CML
CML treatment has evolved through several generations of TKIs. The first-generation TKI, Imatinib (Gleevec), proved the effectiveness of targeting the BCR-ABL1 protein and established a new standard of care. It moved treatment away from older therapies like chemotherapy and is still used as a first-line treatment for many patients.
Second-generation TKIs were developed following Imatinib’s success. This group includes Dasatinib (Sprycel), Nilotinib (Tasigna), and Bosutinib (Bosulif). These drugs are more potent than Imatinib and work faster to reduce leukemia cells. They are approved as initial treatment options and for patients who cannot tolerate Imatinib or whose leukemia stops responding to it.
A third-generation TKI, Ponatinib (Iclusig), was created to overcome TKI resistance and is reserved for patients whose CML has stopped responding to at least two other TKIs. Ponatinib is important for patients with a specific genetic change called the T315I mutation. This mutation alters the BCR-ABL1 protein, preventing other TKIs from binding to it. Asciminib (Scemblix) is another TKI that works differently and can be used after other TKIs have failed, including in cases with the T315I mutation.
Monitoring Treatment and Managing Side Effects
The primary goal of TKI therapy is to reduce the BCR-ABL1 fusion gene in the blood to undetectable levels. Achieving this state, known as a deep molecular response, is associated with long-term disease control. Doctors monitor treatment effectiveness using a quantitative PCR (qPCR) blood test to track the patient’s response over time.
Regular monitoring helps ensure the TKI is working as expected. For patients who maintain a deep and stable molecular response for at least two years, discontinuing TKI therapy under close medical supervision may be an option. This is referred to as treatment-free remission (TFR).
While TKIs are effective, they can cause side effects, though specific profiles differ between drugs. Patients should report any side effects to their healthcare team, as many can be managed with supportive care or by adjusting the TKI dosage. Common side effects include:
- Fatigue
- Fluid retention (especially around the eyes or in the ankles)
- Muscle cramps
- Skin rashes
- Nausea
- Diarrhea
TKI Resistance and Treatment Adjustments
In some cases, CML cells can change over time and stop responding to a patient’s TKI. This is known as acquired resistance. The most common reason is the development of new mutations within the BCR-ABL1 gene. These mutations can alter the shape of the ATP-binding site where the TKI drug needs to attach.
This change prevents the TKI from fitting into its target, rendering the drug ineffective and allowing leukemia cells to multiply again. The T315I mutation is a well-known example that confers resistance to several TKIs.
When resistance is suspected due to rising levels of the BCR-ABL1 gene detected during routine monitoring, doctors will perform tests to identify the specific mutation responsible. Based on this information, a change in treatment is often recommended. The approach is to switch the patient to a different, later-generation TKI that is known to be effective against the newly identified mutation.