Tyrosine Kinase Inhibitor (TKI) Therapy for Chronic Myeloid Leukemia (CML): The Basics and New Developments

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What is Chronic Myeloid Leukemia (CML)?

CML is a cancer of the WBCs. It starts in cells called the myeloblasts, which are the parents of mature, infection-fighting WBCs. Myeloblasts undergo a spontaneous change within their chromosomes (which contain DNA) that results in the formation of the so-called Philadelphia (Ph) chromosome. This mutation allows the myeloblasts to produce vast quantities of immature WBCs. These cells are not capable of fight off infections, and their presence in the body causes the signs and symptoms experienced by CML patients.

RELATED: Understanding Chronic Myeloid Leukemia (CML)

The Ph chromosome forms when chromosomes 9 and 22 (normal cells have 46 chromosomes in total) break off and fuse together. This fusion joins the DNA and its genes in an unnatural way. In the case of CML, the BCR and ABL1 genes are fused to form the abnormal BCR-ABL1 fusion gene. This gene produces an abnormal BCR-ABL1 tyrosine kinase, which is a protein (enzyme) that stimulates the CML cells to proliferate in great quantities.

CML is classified into three distinct phases, primarily based on the number of immature white blood cells, called blasts, in a patient's blood and circulation. These are chronic, accelerated, and blast phases. These phases have different treatments and patient outcomes, making them a key part of any CML diagnosis.

What are Targeted Therapies?

While all cells within the body share the same DNA, they have certain unique characteristics, which allow certain cells to divide to form the skin while some form the stomach. These characteristics can be unique proteins produced by these cells, which will enable them to do their function. Producing such unique proteins usually requires certain genes within the DNA to either be turned on or turned off. These cells, under normal conditions, do not divide indefinitely. Once they have formed a fully mature cell, such as a skin cell, they stop dividing.

Cancer cells also express unique proteins that are different from those found in normal tissues. Oftentimes, these proteins are the products of abnormal genes, which are also not present in healthy cells. These genes form through errant genetic changes and mutations. Such mutations and their protein products ultimately allow the cancer cells to proliferate unchecked. This feature is a hallmark of cancer.

Such unique genetic mutations and proteins can be used as "targets" for cancer drugs. By doing so, these drugs can spare healthy body tissues, which do not possess these targets. This is unlike chemotherapy, which is indiscriminately toxic to all body cells. By sparing normal tissues, targeted therapies can avoid many of the unpleasant side effects normally associated with chemotherapy, such as mouth sores and ulcers, debilitating nausea and vomiting, etc. Targeted therapies are, however, not without their side effects. These side effects are dependent on the specific kind of targeted therapy used.

There are various kinds of targeted therapies. Some are monoclonal antibodies, which are proteins that can attach to protein structures on the outside of cancer cells, effectively inactivating them. The antibodies can also carry lethal chemotherapy drugs, which can be injected into the specific cancer cells to kill them. Other targeted drugs can stop certain enzymes used by the cancer cells to grow. TKIs are one such therapy.

RELATED: Targeted Therapy for Chronic Myeloid Leukemia: Tyrosine Kinase Inhibitors (TKIs)

What Do Tyrosine Kinase Inhibitors (TKIs) Target?

TKIs block the abnormal protein product resulting from the Ph chromosome, BCR-ABL1 tyrosine kinase. By doing so, they starve the CML cells of the necessary growth signal which ultimately kills these cells.

"To oversimplify… imagine the videogame, Pac-Man. These energy packets [Adenosine triphosphates (ATPs). These are energy stores within cells] that go into the mouth of the Pac-Man [BCR-ABL1 tyrosine kinase], causing it to change its conformation and shape… [This] forces the CML cells to multiply. All of the TKIs block the entrance of the energy packet into the mouth of the Pac-Man, [so it] cannot change its confirmation," explains Dr. Eric Winer, Clinal Director for Adult Leukemia at the Dana-Farber Cancer Institute.

There are several TKIs on the market. Those approved as the first line of defense against CML include:

• Imatinib (brand name: Gleevec)
• Dasatinib (brand name: Sprycel)
• Nilotinib (brand name: Tasigna)
• Bosutinib (brand name: Bosulif)
• Ponatinib (brand name: Iclusig)

While TKIs can be extremely effective, CML cells can develop additional genetic changes and mutations which can make these drugs ineffective. Dr. Winer elaborates, "nature tends to be smarter than those of us who practice medicine, and it makes mutations and finds ways around [TKIs]." This often makes it necessary to use drugs that can overcome these mutations. One such mutation is the T315I mutation. Almost 20% of all imatinib nonresponders carry this mutation. Of all the TKIs, ponatinib has shown some unique efficacy in such cases. However, a newer drug, asciminib (brand name: Scemblix), which works in a way that is different from all other TKIs, could be even more effective for T315I carriers.

A Unique Drug For CML: Asciminib

Asciminib targets the BCR-ABL1 tyrosine kinase, but instead of binding to the same location on this protein as other TKIs, it binds to another unique site on this protein. When anything occupies this location, the BCR-ABL1 protein reverts to an inactive form. The CML cells, therefore, lose the signal required for their growth.

Because asciminib engages a unique port of the kinase, it can inhibit it even when the CML cells have mutations that allow them to escape the older TKIs.

Continuing his Pac-Man analogy, Dr. Winer says, "imagine asciminib binding somewhere outside of the mouth opening, [such as the] cheek. By binding to the cheek, it prevents the mouth from closing, it prevents that confirmational change [that is required by CML cells]. And therefore, it has the same effect no matter what the mutation is in the mouth area."

As of now, this drug is FDA-approved for chronic phase CML patients who have failed to respond to at least two older TKIs or carry the T315I mutation. It is an oral medication taken once or twice daily. Asciminib is not side effect free. It carries the risk of nausea, tiredness, fatigue, skin rashes, diarrhea, muscle pains, and respiratory infections. It can also cause some abnormal values on laboratory testing, such as increased blood triglycerides (fat products), low hemoglobin, low WBC counts, low platelets, and increased markers of kidney or liver damage. Most side effects, however, are mild and can be managed by an experienced physician.

Key Takeaways:

• Targeted therapies have changed the face of CML treatment as they can exploit the unique features of CML cells and weaponize them against it. Tyrosine Kinase Inhibitors (TKIs) are targeted therapies used to treat CML.
• TKIs block the abnormal protein made by the CML cells, eventually killing them.
• There are different TKIs including Imatinib, dasatinib, nilotinib, bosutinib, and ponatinib.
• Oftentimes, CML cells can develop mutations, which can render the TKIs ineffective.
• A relatively new drug, asciminib, works through a unique mechanism. This allows it to block the abnormal protein even if it has such mutations.
• All TKIs, including asciminib, have side effects, which are often milder than those associated with chemotherapy.

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