How Are TKIs Used to Treat Chronic Myeloid Leukemia (CML)?
- Chronic Myeloid Leukemia (CML) is a blood cancer caused by the excessive production of abnormal white blood cells.
- There are different phases of CML, which are, in order of severity: chronic, accelerated, and blast phases.
- CML treatment has come a long way because of highly specific, effective drugs.
- Tyrosine Kinase Inhibitors (TKIs) block the abnormal protein made by the CML cells, eventually killing them. They are especially effective in the earlier phases of the disease.
- Current available TKIs are: imatinib, dasatinib, nilotinib, bosutinib, and ponatinib.
“A stem cell transplant (or allogeneic transplant), which means you get a transplant from someone else … was the standard of care for this condition for many years before the introduction of these tyrosine kinase inhibitors,” Dr. Javier Pinilla, hematologist/oncologist at Moffitt Cancer Center, tells SurvivorNet. “So interestingly, [stem cell] transplant, these days, is almost completely gone from the chronic phase.”
Read MoreChronic Myeloid Leukemia (CML):
CML is a cancer of the white blood cells (WBCs). Specifically, it affects cells called the myeloblasts, which are the parents of mature, infection-fighting WBCs. These cells undergo a genetic mutation due to the formation of the so-called Philadelphia (Ph) chromosome. This mutation allows the myeloblasts to spill immature WBCs into the blood, bone marrow, and spleen. These immature cells are not fit to fight off infections, and their presence in the body causes a host of problems seen in CML patients.RELATED: Understanding Chronic Myeloid Leukemia (CML)
The Philadelphia (Ph) Chromosome:
The Ph chromosome forms when two originally normal chromosomes, 9 and 22 (normal cells have 46 chromosomes in total), break off and fuse together. This fusion brings certain genes together in an unnatural way. In the case of the Ph chromosome, the BCR and ABL1 genes are joined together, forming the abnormal BCR-ABL1 fusion gene. This gene produces a mutant BCR-ABL1 tyrosine kinase, which is a protein (enzyme) that stimulates the CML cells to proliferate in great quantities.
CML patients may carry other mutations, such as the T315I mutation, which can make them uniquely susceptible and resistant to certain drugs. Thus, each CML patient should receive undergo genetic testing to determine their unique mutation profile and select an appropriate treatment.
The Three Phases of CML:
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.
First Line of Defense Against CML: Tyrosine Kinase Inhibitors
Tyrosine Kinase Inhibitors (TKIs) are targeted therapies. This means that they can exploit the unique features of cancer cells and weaponize them against it. This way, they can eliminate the cancer cells without harming normal, healthy tissues. For CML, the exploitable feature is the abnormal protein product resulting from the Ph chromosome, BCR-ABL1 tyrosine kinase. TKIs block this enzyme, starving the CML cells of their most important growth signal. Ultimately, the cells are killed off.
TKIs really are powerful therapies for CML. Before their introduction, advanced cases of CML were treated with chemotherapy drugs borrowed from acute leukemia (AL) and acute lymphoblastic leukemia (ALL), two other forms of blood cancer. Less than 50% of the patients responded to this cookie-cutter treatment. Even the responders only survived for around 3 to 10 months. This was significantly better than non-responders, who only lived for 1 to 5 months on average. However, there was room for improvement.
RELATED: Treatment Options for Myeloproliferative Neoplasms
The landscape changed with the introduction of TKIs. These drugs could target CML cells specifically and be much more effective. There are several TKIs on the market. Those approved as the first line of defense (initial treatment) against CML include:
- Imatinib (brand name: Gleevec)
- Dasatinib (brand name: Sprycel)
- Nilotinib (brand name: Tasigna)
- Bosutinib (brand name: Bosulif)
- Ponatinib (brand name: Iclusig)
TKIs, however, are not the only treatment for CML. Chemotherapies and immunotherapies can also be used to treat the disease, and are often combined with TKIs for maximal effect, especially in the advanced phases of CML. Furthermore, these therapies are not curative even though they can control the disease for long periods of time. The only curative treatment for CML is a stem cell transplant which replaces the diseased bone marrow with a healthy one from a donor.
Imatinib, The First-Generation TKI:
Imatinib was the first TKI approved by the U.S. Food and Drug Administration (FDA) at the turn of the 20th century. CML patients, especially those in the chronic phase of the disease, respond remarkably well to this drug. Almost all chronic phase patients have their WBC counts return to normal after initiating this drug. This also shrinks their spleens, which are usually painful and enlarged because of the flood of CML WBCs. Another marker of response to TKI treatment is the level of cells with the Ph chromosome. In 80% to 90% of the chronic phase imatinib responders, these cells become undetectable.
Once a patient responds to imatinib, they are likely to remain in remission for long periods of time. It is unlikely for such patients to develop resistance to this drug, but it can happen. However, there are many people who started Imatinib therapy when it was first introduced and remain in remission to this day. This speaks to the remarkable efficacy of this powerful drug.
Beyond its efficacy, imatinib is also an easy-to-take, once or twice-a-day oral medication that is well-tolerated by patients. Side effects are usually mild and manageable. These can include stomach pains, diarrhea, cramps, tiredness, fluid retention often in the legs as well as other organs like the heart and lungs, changes in blood counts, etc.
Patients who never respond to this drug or become resistant to it over the course of their treatment can usually be treated with second-generation TKIs, such as Dasatinib, Nilotinib, Bosutinib, and Ponatinib.
Dasatinib, A Second-Generation TKI With Brain Penetration:
There are variations of the BCR-ABL1 mutations that can make imatinib useless against CML. For a great majority of such cases, dasatinib could be effective. It is a second-generation TKI that was initially approved by the FDA in 2010. Like imatinib, it is a well-tolerated, once or twice-a-day oral medication. It requires stomach acid for absorption so it should not be taken alongside any anti-acid drugs.
Dasatinib is usually the first alternative used by doctors for imatinib non-responders. A remarkable feature of this drug is that it can cross the blood-brain barrier, a feat that imatinib is not as capable of. This makes it an excellent choice for CML which has invaded the central nervous system (CNS), which includes the brain and the spinal cord. The blood-brain barrier is a protective shield around the CNS, which prevents harmful infections from penetrating this critical tissue. This, however, also prevents many drugs from reaching the CNS, which can make treating diseases that involve the CNS especially challenging.
Side effects of dasatinib are usually mild and can include headaches, fever, fatigue, diarrhea, low blood counts, and lung problems, among others.
Nilotinib, A Second-Generation TKI:
This is another second-generation, oral TKI, which can be useful for certain imatinib nonresponders. Like dasatinib, it was approved for use by the FDA around 2010. It is efficacious and usually well-tolerated.
Most of its side effects are like the other TKIs and can include headaches, nausea, diarrhea, fluid retention often in the legs and which can envelop other organs like the heart and lungs, and a change in blood counts. It does, however, have special considerations. It can increase blood glucose levels in almost 40% of patients. Thus, glucose levels need to be closely monitored in patients on nilotinib therapy. It also carries the rare but serious risk of damage to the heart and blood vessels, which can present as irregular heartbeat and narrowed blood vessels. Patients who are prone to these side effects can suffer life-threatening complications, including debilitating strokes.
Therefore, prescribing nilotinib requires careful consideration of its benefits versus risks.
Bosutinib, A Second-Generation TKI:
Bosutinib was approved by the FDA in 2012. It is usually prescribed when one or more of the other TKIs prove to be unreasonable therapies, either due to a lack of disease response or an intolerable volley of side effects. It is an oral medication taken with food once a day.
Common side effects are usually manageable, such as nausea, diarrhea, headaches, a loss of appetite, weakness, fluid retention often in the legs as well as other organs like the heart and lungs, change in blood counts, and ringing in the ears. Serious side effects can occur and include easy bruising and bleeding, blood in the urine and stool, chest pains, shortness of breath, and skin rashes, among others. These require constant monitoring by the prescribing physician.
Ponatinib, A Second-Generation TKI With A Unique Spin:
Like bosutinib, ponatinib was approved by the FDA in 2012 for patients who do not respond to or cannot tolerate other TKIs. However, ponatinib is unique in its ability to target a very specific group of non-responders, those carrying the T315I mutation in their CML cells. This mutation makes CML resistant to all the previously mentioned TKIs: imatinib, dasatinib, nilotinib, and bosutinib. Almost 20% of all imatinib non-responders carry this mutation, making ponatinib an excellent choice.
It is a well-tolerated oral medication, usually taken once a day. Common side effects can include headaches, dizziness, tiredness, loss of appetite, high blood pressure, muscle and joint pain, skin dryness and rashes, and bleeding gums, among others. With careful monitoring during treatment, these side effects are usually manageable. There are occasional serious side effects associated with ponatinib, which include jaundice, stomach bleeding, liver inflammation, blood clots that can cause strokes, and inflammation of the pancreas.
Key Takeaways:
- Tyrosine Kinase Inhibitors (TKIs) block the abnormal protein made by the CML cells, eventually killing them. They are especially effective in the earlier phases of the disease.
- There are different TKIs including Imatinib, dasatinib, nilotinib, bosutinib, and ponatinib.
- The selection of an appropriate TKI depends on a patient's combination of mutations, response to earlier medications, and ability to tolerate the side effects inherent to the drugs.
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