March 13, 2023
Contributed by Dr. Muneeb Niazi, Medical Fellow at SurvivorNet.
These days, the standard of care for chronic myeloid leukemia (CML) is a type of targeted therapy known as tyrosine kinase inhibitors (TKIs). When a patient begins this treatment, they need to be monitored regularly to ensure their body is tolerating the drugs.
“When someone starts a TKI, what’s nice is you can take this pill at home, but it does require a good deal of work for the patient to do. It really does require a diligent patient and a diligent physician to follow up on the labs,” Dr. Tiffany Tanaka, hematologist/medical oncologist at UC San Diego, tells SurvivorNet. Initially, this could mean undergoing tests every week.
Even with the upkeep, TKIs have changed the game when it comes to treating CML. Before we get into how they work, it’s important to understand what CML does to the blood. The myeloid tissue produces life-sustaining components of the blood, including red blood cells, white blood cells, and platelets. Rarely, the bone marrow can overproduce one or more of these components, which is a recipe for the development of several blood cancers called myeloproliferative neoplasms, one of which is Chronic Myeloid Leukemia (CML).
RELATED: Myeloproliferative Neoplasms
Chronic 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, 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
RELATED: Treatment Options for Myeloproliferative Neoplasms
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. 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)
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 may 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.
TKIs are also not without their side effects. Thus, patients receiving them need to be monitored closely for these in addition to being monitored for the efficacy of the drugs.
TKIs Are Effective Drugs That Require Close Monitoring
Measuring Treatment Effectiveness Through Regular Testing
After starting TKIs, patients are monitored closely to see if the treatment is working or if they need to switch to another medication. Response to these drugs can be measured in many ways, including using hematologic (complete blood count, or CBC), cytogenetics, or molecular analyses.
CBC distinguishes between partial and complete hematologic responses to treatment.
Partial response means:
- Improved but abnormal blood counts
- The continued presence of blasts or immature WBCs in the blood
- Enlarged spleen with possible improvement from baseline
- Improvement in disease symptoms
A complete response means:
- A return to normal blood counts (RBCs, WBCs, and platelets are within the normal range)
- An absence of immature WBCs or blasts in the blood
- A normal-sized spleen
- Freedom from all disease symptoms.
When gauging treatment response cytogenetically, the percentage of the marrow and blood cells with Ph chromosomes dictates the patient response level:
- More than 35% Ph chromosome: minor response
- 1%-35% Ph chromosome: partial response
- 0% Ph chromosome: complete response
Lastly, a molecular response is measured using a very sensitive test called the quantitative reverse transcriptase polymerase chain reaction (Q-RT-PCR) test to measure the levels of the BCR-ABL1 fusion gene within the blood or bone marrow:
- A thousand-fold reduction in the number of cells with the BCR-ABL1 fusion gene: major response
- Undetectable levels of cells with the BCR-ABL1 fusion gene: complete response
A combination of CBC, cytogenetics and Q-RT-PCR is recommended at regular time intervals to monitor treatment response. During the first year, treatment response is evaluated every 3 months. After the first year, testing can be spaced out more for patients with a good response.
For a patient with an ideal response to a TKI, 3-month testing will usually reveal a complete hematologic response but may only show a minor or partial cytogenetic response. At this time, a significant molecular response may not be evident. At the 6-month mark, a continued complete hematologic response and a complete cytogenetic response will usually be seen. After a year of therapy, the patient will likely manifest a major molecular response, which will progress to a complete molecular response with time.
Patients who do not follow this timeline may likely have a suboptimal response to their particular TKI and may benefit from switching to a different TKI. In other cases, a patient may initially have an excellent response to therapy but could start to relapse after a few months or years. This usually happens when CML develops resistance to a TKI, oftentimes due to additional genetic mutations, therefore another TKI must be used to control the disease.
It is important to note that while TKIs may control the disease very well, it is unclear whether they cure CML. Thus, patients will likely need to continue their therapy throughout their lifetime to keep the disease at bay.
TKI Side Effects
Like all therapies, TKIs carry side effects ranging from common to rare but serious. The more common side effects include:
- Stomach pains
- Fluid retention
- Changes in blood counts
- Easy bruising and bleeding
- Shortness of breath
- Skin rashes
- Increase in blood glucose levels.
Rare side effects include a risk of damage to the heart and blood vessels, which can present as irregular heartbeat and narrowed blood vessels, liver damage, stomach bleeds, pancreatitis, and blood clots leading to strokes.
All patients need to be monitored for these side effects. Serious side effects need to be investigated with additional testing, such as liver function tests and electrocardiograms. These side effects may also mean that patients need to be switched to a TKI with a more favorable risk profile.
The more common side effects can be managed with symptomatic or palliative care. There are some misconceptions about palliative care. It is not the same thing as hospice. The National Cancer Institute (NCI) defines palliative care as “an approach to care that addresses the person as a whole, not just their disease” Studies have shown that palliative care, which encompasses many different support services—from symptom management to emotional support and financial help— can be incredibly helpful when it’s incorporated at the start of your cancer journey. Palliative care plans are tailored to address each person’s specific concerns and symptoms. This is care aimed at reducing symptoms and improving the quality of life for the patients. This may include medications to alleviate symptoms like nausea and diarrhea. It can also include certified nutritional support to counter weight loss. This care does not need to be limited to just physical symptoms. Patients can be offered emotional and logistical support through counseling and social work. Such care is most effective when it is started early.
RELATED: Living Better — What is Palliative Care?
- CML treatment has come a long way because of highly specific, effective drugs called Tyrosine Kinase Inhibitors (TKIs). These drugs block the abnormal protein made by the CML cells, eventually killing them. They are especially effective in the earlier phases of the disease.
- Patients receiving TKIs need to be monitored closely for treatment effectiveness and side effects. Monitoring can include regular lab work and specialized testing, based on the needs of the patient.
- While most TKIs have manageable risks, serious side effects can occur and may include damage to the heart and blood vessels, which can present as irregular heartbeat and narrowed blood vessels, liver damage, stomach bleeds, pancreatitis, and blood clots leading to strokes.
- TKIs that are suboptimal for a patient’s CML or cause unmanageable side effects may need to be switched for other TKIs with more favorable risk profiles.