Targeted therapy for chronic myeloid leukemia

Targeted therapy uses drugs to target specific molecules (such as proteins) on cancer cells or inside them. These molecules help send signals that tell cells to grow or divide. By targeting these molecules, the drugs stop the growth and spread of cancer cells and limit harm to normal cells. Targeted therapy may also be called molecular targeted therapy.​

​If you have targeted therapy, your healthcare team will use what they know about the cancer and about your health to plan the drugs, doses and schedules.​

​The targeted therapy drugs used for CML are called tyrosine kinase inhibitors (TKIs). They work by turning off the abnormal tyrosine kinase ​protein​ made by the BCR-ABL gene. This stops the bone marrow from making more cells with this gene.​

​To manage CML, TKIs are taken for as long as the disease responds to them. For most people, this may be for the rest of their lives.​​

​Treatment with TKIs is only effective if you take the drugs as prescribed.

The TKIs used to treat CML are given as pills.

Imatinib (Gleevec) was the first TKI developed to treat CML. Almost everyone diagnosed with CML will be given imatinib as the first treatment. The dose may be increased in the chronic phase if blood cell counts do not improve. It may also be increased if CML progresses from the chronic phase to the accelerated or blast phase. Treatment with imatinib can continue for a long period of time if it controls the disease.

Second-generation TKIs were developed after imatinib. They are better than imatinib at turning off the abnormal tyrosine kinase protein made by the BCR-ABL gene, and they may lower the number of additional chromosome abnormalities (ACAs) that develop in the cells. You may be offered second-generation TKIs if the side effects of imatinib are severe or if CML does not respond to, or stops responding to, imatinib. Second-generation TKIs include:

• dasatinib (Sprycel)
• nilotinib (Tasigna)
• bosutinib (Bosulif)

Ponatinib (Iclusig) is a third-generation TKI. It is more potent than the other TKIs. It may be given if CML doesn't respond to, or stops responding to, other TKIs. It is also used if there are additional chromosome abnormalities. This is because dasatinib, nilotinib and bosutinib can't be used to treat CML that has other gene mutations.

During treatment with TKI drugs, your healthcare team will do regular polymerase chain reaction (PCR) tests to find out how many cells with the BCR-ABL gene are in the blood and bone marrow. If CML doesn't respond to TKI drugs at the beginning of treatment, or stops responding during treatment, it means that the TKI drug you are taking isn't working. This is called TKI resistance.

TKI resistance is caused by changes (mutations) in the cells in addition to the BCR-ABL gene (called additional chromosomal abnormalities, or ACAs). Your healthcare team will do tests to look for ACAs that can cause TKIs to stop working. One of the most common changes is the T315I gene mutation.

Your healthcare team will use the following guidelines to decide if the treatment is working or if CML is TKI resistant. If TKI treatment is working, the percentage of cells with the BCR-ABL gene will start to go down. The longer you take TKIs, the lower the percentage should get. But if TKIs aren't working, the percentage will not go down. If TKIs stop working, the percentage will start to go up.

If CML is resistant to a TKI drug, your healthcare team will try another one. They may also talk to you about a stem cell transplant as a treatment option. If TKI-resistant CML progresses, it may change to look like an acute leukemia. When this happens, you may be offered chemotherapy for acute myeloid leukemia (AML) or chemotherapy for acute lymphoblastic leukemia (ALL).

Taking TKIs for long periods of time can lead to chronic side effects that affect your quality of life, including fatigue, diarrhea, depression and sleep problems. Being able to stop treatment for a while may help lessen these side effects.

It isn't safe to take TKIs during pregnancy. So you may also want to stop TKI treatment if you intend to become pregnant.

Your healthcare team will confirm all of the following before they consider stopping TKI treatment:

• CML was diagnosed in the chronic phase and hasn't progressed.
• CML has always responded to treatment.
• There are no chromosome changes other than the BCR-ABL gene.
• You have taken only one type of TKI or you switched to a second TKI only because you had severe side effects from the first one.
• You have taken imatinib for more than 5 years or a second-generation TKI drug for more than 4 years. (Ideally, you have been on TKI treatment for more than 5 years.)
• You had a deep molecular response of MR4.5 or better for more than 2 years, or of MR4 for more than 3 years.

If you stop taking TKIs, you will need to have PCR tests on a regular basis to make sure that CML doesn't start to progress. Your healthcare team will confirm that you have access to reliable PCR tests and can get the results quickly, and that you are willing to go for more frequent testing. The usual schedule for testing is once a month for the first 6 months, every 2 months until a year has passed, and then every 3 months after that.

When CML maintains a major molecular response after stopping TKI treatment, it is called treatment-free remission.

CML is most likely to start to progress in the first 6 months after stopping TKI treatment. If PCR tests show that CML is getting worse, your healthcare team will start treatment with TKI drugs again. Most people who restart TKI treatment will go back into a major molecular response.

Between 20% and 30% of people may have pain in their muscles or joints in the first few weeks after stopping TKI treatment. The pain is mild for most people, but it may be more troublesome for some. Your healthcare team can help you cope with this side effect.

Side effects of targeted therapy will depend mainly on the type of drug or combination of drugs, the dose and your overall health. Tell your healthcare team if you have side effects that you think are from targeted therapy. The sooner you tell them of any problems, the sooner they can suggest ways to help you deal with them.

Some common side effects of TKIs used for CML are:

• flu-like symptoms, such as fever and chills
• fatigue
• diarrhea or constipation
• sore mouth
• skin problems, including redness, itching and dryness
• abdominal cramps or pain
• headaches
• liver problems
• fluid buildup in the body, including the abdomen, arms and legs
• low blood cell counts, which can cause infection, bleeding and anemia
• tumour lysis syndrome
• heart problems, including fluid around the heart
• kidney problems
• a buildup of fluid around the lungs (called pleural effusion)

Different TKIs may have other side effects. Talk to your healthcare team or pharmacist about what side effects to expect.

Be sure to let your healthcare team know if you are taking any other medicines, vitamins or herbal supplements, or if you use cannabis or other recreational drugs. This is because they can affect the effectiveness or safety of TKIs.

Find out more about targeted therapy. To make decisions that are right for you, ask your healthcare team questions about targeted therapy.

Details on specific drugs change regularly. Find out more about sources of drug information and where to get details on specific drugs.