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What Can We Do After Imatinib Treatment Failure in Chronic Phase CML (Chronic Myeloid Leukemia)?

News August 14, 2020 | CanadaOnlineHealth

Chronic myeloid leukemia (CML) is a myeloproliferative disorder of stem cells. About 20% of all leukemia in adult is CML.

In people with CML a section of chromosome 9 switches places with a section of chromosome 22, creating an extra-short chromosome 22 and an extra-long chromosome 9.

The extra-short chromosome 22 is called the Philadelphia chromosome, and is present in over 90% of people with CML.

This translocation (switch) creates a new gene called BCR-ABL. This gene will tell the abnormal blood cell to produce too much of a tyrosine kinase protein, referred to as the BCR-ABL protein. This protein promotes cancer by allowing certain blood cells to grow out of control. They build up in large numbers, crowding out healthy blood cells and damaging the bone marrow.  

Imatinib is the first line of tyrosine kinase inhibitor (TKI) to treat chronic phase of CML, but resistance has been a significant problem. For patients failing a TKI, a treatment change is mandatory to limit the risk of progression and death.

What Is Chronic Myeloid Leukemia (CML)?

CML is called chronic because the disease typically progresses slowly. The term myeloid has to do with, or is related to, bone marrow—a sponge-like tissue found in the center of most bones.

What Is Ph+ CML?

More than 95% of people with CML have what is called the “Philadelphia chromosome.” These patients have Ph+ CML, which stands for Philadelphia chromosome–positive chronic myeloid leukemia.

The name of the chromosome comes from where it was first discovered by researchers at the Fox Chase Cancer Center and the University of Pennsylvania, both in Philadelphia.

TKIs Used to Treat Chronic Phase CML

Since 2001, a class of prescription medications called tyrosine kinase inhibitors (TKIs) has helped transform Philadelphia chromosome–positive chronic myeloid leukemia in chronic phase (Ph+ CML-CP) from a type of leukemia that was life-threatening into a manageable disease that more people are living with.

All this progress has led some people to talk about Ph+ CML-CP as a “good cancer.” But in reality, there’s no such thing. That’s why it’s important to make sure your blood is getting the treatment—and the attention—it deserves.


Imatinib (Gleevec) was the first drug to specifically target the BCR-ABL tyrosine kinase protein, because of this it's known as a first-generation tyrosine kinase inhibitor.

Almost all CML patients respond to treatment with imatinib, and most of these responses seem to last for many years. Imatinib is taken by mouth as a pill with food, usually once a day.

Generic imatinib is also available. Studies have shown that it works as well as and causes the same kinds of side effects as the brand name, Gleevec.

In some patients, imatinib seems to stop working overtime. This is known as imatinib resistance. Resistance to imatinib seems to be caused by changes in the genes of the CML cells.

Sometimes this resistance can be overcome by increasing the dose of imatinib, but some patients need to change to a different drug, such as one of the other TKIs.


Dasatinib (Sprycel) is another TKI that targets the BCR-ABL tyrosine kinase protein. Because it was developed after imatinib, it's called a second-generation TKI. This drug is a pill taken once a day with or without food.

Dasatinib can be used as the first treatment for CML, but it can also be helpful for patients who can’t take imatinib because of side effects or because imatinib isn’t working.


Nilotinib is another second-generation TKI that targets the tyrosine kinase protein.

This drug can be used as a first treatment for CML and is also used for people who can’t take imatinib or whose CML no longer responds to it.

Tasigna® (nilotinib) capsules is a prescription medication that has been proven effective among 2 key groups:

  • People who were newly diagnosed with Ph+ CML-CP

  • People who switched to Tasigna from another medication due to side effects or because they were no longer responding to their prior treatment.


QTc Prolongation and Sudden Death:

Tasigna can cause QTc prolongation, a possibly life-threatening heart problem. QTc prolongation causes an irregular heartbeat, which may lead to sudden death. Call your doctor right away if you feel lightheaded, faint, or have an irregular heartbeat while taking Tasigna. These can be symptoms of QTc prolongation.

  • Your doctor should check your heart with a test called an electrocardiogram (ECG) before starting nilotinib (Tasigna) and periodically thereafter
  • Do not take Tasigna if you have long QTc syndrome or low levels of potassium or magnesium in your blood
  • Tasigna can interact with many medicines and supplements. This may increase your chances for serious and life-threatening side effects. Do not take any other medicine while taking Tasigna unless your doctor tells you it is okay to do so
  • Food and grapefruit products increase the amount of Tasigna in your body. This may increase your chances for serious and life-threatening side effects. Take Tasigna on an empty stomach
    • Avoid eating food for at least 2 hours before the dose is taken, and avoid eating food for at least 1 hour after the dose is taken
    • Avoid grapefruit, grapefruit juice, and any supplement containing grapefruit extract while taking Tasigna

TKIs Used When Firstline TKIs Stop Working

Even if patients do take the medication correctly, CML may still become resistant to a TKI, which is why it is also important to receive regular monitoring with cytogenetic testing, FISH, or PCR to see how well the drug is continuing to work.

Bosutinib and ponatinib are newer drugs but both have also produced complete cytogenetic responses in people with CML. Because of possible severe side effects, caution and careful monitoring is needed if ponatinib is recommended only after other drugs have stopped working.


Bosutinib (Bosulif) is another TKI that targets the BCR-ABL tyrosine kinase protein. It can be used as the first treatment for CML, but most often it’s used if another TKI is no longer working.


Ponatinib (Iclusig) is a newer, third generation TKI targeting the BCR-ABL protein. Because this drug can cause some serious side effects, it's only used to treat patients with CML if all of the other TKIs don’t work or if their leukemia cells have a gene change called the T315I mutation. Ponatinib is the first TKI to work against CML cells that have this mutation.

More Information About Targeted Therapy

To learn more about how targeted drugs are used to treat cancer, see Targeted Cancer Therapy.

To learn about some of the side effects listed here and how to manage them, see Managing Cancer-related Side Effects.


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