Targeted therapies for chronic myeloid leukemia

In the last 10 years, new drugs that target specific parts of cancer cells have become a standard treatment option for many people with cancer. Chronic myeloid leukemia (CML) cells contain an oncogene, BCR-ABL, that isn't found in normal cells. This gene makes a protein, BCR-ABL, which causes CML cells to grow and reproduce out of control. BCR-ABL is a type of protein known as a tyrosine kinase. Drugs that target BCR-ABL, known as tyrosine kinase inhibitors (TKIs), have become standard treatment for CML. These drugs are less likely to affect normal cells, so their side effects are generally not as severe as those seen with standard chemotherapy drugs or with interferon (described in the “Interferon therapy for chronic myeloid leukemia” section). Still, these drugs do have side effects, some of which are discussed below. It is also important to understand that all of the TKIs can cause harm to the fetus if taken during pregnancy. These drugs seem to work best on CML that is still in the chronic phase, but some of the newer drugs also help patients with more advanced disease.

Imatinib

Imatinib (Gleevec) was the first drug to specifically target the BCR-ABL tyrosine kinase protein, and it quickly became the standard treatment for patients found to have CML. Because it was the first TKI, imatinib is 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. This drug doesn't seem to make the leukemia go away and stay away, so patients need to take it indefinitely (or until it stops working). Imatinib is taken by mouth as a pill with food, usually once a day.

The possible side effects of imatinib are usually less severe than those seen with standard chemotherapy drugs or with interferon (described in the “Interferon therapy for chronic myeloid leukemia” section). But side effects can be more serious at higher doses of the drug.

Common side effects can include diarrhea, nausea, muscle pain, and fatigue. These are generally mild. Itchy skin rashes occur in about 30% of people on the drug. Most of these symptoms can be treated effectively, if needed.

Another common side effect is fluid buildup around the eyes, feet, or abdomen. In rare cases the fluid may collect in the lungs or around the heart, which can cause trouble with breathing. Some studies have suggested that some of this fluid buildup may be caused by effects of the drug on the heart, though this is rare. It's not yet clear how serious this is or if it might go away if treatment is stopped. If you are taking this drug, tell your doctor right away if you notice sudden weight gain, trouble breathing, or fluid buildup anywhere in the body.

Many drugs can interact with imatinib, causing problems. Be sure that your doctor always has an up-to-date list of any medicines you are taking, including over-the-counter medicines, vitamins, and supplements.

Another possible side effect is a drop in a person's white blood cell and platelet counts. When this happens at the beginning of treatment, it might be because the blood-forming cells that are making these are part of the malignant process. If this is the case, normal blood-forming cells take over and the blood counts will begin to rise to normal over time. Your doctor might tell you to stop taking the drug for a short period if your blood counts get too low. This can also happen later on in treatment. In the past, low red blood cell counts were treated with a red cell growth factor, such as erythropoietin (Procrit^®) or darbepoietin (Aranesp^®), but these drugs are used less often now. Instead, your doctor may lower the dose of imatinib to see if counts improve.

In some patients, imatinib eventually seems to stop working. 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 described further on.

Dasatinib

Dasatinib (Sprycel) is another tyrosine kinase inhibitor that targets the BCR-ABL protein. Because it came after imatinib, it is called a second generation TKI. Like imatinib, this drug is taken by mouth as a pill.

Dasatinib was first used to treat CML in patients who couldn't take imatinib because of side effects or because imatinib wasn't working. Later studies showed that when it was used as the first treatment, it worked better than imatinib for many patients with CML. It has now been approved to be used as the first treatment for CML.

The dose of dasatinib that was first used was 70 mg twice a day. Later, doctors realized that giving 100 mg once a day works just as well with fewer side effects, and so this dose is used most often. The dose for patients in accelerated or blast phase is 140 mg once a day.

The possible side effects of dasatinib seem to be similar to those for imatinib, including fluid buildup, lowered blood cell counts, nausea, diarrhea, and skin rashes. A serious side effect that can occur with this drug is fluid buildup around the lung (called a pleural effusion). This side effect is more common in patients taking this drug twice a day. The fluid can be drained off with a needle, but it can build up again, and may require the dose of dasatinib to be decreased.

As with imatinib, there are many drugs that interact with dasatinib and should be avoided. Be sure that your doctor always has an up-to-date list of any medicines you are taking, including over-the-counter medicines.

Nilotinib

Nilotinib (Tasigna) is another second generation TKI that targets the BCR-ABL protein. Like dasatinib, this drug was initially approved for use in people who couldn't take imatinib or whose CML no longer responds to it. This includes patients in accelerated and blast phase. It has also been studied as a first treatment in a clinical trial comparing nilotinib to imatinib in patients who were newly diagnosed with CML. In this study, nilotinib was more effective than imatinib, and nilotinib is now approved as a first treatment for CML.

Side effects of nilotinib seem to be mild, but can include fluid buildup, lowered blood cell counts, nausea, diarrhea, and some lab test abnormalities. It can cause high blood sugars and pancreatitis, although this is rare. This drug can also affect the rhythm of the heart, causing something called prolonged QT syndrome. This usually doesn't cause any symptoms, but can be serious or even fatal. This is why patients should have an electrocardiogram (EKG) before starting nilotinib and then again while being treated.

Like other tyrosine kinase inhibitors, certain drugs can interact with nilotinib and should be avoided. This drug can cause a serious (or even fatal) heart rhythm problem, so it's especially important to be sure that your cancer doctor is aware of any medicines you take, including over the counter medicines and supplements. You also need to check with your doctor before starting any new medicine, to be sure it is safe.

Bosutinib

Bosutinib (Bosulif^®) is another TKI targeting the BCR-ABL protein. At this time, this drug is only FDA approved to treat patients after they have been treated with another TKI.

Common side effects are usually mild and include diarrhea, nausea, vomiting, abdominal pain, rash, fever, fatigue, and low blood cell counts (including low platelet counts, low red blood cell counts, and low white blood cell counts). Less often, this drug can also cause problems with fluid retention, liver damage, and severe allergic reaction. Your doctor will check blood work regularly to watch for problems with your liver and low blood counts.

Like other TKIs, bosutinib can interact with a number of other drugs, so it is important to be sure that your cancer doctor is aware of any medicines you take, including over the counter medicines and supplements. You also need to check with your doctor before starting any new medicine, to be sure it is safe.

Ponatinib

Ponatinib (Iclusig^™) is a new TKI targeting the BCR-ABL protein. This drug is used to treat patients with CML after they have already been treated with another TKI. This drug often works when all of the other TKIs don’t. In some patients with CML, treatment with a TKI can cause the cancer cells to develop a particular gene change (called the T315I mutation) that makes other TKIs not work. Ponatinib is the first TKI to work against CML cells that have this mutation.

This drug is taken as a pill, once a day.

Most side effects are mild and can include abdominal (belly) pain, headache, rash or other skin problems, and fatigue. High blood pressure is also fairly common, and it may need to be treated with a blood pressure drug. Less often, more serious side effects can occur, such as blood clots affecting arteries that can cause heart attacks or stroke, liver problems, and pancreatitis (inflammation of the pancreas, which can lead to severe belly pain, nausea, and vomiting).