MEDICAL BLOG: Targeted Therapies for Chronic Myeloid Leukemia

Chronic myeloid leukemia (CML) cells contain an oncogene, BCR-ABL.

(BCR-ABL is not seen 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 known as Tyrosine Kinase Inhibitors (TKIs) target the BCR-ABL and 

are today the standard treatment for CML (in the chronic phase).

These include:

§  Imatinib (Gleevec)

§  Dasatinib 

§  Nilotinib 

§  Bosutinib

§  Ponatinib 

All of these drugs can have serious interactions with other drugs, over the counter supplements, and even certain foods (such as grapefruit and pomegranate). 

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 herbal supplements. 

You also need to check with your doctor before starting any new medicine, to be sure it is safe.It is also important to understand that all of the TKIs can harm the fetus if taken during pregnancy.

IMATINIB:

Imatinib (Gleevec) was the first drug that specifically targeted the BCR-ABL tyrosine kinase protein and is known as a first generation tyrosine kinase inhibitor.CML patients respond to treatment with imatinib, and most of these responses seem to last for many years. 
This drug is taken orally with food once a day. It doesn't seem to make the leukemia go away and stay away, so patients need to take it indefinitely (or until it stops working). 

Common side effects:

• diarrhea
• nausea
• muscle pain
• fatigue. 
• itchy skin rashes
• 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 breathing. If you are taking this drug, tell your doctor right away if you notice sudden weight gain or fluid buildup anywhere in the body or have trouble breathing.
• drop in WBC & platelet counts. 

In some patients, imatinib eventually seems to stop working.

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.

DASATANIB:

Dasatinib (Sprycel) is a second generation tyrosine that is taken orally(by mouth) once or twice daily.

Dasatinib can be used 

* As the first treatment for CML

* It can be used for patients who can’t take imatinib because of side effects 

* If Imatinib is not working. 

Common side effects:

• fluid buildup
• lowered blood cell counts
• nausea
• diarrhoea
• skin rashes. 
• A serious side effect is pleural effusion) and is more common in patients taking this drug twice a day. 

NILOTINIB:

Nilotinib (Tasigna) is another second generation TKI that targets the BCR-ABL protein. 

* Can be used as a first treatment for CML 

* Patient who can’t take imatinib 

* CML no longer responds to imatinib.

Common side effects:

• fluid buildup
• lowered blood cell counts
• Nausea
• Diarrhoea
• high blood sugar
• pancreatitis (rarely)
• This drug can also affect the rhythm of the heart, causing a condition called prolonged QT syndrome. This is why patients should have an electrocardiogram before starting nilotinib and then again while being treated. 

BOSUTINIB:

Bosutinib (Bosulif®) is another TKI that targets the BCR-ABL protein.

Approved by the US Food and Drug Administration to treat patients after they have been treated with another TKI.

Common side effects:

• diarrhoea
• nausea/vomiting
• abdominal pain
• rash
• fever
• fatigue
• low blood cell counts (including low platelet counts, low red blood cell counts, and low white blood cell counts). 

Less common side effects:

• fluid retention
• liver damage, 
• severe allergic reaction. 

PONATINIB:

Ponatinib (Iclusig®) is a new TKI targeting the BCR-ABL protein.

IT HAS SERIOUS SIDE  EFFECTS 

So only used to treat patients with CML if all of the other TKIs don’t work 

or if their leukemia cells have a certain gene change called the 

T315I mutation. 

This mutation (gene change) occurs in the leukemia cells of some CML 

Common Side effects:

• abdominal pain
• headache
• rash 
• fatigue
• High blood pressure
• Blood clots leading to heart attacks and strokes, or block arteries and veins in the arms and legs. 
• Weaken the heart muscle, leading to a condition known as congestive heart failure
• liver problems, including liver failure
• pancreatitis (inflammation of the pancreas, which can lead to severe belly pain, nausea, and vomiting).

Whats new in CML!

Treatment:

Combining the targeted drugs with other treatments:

Imatinib and other drugs that target the BCR-ABL protein have proven to be very effective, but by themselves these drugs don't help everyone. Studies are now in progress to see if combining these drugs with other treatments, such as chemotherapy, interferon, or cancer vaccines might be better than either one alone.One study showed that giving interferon with imatinib worked better than giving imatinib alone. 

A study going on now is looking at combing interferon with nilotinib.Other studies are looking at combining other drugs, such as cyclosporine or hydroxychloroquine, with a TKI.

New drugs for CML:

Because researchers now know the main cause of CML (the BCR-ABL gene and its protein), they have been able to develop many new drugs that might work against it. 

In some cases, CML cells develop a change in the BCR-ABL oncogene 

known as a T315I mutation which is resistant to many of the current 

targeted therapies (imatinib, dasatinib, and nilotinib)

Ponatinib is the only TKI that can work against T315I mutant cells. 

Other drugs called farnesyl transferase inhibitors, such as 

* lonafarnib

* tipifarnib

CML patients may respond when these drugs are combined with imatinib. These drugs are being studied further.

Other drugs being studied in CML include the histone deacetylase inhibitor 

* Panobinostat 

* Proteasome Inhibitor.... Bortezomib (Velcade).

Cancer vaccines:

Cancer cells are different from normal cells, so it is sometimes possible to get the body's immune system to react against them. One way to do this is to use a cancer vaccine -- a substance injected into the body that boosts the immune system and causes it to attack certain cells. Several vaccines are now being studied for use against CML. For instance, in one small study, a vaccine called CMLVAX100 was given along with imatinib and seemed to increase its effectiveness. Research into this and other vaccines is continuing.

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Author- 

   

Dr. Ganjoo 

Head-Yoddhas Medical Expert Panel