Targeted Therapy for Chronic Myeloid Leukemia: Tyrosine Kinase Inhibitors (TKIs)

In Chronic Myeloid Leukemia (CML), the bone marrow (the spongy, red tissue that fills large bones) produces too many myeloid blood cells, which are at various maturation stages including cells known as immature granulocytes, metamyelocyte, and myeloblasts. Platelets and basophils (different myeloid cells responsible, in part, for the allergic response) are also often overproduced at diagnosis.

Excess production of myleloid blood cells in the bone marrow ultimately prevents the normal production of red blood cells, which are important in delivering oxygen to all cells in the body, and can also decrease production of platelets or thrombocytopenia.

Patients with CML may be diagnosed at a routine checkup, or after seeking medical care due to lack of energy and fatigue from anemia, or bleeding, abdominal pain or discomfort, and rarely bruising from insufficient platelets.

Enlargement of the spleen, known as splenomegaly, leads to abdominal and left chest discomfort, feeling full after a small amount of food, or a change in bowel patterns. Other possible symptoms include fever, shortness of breath and bone pain. At diagnosis, most patients, have a white blood count (the number of white blood cells circulating in the blood) increased above normal.

Phases of Chronic Myeloid Leukemia

There are 3 phases of chronic myeloid leukemia: chronic, accelerated, and blast phases. Most patients are diagnosed with CML at the chronic phase when there are no significantly noticeable symptoms through routine checkups and abnormal blood work.

• Chronic phase: Approximately 85% of people are in the chronic phase of CML when they are initially diagnosed. In chronic phase CML, there are less than 5% immature leukemic blast cells (the abnormal white blood cells) in the bone marrow. Chronic phase CML is well-controlled with oral medications (pills taken by mouth) in nearly all cases. Left untreated, patients will eventually progress to the accelerated or blast phase. However, this can take years to happen.
• Accelerated phase: During the accelerated phase, the white blood cells become increasingly unable to mature normally, and there are between 10% – 20% leukemic blast cells in the blood or bone marrow. In this phase, symptoms like night sweats, fatigue, weight loss, and frequent infections start to manifest more clearly as the number of blast cells starts to increase. Accelerated phase CML is more difficult to control with medications, probably because of new mutations that develop in the CML cells. This stage can take from three to nine months. Similarly, if left untreated patients will progress to the blast phase.

• Blast phase: In blast phase of CML (also called “blast crisis”), there are more than 20% blast cells in the blood or bone marrow. This is the last phase of chronic myeloid leukemia and leukemia has become more aggressive with noticeable symptoms. This phase is also called the “blast crisis.” CML can progress to blast phase from the chronic or accelerated phase, or in some cases a person is already in the blast phase at the time of diagnosis. Blast phase CML is difficult to control with medications. Unfortunately, at the blast phase if patients aren't treated, it will likely be fatal.

Most Common Treatments

The main treatment for CML is targeted cancer drugs (such as tyrosine kinase inhibitors). Other possible treatments include chemotherapy and a stem cell transplant.

• Targeted Treatment: For most people, CML is treated with an oral medication, called a tyrosine kinase inhibitor (TKI). This medication blocks the effects of BCR::ABL1 (the abnormal protein found in people with CML).
• Chemotherapy: drugs that carry toxic substances that inhibit the cancer cells. These are mostly used when TKIs aren't effective, or they cause intolerable side effects. (ex. Omacetaxine – brand name: Synribo).
• Stem cell transplantation (also called bone marrow transplantation) is usually used after the disease stops responding or relapses during treatment with a TKI.
• Symptom control: Certain chemotherapy medications (hydroxyurea, busulfan, or interferon alfa) may be used to reduce symptoms of CML in special circumstances, although they do not cure the disease.

Tyrosine kinase inhibitors (TKIs)

Targeted cancer drugs can change the way that cells work and help the body control the growth of cancer. The main type for CML are tyrosine kinase inhibitors. TKIs are an oral medication and they are the initial treatment of choice for most people with CML.

The Philadelphia chromosome, which is a defining characteristic of CML, produces an abnormal protein called BCR-ABL1. TKI treatment blocks the effects of BCR-ABL1, which rapidly kills CML cells. SurvivorNet has put together all the information the philadelphia chromosome and the BCR-ABL1 gene, make sure to check that.

More than two-thirds of patients with chronic phase CML achieve long-term control of the disease with TKIs. Although TKIs have not been proven to cure CML, people who have an excellent response to TKI therapy have expectations for survival that are similar to age-matched individuals without CML. The rates of progression have reduced significantly from over 20% in the pre-TKI era to less than 5% now.

Examples of TKI drugs for CML are:

• Imatinib mesylate (brand name: Gleevec)
• Dasatinib (brand name: Sprycel)
• Nilotinib (brand name: Tasigna)
• Bosutinib (brand name: Bosulif)
• Ponatinib (brand name: Iclusig)
• Asciminib (brand name: Scemblix)

Sometimes the CML cells are tested to see if they have genetic changes (mutations) that may mean that a certain TKI is more or less likely to work.

T315I mutation

Some patients with CML develop a gene change called the T315I mutation that keeps most of the TKIs from working.  Patients with this mutation may be treated with Ponatinib (brand name: Iclusig) or Asciminib (brand name: Scemblix) and are generally encouraged to consider transplantation.

Scemblix and Iclusig

Scemblix® (asciminib) and Iclusig® (Ponatinib) are newer TKIs that are generally reserved for people who have not responded to other TKIs.

These TKIs are usually used for the treatment of CML in the following scenarios:

• Patients with Philadelphia chromosome-positive CML (Ph+CML) in the chronic phase who were previously treated with more than two tyrosine kinase inhibitors (TKIs).
• Chronic phase Ph+CML patients with the T315I mutation.

Side Effects

The decision of which TKI to use is usually based on potential side effects, your medical history, and cost. Most people can return to their usual daily activities after starting treatment with a TKI. The side effects of tyrosine kinase inhibitors are usually mild and should improve with time. They can include:

• Fatigue (feeling and being sick/Tiredness)
• Headaches
• Abdominal (tummy) pain
• Swelling in the face and lower legs
• Muscle cramps/pain
• Rash
• Diarrhea

Regular blood tests and occasional tests of your bone marrow will be carried out to check whether the treatment is working. If it does work, it will usually be taken for life.

Treatment Adherence

It is important for patients to take their TKIs as prescribed by their doctor. Adherence to an oral therapy means that a patient:

• Takes the correct dose of medication
• Takes the medication at the correct time
• Never misses a dose
• Never takes an extra dose
• Does not take a dose with foods, liquids or other medications that are not allowed

In most patients, TKIs can control CML. Patients should not skip doses to try to reduce the side effects of the medication and they should tell their doctors about any side effects that they are experiencing.

Treatment Goals

The primary goals of treatment are to relieve symptoms, help you live as long as possible, and prevent your CML from progressing to the blast phase. Achieving these goals generally requires markedly reducing the number of cells that contain the abnormal “Philadelphia chromosome” and enabling the return of normal (non-leukemic) blood cells.

There are several ways to measure how well your treatment is working, using various blood tests:

• Hematologic response: it refers to the disappearance of CML cells from the blood and a return to normal blood cell counts.
• Cytogenetic response: refers to the disappearance of cells that contain the Philadelphia chromosome from the blood or bone marrow. Measurement of the cytogenetic response can detect as few as one CML cell among 100 normal blood or bone marrow cells.
• Molecular response indicates whether the abnormal BCR-ABL1 gene is present, using a sensitive molecular test called RT-PCR (reverse transcriptase polymerase chain reaction). PCR can detect as few as one BCR-ABL1-positive CML cell among 10,000 to 100,000 normal cells.

Questions to Ask Your Doctor

• Am I eligible to receive TKIs?
• Am I more, or less, likely to respond to this treatment?
• How will I feel during treatment?
• What are the most common side effects of it?
• What will my treatment cost? Will my treatment be covered by my medical insurance?
• Should I get a second option regarding my diagnosis?

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