Chronic Myeloid Leukemia (CML)

What is Chronic Myeloid Leukemia?

Like all leukemias, chronic myeloid leukemia is a cancer of the blood and bone marrow. Leukemia occurs when the bone marrow starts making too many cancer cells that crowd out healthy blood cells. Without enough healthy blood cells, the body can’t fight infection, and the blood doesn’t function correctly.

CML is a chronic leukemia. That means it develops slowly over time. So it may be weeks or months before children develop symptoms. In contrast, acute leukemias make children ill very quickly because symptoms develop rapidly.

CML is very rare in children. Only 110-120 cases are seen each year in the United States and Canada. It makes up about 3 percent of pediatric cancers.

About 90 to 95 percent of children with CML have a genetic mutation called the Philadelphia chromosome. Drugs called tyrosine kinase inhibitors (TKIs) that target this cancer-causing mechanism of CML are the first line of treatment.

Every human being normally has 23 pairs of chromosomes. They carry all the genetic information (genes) that make up a person. A mutation (mistake) in genes can cause a disease such as cancer to occur.

The Philadelphia chromosome mutation forms when a piece of chromosome 9 and a piece of chromosome 22 break off and trade places. The bcr-abl gene is formed on chromosome 22 where the piece of chromosome 9 attaches. This gene makes an enzyme called tyrosine kinase. It causes too many blood-forming stem cells to become white blood cells (granulocytes or blasts.) Drugs called tyrosine kinase inhibitors (TKIs), which are designed to stop the enzyme, are the front line of therapy for CML.

The Philadelphia chromosome is not passed from parent to child. It occurs sporadically and at random.

Signs and Symptoms of Chronic Myeloid Leukemia

CML is a chronic disease, which means it develops slowly, unlike acute leukemias in which symptoms happen quickly. Children with CML may not have any symptoms at first. Once they do develop, common symptoms include:

Tiredness and weakness
Weight loss
Fever
Night sweats
Pain or feeling of fullness under the rib cage
Bone and joint pain

Diagnosis of Chronic Myeloid Leukemia

Results of blood and bone marrow tests suggest the diagnosis of CML. Further tests will confirm the diagnosis, determine the genetic basis of the disease, and if it has spread to other places in the body.

The types of medical tests include:

Physical exam and history
Blood test
Bone marrow test
Tests on bone marrow cells to examine chromosome and gene changes

At first, a physician will perform a physical exam and look at the patient’s medical history. During the physical exam, the doctor will check general signs of health, including signs of disease, such as lumps or anything else that seems unusual. The eyes, mouth, skin, and ears will be looked at carefully. A nervous system exam may be done. The doctor will feel the patient’s abdomen for signs of an enlarged spleen or liver.
Complete blood count

Doctors will order a blood test called a complete blood count. A sample of blood is drawn and checked for the:
- Number of red blood cells and platelets
- Number and type of white blood cells
- Amount of hemoglobin in the red blood cells
- Portion of the blood sample made up of red blood cells
In leukemia, the blood may have too many white blood cells and many of these cells can be blasts, an early form of cell that is normally found only in the bone marrow in healthy children.

Blood chemistry studies

A blood sample is checked to measure the amounts of certain substances released into the blood by organs and tissues in the body. An unusual (higher or lower than normal) amount of a substance can be a sign of disease.
Doctors may begin to suspect leukemia after conducting a physical exam, taking a medical history, and looking at the results of blood tests.
Bone marrow tests like bone marrow aspiration and biopsy will confirm a diagnosis of cancer and pinpoint the type of cancer. Most children are asleep (sedated) during the procedure. If awake during the procedure, patients are given appropriate pain medicine.

Bone marrow aspiration: Doctors will obtain a bone marrow sample by inserting a thin, hollow needle into the hipbone. A pathologist will view the bone marrow under a microscope to look for signs of cancer.

Bone marrow biopsy: Doctors will remove a small piece of bone tissue to determine how much the cancer has spread in the bone marrow. The biopsy is typically performed right before or after the aspiration.

How is a bone marrow aspiration/ biopsy performed?
- Patients will lie on their side on the bed, or, less commonly, sit up with legs bent and crossed at the ankles.
- The doctor or nurse practitioner will feel the patient’s lower back to find the right spot for the test.
- Next, the health care provider will put on gloves and clean the patient’s back with a germ-killing soap. Then, the health care provider might place plastic towels over the back, leaving only a small area of skin showing.
- If the health care provider is going to be awake during the aspirate or biopsy, numbing cream will be placed on the spot where the bone marrow aspirate or biopsy will be taken about one hour before the procedure. Liquid numbing medicine might be injected at the procedure site.
- The health care provider will push a needle through the skin into the bone marrow. If both an aspiration and biopsy are done, a separate needle will be used for each procedure.
- The health care provider will take out the needle, clean the spot with alcohol, and put on a bandage.
Bone marrow tests are usually required to diagnose leukemia.

If cancer is determined, more tests will be performed to pinpoint the subtype of the cancer. These tests include:

Immunophenotyping is used to diagnose specific types of leukemia by comparing the cancer cells to normal cells of the immune system.

Immunohistochemistry and flow cytometry are the laboratory tests.
- Immunohistochemistry is a test that uses antibodies to show specific proteins in a sample of tissue. The complexes of proteins and antibodies are stained brown or red and can be seen under a microscope.
- In flow cytometry, cells are stained with a light-sensitive dye, placed in a fluid, and passed in a stream before a laser or other type of light. The test measures the number of cells, the percentage of live cells, and certain characteristics of cells, such as size, shape, and the presence of tumor markers on the cell surface.
Cytogenetic analysis involves laboratory tests in which pathologists look for certain changes in the chromosomes.

One such test is FISH (fluorescence in situ hybridization). This test looks at genes or chromosomes in cells and tissues. Pieces of DNA that contain a fluorescent dye are made in the laboratory and added to cells or tissues on a glass slide. When these pieces of DNA attach to certain genes or areas of chromosomes on the slide, they light up.
The doctor may recommend running laboratory tests to identify specific genes, proteins, and other factors involved in the leukemia. This examination is important because cancer is caused by mistakes (mutations) in the cell’s genes. Identifying these mistakes helps diagnose the specific subtype of leukemia. Based on that information, doctors can choose treatment options tailored to the individual case. Children whose leukemia shows mutations associated with a good outcome may be prescribed less toxic treatments. On the other hand, doctors may prescribe more intensive treatments for patients with a leukemia with mutations associated with poorer outcomes. Mutations may be identified for which a treatment targeted to that specific mutation are available.

Tests to determine if the cancer has spread include:

A lumbar puncture is performed to collect a sample of cerebrospinal fluid from the spinal column to determine if the cancer has spread to the central nervous system. This procedure is also called an LP or spinal tap.

A needle is placed between two bones in the spine and into the fluid around the spinal cord. A sample of fluid is removed. It is checked under a microscope for signs that leukemia cells have spread to the brain and spinal cord. Our bodies make spinal fluid constantly, so the body quickly replaces the small amount an LP takes.
An X-ray is a type of energy beam that can go through the body and onto film, making a picture of areas inside the body on a computer screen or special film. The chest X-ray is done to see if leukemia cells have formed a mass in the middle of the chest.

Treatment for Chronic Myeloid Leukemia

Treatment depends on the phase of the cancer. CML has 3 phases. The phase depends on the number of leukemia (blast) cells in the blood and bone marrow.

Chronic: Fewer than 10% are blast cells.

Accelerated: 10-19% are blast cells.

Blastic: 20% or more are blast cells. When tiredness, fever, and an enlarged spleen occur during the blastic phase, it is called a blast crisis.

Targeted therapy

First-line treatment for CML is usually the drug imatinib (Gleevec®). It is a tyrosine kinase inhibitor (TKI), which is designed to stop the enzyme, tyrosine kinase, which causes cancer cells to grow out of control. Other TKI drugs called dasatinib and nilotinib are sometimes used if patients can’t tolerate imatinib.

The reason imatinib and other tyrosine kinase inhibitors (TKIs) are usually the choice for front-line therapy is that these medicines typically have few serious side effects. However, because the TKI inhibitors most of the time do not eradicate CML, they may potentially be taken by patients for the rest of their lives. Because TKIs are relatively new drugs, doctors don’t yet know the side effects of taking these medicines for what could be several decades.

Learn More About Targeted Therapy

Hematopoietic cell transplant

An allogeneic hematopoietic cell transplant (also known as bone marrow transplant or stem cell transplant) is another treatment option for CML. A transplant can cure CML, but the treatment can have serious side effects. In an allogeneic transplant, children receive hematopoietic (blood cell-producing) cells from a healthy donor. Patients must have a suitable donor to be eligible for a transplant. Before receiving the donor cells, the patient’s existing blood cells in the bone marrow are destroyed by chemotherapy and sometimes radiation. The patient receives the healthy donor cells through an infusion. If successful, these new donor cells will grow into and replace the patient’s cells. As a result, the patient should start to produce healthy blood cells.

Prognosis of Chronic Myeloid Leukemia

When discussing cancer survival statistics, doctors often use a number called the 5-year survival rate, the percentage of patients who live at least 5 years after their cancer is diagnosed. For chronic leukemias, 5-year survival rates are less helpful because children may live for a long time with leukemia without actually being cured. Five-year survival rates for pediatric chronic myeloid leukemia (CML) are 80-90 percent.

Focus of Current Chronic Myeloid Leukemia Research

CML cells are not typically eradicated (destroyed) with TKI alone. Bone marrow transplant can potentially cure CML, but it has lifelong, potentially life-threatening complications. Research question: Is it possible to eradicate CML cells with other treatments?
There are several side effects associated with the prolonged use of TKIs in children, particularly those that affect growth and development and fertility.

Research question: Is it possible to intervene early in the treatment course to reduce these complications?

Treatment outlook (prognosis) is based on the adult experience. Researchers are working to develop and implement a score system for prognosis in children.
There is a subset of children who have been in remission for a prolonged time. Research questions: Is it possible to stop or modify the dosage of TKI?
Which are the best candidates to stop the medication? Is there a possibility of reducing the dose of the medication?
The natural history of CML in children receiving TKI for a long time has not been established. Research question: Is it possible to create a pediatric CML registry to follow these patients for life?

Current treatment of CML in children is based on treatment in adults. However, over the past few years, particularly with the introduction of TKI inhibitors, there has been an increasing concern that pediatric CML has many unique aspects that need to be addressed and investigated separately.

This concept has been corroborated by the several genomic differences between pediatric and adult cases, some of these associated with response to therapy. Clarification of these findings and evaluating their impact on the disease course have implications for the management of children with CML. For example, identification of genetic changes, potentially targeted by other drugs, might be used with TKIs to eradicate the leukemic cells, which is not possible presently without bone marrow transplant.

Current prognostic scores that predict outcome have not been developed for children. A systematic investigation of a large number of children with CML treated with TKI inhibitors might provide information to improve treatment.

It is still unknown why a subset of children with CML treated with TKI inhibitors develops off-target side-effects. Likely host genetic factors mediate these responses. Investigation of possible host factors that are associated with TKI toxicity might reveal a subset of patients who might benefit from alternative treatment such as bone marrow transplant.

The intervention aimed to reduce lifelong side effects, such as using growth hormone for children with short stature associated with TKI inhibitors, is another area for clinical investigation. Taking into account the long life expectancy of children and the relatively short period of about 15 years that TKI has been utilized, there are still uncertainties about the potential side effects in individuals exposed to TKI for longer periods. Hence, carefully monitoring of these children represents another area of research. The indication for bone marrow transplant is an area of investigation where the benefits and toxicity of the transplant have to be weighed with those of disease control and acute and long-term complications of TKI inhibitors.

Finally, for patients who remained in molecular remission for several years, discontinuation of TKI has been associated with a disease-free state in about 40% of them. Attempts to identify patients for whom TKI can be safely stopped is also an area of investigation.

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Reviewed: June 2018