Chronic myeloid leukemia (CML)

Also known as: Chronic granulocytic leukemia, chronic myelocytic leukemia, chronic myelogenous leukemia

Related conditions: Acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelomonocytic leukemia, chronic neutrophilic leukemia, juvenile myelomonocytic leukemia, other myeloproliferative disorders such as essential thrombocythemia, myelofibrosis, and polycythemia vera

Definition:Chronic myeloid leukemia (CML) is one of the four types of leukemia, cancers of the white blood cells. Patients with CML have a growth of malignant bone marrow cells, and these bone marrow cells begin to accumulate in the blood. Usually, these patients have a chromosome abnormality called the BCR-ABL cancer gene. “Chronic” means this cancer is more slow growing than an acute type of cancer. “Myeloid” describes the type and stage of white blood cell that is affected.

Risk factors: The National Cancer Institute (NCI) reported in 2017 that more than 95 percent of people with CML have a chromosome abnormality called the Philadelphia chromosome (named after the city where it was first documented). The Philadelphia chromosome occurs when a piece of chromosome 22 breaks off at a gene called BCR. If a piece of chromosome 9 breaks at a gene called ABL1 and switches with the break in chromosome 22, the BCR-ABL1 cancer gene forms. This gene instructs cells to make the BCR-ABL1 protein, a tyrosine kinase that leads to uncontrolled cell growth and eventually to CML. This gene appears only in the cells that form blood and is not passed on to other family members. This switch in chromosomes may be affected by very high levels of radiation (such as in atomic bomb survivors) or high-dose radiation therapy for other kinds of cancers. However, most people with CML do not have these risk factors, and others who have these risk factors do not develop CML.

Etiology and the disease process: Like all leukemias, CML begins with a change in a single cell. At diagnosis, patients may be feeling well. Usually, the body makes more white blood cells only when fighting an infection, and when the infection has passed, the number of white blood cells returns to normal. However, if this disease is not treated, the white blood cells begin to increase rapidly and start to circulate in the blood, causing swelling of the liver and spleen. The number of BCR-ABL cancer genes in the body increases. The disease may progress to a phase in which the patient has a low red blood cell count (anemia) and the platelets are not able to function properly. Eventually the ability of the white blood cells to fight infection is affected.

Incidence: According to the American Society of Clinical Oncology (ASCO) in 2016, approximately 10 percent of all leukemia is CML. The American Cancer Society (ASC) estimated that during 2018, 8,430 people in the United States will be diagnosed with CML. Though children may have CML, it is very uncommon; only about 0.7 children in a million and 1.2 teenagers in a million develop CML, as reported by the National CML Society in 2010. Most CML occurs in adults. It is slightly more common in men than women. The risk of getting this cancer increases with age; most patients are adults older than age sixty, with the average age at diagnosis being around sixty-four as of 2018, according to the ASC.

Symptoms: Symptoms of CML usually develop slowly. Patients may find they have this type of cancer after getting blood tests for another condition. Symptoms may include anemia (low red blood cell count), bleeding easily, bone pain, bruising easily, fever, loss of appetite, night sweats, pain or a feeling of fullness below the ribs (especially in the upper left abdomen), paleness, shortness of breath, stomach pain, swollen liver, swollen spleen, tiredness, unexplained or repeated infections, weakness, and weight loss.

Screening and diagnosis: There is no screening test for CML. Generally, CML can be diagnosed from an examination of the blood cells. However, bone marrow tests may be done to look for changes not seen in the blood. Cytogenetic tests (tests that analyze a cell’s chromosomes) may also be used to confirm the diagnosis by looking for the BCR-ABL cancer gene. The results of these tests help determine which type of drug therapy to use and how long treatment should last.

CML has three phases that are determined by how many immature leukemia cells (blasts) are in the bone marrow and blood:

• Chronic phase: Most patients—as many as 90 percent, as reported by the ASCO in 2016—are in this stage when their CML is diagnosed. According to the ACS in 2016, during this time, the blood and bone marrow have fewer than 10 percent blasts. Red blood cells and platelets are affected; however, white blood cells are still fighting infection. This stage may last for years.
• Accelerated phase: During this phase, there are between 10 and 20 percent blasts in the blood and bone marrow, according to the ACS in 2016. Patients may begin to feel ill. They may have anemia, the number of platelets in the blood may drop, and the white cells may either increase or decrease. The number of blast cells begins to increase, and the spleen may swell. At this phase, the disease is progressing, and patients are likely to move into the next phase.
• Blast crisis (or blastic) phase: In this phase, there are more than 20 percent blasts in the blood and bone marrow, according to the ACS in 2016. Patients in this phase often have infections. They may also be short of breath or tired and have stomach pain, bone pain, or bleeding. The number of blast cells in the blood and bone marrow increases, and the number of red blood cells and platelets drops. At this phase, CML may begin to act more like an acute leukemia.

Treatment and therapy: Drugs or chemotherapy are usually used to achieve treatment goals for patients with CML. These goals include bringing the red blood cell and platelet counts back to normal and eliminating all the cells with the BCR-ABL1 gene. This treatment also helps shrink the spleen back to normal size. Treatment does not cure CML. However, patients usually achieve a positive response, during which they feel well and are able to return to normal activities. If treatment is stopped, the symptoms are likely to flare up again. This may also happen if a patient becomes resistant to the drug treatment.

Targeted therapies such as tyrosine kinase inhibitors (TKI) are commonly used as a first-line treatment for chronic stage CML to stop uncontrolled cell proliferation. Blood counts return to normal for those who experience a complete hematologic response to the TKI treatment. Similarly, immunotherapy with such agents as interferon can bring white blood cell counts down.

Another possible treatment for CML is to have white blood cells removed from the blood (leukapheresis). This may help if a patient has a very high white blood cell count, so high that the white blood cells are interfering with blood flow to parts of the body, such as the brain.

Monitoring whether treatment is working is important with this disease. Patients will continue to have blood tests to see if red blood cell, white blood cell, and platelet counts are returning to normal. A blood test or bone marrow biopsy (surgically removing some bone marrow) can show whether the BCR-ABL1 gene count is decreasing. Cytogenetic tests such as fluorescent in situ hybridization (FISH) or polymerase chain reaction (PCR) may be used to monitor the level of BCR-ABL1 genes. Other tests, such as computed tomography (CT) scans or ultrasounds, may be used to see how this cancer is affecting other parts of the body, such as the spleen.

A bone marrow or stem cell transplant may help some CML patients. A transplant is a high-risk procedure but is the only cure for CML. Whether a patient is a good candidate for a bone marrow transplant depends on the patient’s age and overall health, how the patient is responding to treatment with drugs, and how well donor cells and patient cells match. Transplants are generally more successful in younger patients and in those patients who are still in the chronic phase. Donor lymphocyte infusions may be performed after transplantation.

Prognosis, prevention, and outcomes: There is no known way to prevent CML. A bone marrow or stem cell transplant is the only cure for CML; however, many patients can control CML with drug therapy.

Outcomes for this disease depend on many factors, including age, size of spleen, and blood cell counts. The median survival rate for CML was historically four to six years. As of 2016, the ACS reported that the five-year survival rate of patients taking the TKI drug imatinib may be as high as 90 percent. The National CML Society further noted that between 2005 and 2009, CML patients had a median life expectancy of seventy-five as compared to seventy-eight for the general population in 2010.

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