Chronic Myeloid Leukemia Notes

Chronic Myeloid Leukemia (CML)

Definition

• Chronic Myeloid Leukemia (CML), also known as chronic myelogenous leukemia, is a type of cancer originating in the blood-forming cells of the bone marrow.

• A genetic change occurs in an early (immature) myeloid cell (cells that produce red blood cells, platelets, and most white blood cells except lymphocytes).

• This change results in an abnormal gene called BCR-ABL, transforming the cell into a CML cell.

• The leukemia cells proliferate, accumulating in the bone marrow and spilling into the blood; they can also settle in other areas of the body, such as the spleen.

• CML is typically slow-growing but can evolve into a fast-growing acute leukemia that is difficult to treat.

Epidemiology

• American Cancer Society's 2023 estimates for CML in the United States:

  • Approximately 8,930 new cases will be diagnosed (5,190 in men, 3,740 in women).

  • About 1,310 deaths are expected (780 men, 530 women).

  • CML accounts for about 15% of all new leukemia cases.

  • Approximately 1 in 526 people in the United States will develop CML during their lifetime.

• The average age at CML diagnosis is approximately 64 years.

• Almost half of CML cases are diagnosed in individuals aged 65 and older.

• CML primarily affects adults and is rare in children.

Risk Factors

• While exposure of skin to strong sunlight is a risk factor for skin cancer and smoking is a risk factor for several cancers, having risk factors doesn't guarantee the disease, and many affected individuals may have no known risk factors.

• Established risk factors for CML:

  • Radiation exposure: High-dose radiation exposure (e.g., atomic bomb survivors or nuclear reactor accident victims) increases CML risk.

  • Age: CML risk increases with age.

  • Sex: CML is slightly more prevalent in males, though the underlying cause is unknown.

• Other factors like smoking, diet, chemical exposure, or infections do not appear to affect CML risk.

• CML does not typically run in families.

Etiology

• Normal cell growth and function depend on the information within the cell's chromosomes.

• Chromosomes consist of long DNA molecules containing our genes.

• Genes dictate how our cells function, and we inherit our DNA from our parents.

• Gene mutations affect more than appearances.

• During cell division, when cells copy DNA, errors can occur, leading to mutations that affect genes.

• Certain genes, called oncogenes, promote cell growth and division.

• Tumor suppressor genes slow down cell division or cause cells to die at the correct time.

• Cancers may result from DNA changes (mutations) that activate oncogenes or deactivate tumor suppressor genes.

• Scientists have made significant progress, in recent years, in elucidating how specific DNA changes can cause normal bone marrow cells to transform into leukemia cells; this is more understood in CML than any other cancer.

• Human cells contain 23 pairs of chromosomes.

• Most CML cases initiate during cell division when DNA is exchanged between chromosomes 9 and 22.

• A translocation occurs where part of chromosome 9 moves to 22, and vice versa, resulting in a shorter chromosome 22 called the Philadelphia chromosome.

• The Philadelphia chromosome is present in the leukemia cells of almost all CML patients.

• The DNA swapping leads to the creation of a new gene (oncogene) called BCR-ABL, which produces the BCR-ABL protein (a tyrosine kinase).

• The BCR-ABL protein causes CML cells to proliferate uncontrollably.

• Rarely, CML patients may have the BCR-ABL oncogene without the Philadelphia chromosome, suggesting the BCR-ABL gene formed differently.

• Very rarely, individuals who appear to have CML lack both the Philadelphia chromosome and the BCR-ABL oncogene; these individuals may have other unknown oncogenes responsible for their disease and may not truly have CML.

• Inherited DNA mutations do not cause CML; CML-related DNA changes arise during a person's lifetime rather than being inherited.

Diagnosis

• The American Cancer Society advises screening tests for certain cancers in asymptomatic individuals, as early detection improves treatment outcomes.

• Currently, no routine screening tests are recommended for the early detection of CML.

• CML may be incidentally discovered during routine blood tests performed for other purposes, such as a routine physical examination, when a high white blood cell count is observed in the absence of symptoms.

• Reporting potential CML symptoms is crucial.

Signs and Symptoms

• CML symptoms are often vague and commonly caused by other conditions.

• Symptoms may include:

  • Weakness

  • Fatigue

  • Night sweats

  • Weight loss

  • Fever

  • Bone pain (due to leukemia cells spreading from the marrow cavity to the surface or into the joint)

  • Enlarged spleen (palpable as a mass under the left ribcage)

  • Pain or fullness in the abdomen

  • Feeling full after consuming a small amount of food

• These symptoms are not exclusive to CML and can occur in other cancers and non-cancerous conditions.

  • Anemia (shortage of red blood cells) leads to weakness, fatigue, and shortness of breath.

  • Leukopenia increases the risk of infections; leukemia cells do not protect against infection like normal white blood cells, despite high white blood cell counts.

  • Neutropenia increases the risk of severe bacterial infections.

  • Thrombocytopenia can cause easy bruising or bleeding, including frequent or severe nosebleeds and bleeding gums.

• Conversely, some CML patients have thrombocytosis (too many platelets); however, dysfunctional platelets can still result in bleeding and bruising.

• The most common sign of CML is an abnormal white blood cell count.

Lab tests

• WB cell counts

  • Most CML patients have elevated white blood cell counts with a high proportion of early (immature) cells called myeloblasts or blasts.

  • Doctors assess the size and shape of cells and check for the presence of granules (small spots in some white blood cells).

  • An important diagnostic factor is whether the cells appear mature (like normal circulating cells) or immature (lacking features of normal cells).

  • CML patients may exhibit low levels of red blood cells or blood platelets.

  • These findings can suggest leukemia, but confirmation requires additional blood or bone marrow tests.

  • Bone marrow biopsy

  • Chemistry tests

  • Genetic tests

  • Imaging tests

Phases of CML

• Most cancers are staged based on tumor size and the extent of cancer spread; however, CML, being a bone marrow disease, is not staged like most cancers.

• The prognosis for CML depends on disease phase, blast count in the bone marrow, patient age, blood counts, and spleen size.

• CML is classified into three phases that help predict prognosis, primarily based on the percentage of immature white blood cells (blasts) in the blood or bone marrow.

Chronic Phase

• Patients in the chronic phase typically have less than 10% blasts in their blood or bone marrow samples.

• These patients usually have mild or no symptoms.

• Most patients are diagnosed in the chronic phase.

Accelerated Phase

• Patients are considered to be in the accelerated phase if any of the following criteria are met:

  • Blood samples contain 15% or more, but fewer than 30% blasts.

  • Basophils account for 20% or more of the blood.

  • Combined blasts and promyelocytes constitute 30% or more of the blood.

  • Very low platelet counts ($100 \times 1,000/mm^3$$$100 \times 1,000/mm^3$$ or less) not caused by treatment.

  • New chromosome changes are present in leukemia cells with the Philadelphia chromosome.

• Accelerated phase CML may present with symptoms such as fever, poor appetite, and weight loss.

• Accelerated phase CML does not respond as favorably to treatment as chronic phase CML.

Blast Phase (Acute Phase or Blast Crisis)

• In this phase, bone marrow and/or blood samples contain 20% or more blasts.

• Large clusters of blasts are observed in the bone marrow.

• Blast cells have spread to tissues and organs beyond the bone marrow.

• These patients often have fever, poor appetite, and weight loss.

• In the blast phase, CML behaves similarly to acute leukemia.

Prognosis

• Besides the CML phase, other factors can help predict survival outcomes and inform treatment decisions.

• Factors associated with shorter survival times are considered adverse prognostic factors.

Adverse prognostic factors:

• Accelerated or blast phase

• Enlarged spleen

• Areas of bone damage due to leukemia growth

• Increased basophil and eosinophil counts in blood samples

• Very high or very low platelet counts=

• Age 60 years or older

• Multiple chromosome changes in CML cells

Survival Rates

• Highly effective CML treatments became available in 2001.

• Long-term survival data for patients treated with these drugs is still being collected.

• Most patients treated with these drugs since 2001 are still alive.

• One study of CML patients treated with imatinib (Gleevec) showed approximately 90% survival at 5 years after starting treatment.

• Most of these patients had normal white blood cell counts and chromosome studies after 5 years on the drug.