CML (Chronic Myeloid Leukemia) is a cancer that begins in the bone marrow and impacts the blood as well as the tissues involved in blood production. It is classified as a myeloproliferative disorder marked by the unregulated growth of myeloid cells, which are the precursors to red blood cells, platelets, and certain white blood cells. CML is a captivating yet intricate illness that exemplifies key concepts in cancer biology, targeted treatments, and the molecular foundations of disease. This article seeks to give an informative overview of CML, covering its pathophysiology, diagnosis, treatment options, and recent research developments.

Pathophysiology of CML

Philadelphia chromosome

The underlying mechanism of CML involves a genetic defect known as the Philadelphia chromosome, which was initially identified in 1960. This chromosomal change arises from a reciprocal exchange between chromosomes 9 and 22, referred to as t(9;22)(q34;q11). This translocation forms a fusion gene called BCR-ABL1, which produces a constantly active tyrosine kinase enzyme.

The BCR-ABL1 protein stimulates the unchecked growth of myeloid cells by activating various signaling pathways that encourage cell reproduction, prevent programmed cell death, and decrease cell adhesion. As a result, there is an increase in the number of immature and abnormal white blood cells in both the bone marrow and bloodstream, which is a characteristic feature of CML.

Phases of CML:

• Chronic Phase
  • Description: This is the initial stage of CML, characterized by a gradual disease progression. 80% patients receive their diagnosis during this phase.
  • Symptoms: Patients may experience few or mild symptoms. Typical signs include fatigue, weight loss, night sweats, and an enlarged spleen (splenomegaly).
  • Blood and Bone Marrow: The white blood cell count is elevated no of blast cell <10%, yet most cells are mature and functional. The bone marrow displays a heightened presence of myeloid cells.

• Accelerated Phase
  • Description: The disease becomes more aggressive during this phase, with an increase in the number of immature white blood cells (blasts).
  • Symptoms: Symptoms are more pronounced, with heightened fatigue, fever, weight loss, and a notably enlarged spleen.
  • Blood and Bone Marrow: The blast count in blood and bone marrow ranges from 10% to 19%. There may also be further genetic abnormalities present.

• Blast Phase (or Blast Crisis)
  • Description: This phase represents the most aggressive form of CML, resembling acute leukemia. The disease advances quickly, and the bone marrow is flooded with immature blast cells.
  • Symptoms: Severe symptoms encompass infections, bleeding, bone pain, and significant splenomegaly.
  • Blood and Bone Marrow: The blast count reaches 20% or more in the blood or bone marrow. The blast cells may show similarities to those found in acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL).

Risk Factor of CML

• Age: The likelihood of developing CML rises with increasing age, and it is most frequently diagnosed in older individuals, with the average age at diagnosis being approximately 64 years.
• Gender: The incidence of CML is slightly higher in men compared to women.
• Radiation Exposure: Significant exposure to high radiation levels, such as from nuclear incidents or radiation treatments for other cancers, is a notable risk factor for CML.
• Genetic Mutation: CML is marked by the presence of the Philadelphia chromosome, which arises from a translocation between chromosomes 9 and 22. This genetic alteration results in the formation of the BCR-ABL fusion gene, which is essential in the development of CML.
• Family History: Although CML is generally not regarded as a hereditary condition, having a close family member with CML or other forms of leukemia may marginally elevate the risk.
• Chemical Exposure: Extended exposure to specific chemicals, such as benzene and other industrial solvents, has been associated with a higher risk of developing CML.
• Previous Cancer Treatment: Certain chemotherapy medications and radiation therapy used to treat other cancers can raise the risk of developing CML as a secondary malignancy.

Clinical Presentation and Diagnosis of CML

Symptoms of CML

In its initial phases, CML may show no symptoms or exhibit vague signs such as:

• Tiredness
• Unintentional weight loss
• Sweating at night
• Abdominal discomfort (due to enlargement of the spleen)
• Increased tendency to bruise or bleed

Diagnosis of CML

• Complete Blood Count (CBC):
  • White Blood Cell (WBC) count: Frequently significantly increased (e.g., > 50,000/µL), with a left shift indicating the presence of immature cells such as myelocytes, metamyelocytes, and blasts.
  • Platelet count: Could be elevated (thrombocytosis).
  • Red Blood Cell (RBC) count: Anemia may be observed.
  • Irregular differential count showing an increase in immature granulocytes (myelocytes, promyelocytes) and basophils.
• Peripheral Blood Smear:
  • Myeloid precursors (myelocytes, metamyelocytes, and blasts).
  • Basophils and eosinophils (indicating basophilia and eosinophilia).
• Bone Marrow Examination
  • Cellularity: Hypercellular marrow because of an increase in myeloid cells.
  • Myeloid-to-erythroid ratio: Heightened (often greater than 10:1).
• Genetic and Molecular Testing
  • Philadelphia chromosome (Ph+): Resulting from a reciprocal translocation between chromosomes 9 and 22 (t(9;22)(q34;q11)), which leads to the creation of the BCR-ABL1 fusion gene.
  • BCR-ABL1 fusion gene: Produces a constantly active tyrosine kinase that promotes unchecked proliferation of myeloid cells.
• Additional Tests
  • Lactate Dehydrogenase (LDH): Usually elevated due to the high turnover of cells.
  • Uric Acid: May be increased as a result of rapid cell degradation.
  • serum iron: Increase
  • Serum vitamin B12 and B12 binding capacity: Increase
  • Serum Calcium : Increase

Treatment of CML

The introduction of tyrosine kinase inhibitors (TKIs) has transformed the management of CML. TKIs specifically target the BCR-ABL1 protein, blocking its action and restoring healthy cell operations.

• Initial Treatments
  • Imatinib (Gleevec): The initial TKI authorized for CML in 2001, it has changed CML from a life-threatening illness to a manageable chronic condition.
• Second-Line TKIs:
  • Dasatinib
  • Nilotinib
  • Bosutinib
• These medications are more effective than imatinib and are recommended for patients who do not respond well to or cannot tolerate imatinib.
• Advanced Treatment Options
  • Ponatinib: A third-line TKI utilized for patients with certain mutations, such as the T315I mutation, which leads to resistance against other TKIs.
• Stem Cell Transplant: This option is considered for patients in the blast phase or those who do not respond to TKI therapy.
• Tracking Treatment Progress
• Patients are assessed using quantitative PCR to determine BCR-ABL1 transcript levels. The objectives are to reach:
  • Complete Hematologic Response (CHR): Normal blood counts.
  • Major Molecular Response (MMR): A significant decrease in BCR-ABL1 transcripts.
  • Deep Molecular Response (DMR): Undetectable or very minimal levels of BCR-ABL1.