Chronic Myeloid Leukemia (CML)

What is Chronic Myeloid Leukemia in Children?

A slowly progressing disease in which too many white blood cells (not lymphocytes) are made in the bone marrow which is also called Chronic Granulocytic Leukemia, Chronic Myelogenous Leukemia or Chronic Myeloid Leukemia. Chronic Myeloid Leukemia is more common in adults than in children. This arises from abnormality in Blood Stem Cells resulting in proliferation of both mature and immature white blood cells as well as platelets.

Chronic Myeloid Leukemia was the first disease where the molecular abnormality leading to cancer was deciphered. A unique translocation between chromosomes 9 and 22 results in formation of a protein which stimulates the enzyme Tyrosine Kinase leading to uncontrolled proliferation of white blood cells. This abnormality was called the PHILADELPHIA CHROMOSOME. The molecular basis for this was later established as the translocation of BCR gene to the ABL gene.

Natural History of Chronic Myeloid Leukemia

Phases of Chronic Myeloid Leukemia

• Chronic phase: elevated blood counts with enlarged spleen. Patients are asymptomatic or mildly symptomatic.
• Accelerated Phase: The disease starts getting out of hand. The spleen gets bigger despite treatment. The blasts in the blood and marrow start increasing.
• Blast Crisis: This is when the disease develops to a full blown leukaemia with marrow blasts more than 20%.

What Causes Chronic Myeloid Leukaemia?

This is largely unknown as in most cases of leukaemia. However, there are few risk factors for Chronic Myeloid Leukaemia as under

• More common in males than in females
• More common in the elderly with a median age at diagnosis of 65 years
• Exposure to ionising radiation appears to be a risk factor
• Low Immunity
• Inflammatory bowel conditions, such as ulcerative colitis or Crohn's disease, have a higher risk.
• Using pesticides at work

What are the Symptoms?

In most patients there are no symptoms, 25% of the patients are detected when the disease has progressed to an acute leukemia. 25% of patients are detected on routine blood test. 50% of patients are detected on investigation, when they have the following symptoms :-

• Frequent Infections
• Weight loss
• Tiredness and looking pale
• Swollen lymph glands
• Abnormal bruising or bleeding
• Abdominal discomfort due to an enlarged spleen
• Poor appetite
• Sweating at night
• Headaches
• Bone pain

How is CML in Children different from that in Adults?

• CML is less common in children
• Long term outcome of TKI therapy is not known in children. We are not talking of 10 or 20 years of treatment, but treatment for a lifetime.
• BMT should still be considered in children as first line therapy if the right donor is identified.

How do we Diagnose Chronic Myeloid Leukemia?

• Complete Blood Count: The characteristic finding of Chronic Myeloid Leukemia is high white blood cell count with low haemoglobin and increased platelets. Routine examination of the blood gives the diagnosis in most cases.
• Bone Marrow Examination: This is necessary for confirmation of the diagnosis. In chronic phase, the blast count is less than 5%. In accelerated phase, this is between 5-20% and more than 20% in blast crisis. Bone Marrow Biopsy gives an indication of the degree of fibrosis.
• Flow Cytometry: This is often used to confirm the type of transformation to acute leukemia.
• Cytogenetics: This is testing for abnormalities in the chromosomes and is essential for confirmation of the diagnosis
  • Karyotyping: Routine testing for Chromosomes. This establishes the classic translocation between chromosomes 9 and 22.
  • PCR: This is a test done on the DNA and establishes the amount of BCR/ABL product in the blood or marrow. This test is not only critical to diagnosis, but also essential for following the response to treatment.

How do we treat Chronic Myeloid Leukaemia?

Following different types of treatment are available for patients with Chronic Myeloid Leukaemia.

• Targeted therapy
• Chemotherapy
• Biologic therapy
• High-dose chemotherapy with Bone Marrow Transplant

BMT for Chronic Myeloid Leukemia

BMT was the treatment of choice for Chronic Myeloid Leukemia until Tyrosine Kinase Inhibitors (TKI) drugs came in use.

When is BMT needed for Chronic Myeloid Leukemia?

• When patients stop responding to Tyrosine Kinase Inhibitors (TKI)
• When Chronic Myeloid Leukemia is in Accelerated Phase or Blast Crisis.

How is Conditioning for BMT done in Chronic Myeloid Leukemia?

High to Moderate dose of chemotherapy is generally used in conditioning for BMT in younger patients and Reduced Intensity Conditioning in Older patients.

Who can be a donor for BMT?

Although, a matched family donor is preferred, a Half matched (Haploidentical) family donor or an unrelated cord blood are also suitable alternatives.

However a Haploidentical (Half Matched) Donor who has Natural Killer Cell mismatch with the patient provides the best chance of cure

What are the results of BMT in Chronic Myeloid Leukemia?

BMT remains the only curative treatment for Chronic Myeloid Leukemia.

• Chronic Phase: 90% are cured
• Accelerated Phase: 40-60% are cured
• Blast Crisis: 20-40% are cured