Chronic myeloid leukemia: see what is known about the disease

The incidence of chronic myeloid leukemia (CML) is one to two cases per 100,000 people per year, corresponding to 15% of leukemias in adults.

The preferred age range is between 45 and 55 years, although it can occur, more rarely, in the elderly, children and adolescents.

Classically, CML manifested itself in three consecutive phases:

• the chronic phase in which the patient remains clinically and laboratory stable for 3 to 5 years;
• the accelerated phase generally characterized by one or more of the following findings: significant enlargement of the spleen, presence of more than 15% blasts, more than 20% basophils, and thrombocytopenia; and
• the call blast crisis an exacerbation of leukemia that is difficult to control with treatment. This phase is characterized by the presence of 30% blasts or extramedullary leukemic infiltration. Depending on the nature of the blast cells, the exacerbation may be lymphoid (30% of cases) or myeloid (70% of cases).

CML is a disease that involves a specific chromosomal alteration with environmental influences, such as exposure to radiation and chemical agents.

The genetic event responsible for CML consists of a reciprocal translocation t(9;22) (q34;q1.1) in hematopoietic stem cells. Approximately 95% of CML cases have the translocation between chromosomes 9 and 22, which results in the Philadelphia (Ph) chromosome.

Cytogenetic detection of this translocation identifies typical CML. The detection of this abnormality in the 1960s at the University of Pennsylvania was the first evidence that cancer could arise from acquired genetic alterations.

Later studies in this regard demonstrated that chromosomal translocation produces a chimeric gene, formed by the fusion of two genes: the breakpoint cluster region (BCR) gene — located on chromosome 22 — and the abelson oncogene (ABL) gene — located on chromosome 9 — producing an active BCR-ABL transcript on the rearranged Philadelphia (Ph) chromosome.

In CML, BCR-ABL transcripts may have different sizes because chromosomal breaks occur at different sites in the BCR gene, resulting in two messenger ribonucleic acid (RNA) isoforms (b3a2 and b2a2), which are generally translated into a protein of approximately 210 kDa with tyrosine kinase function.

Some CML patients may have an alternative breakpoint on chromosome 22, resulting in a 190 kDa protein.

Approximately 50% of patients are completely asymptomatic, and the diagnosis is made with a blood count, performed for any clinical situation, pre-operatively or even during a check-up.

Systemic symptoms may occur, such as fatigue, tiredness, sweating or weight loss. Due to the enlarged spleen, there may be distension or an increase in abdominal volume, pain or a feeling of fullness. It is common to have an increase in uric acid or signs of gouty arthritis.

Splenomegaly occurs in 50% to 80% of cases; anemia, in approximately 50%; and large leukocytosis (> 100,000/mm3), in 50% to 70% of patients. A possible finding is thrombocytosis (> 600,000/mm3). An investigation for CML should always be performed in patients suspected of essential thrombocythemia.

The white blood cell differential shows a left-shifted scaling of mature neutrophils to myeloblasts. Basophilia and eosinophilia are common findings. Leukocyte alkaline phosphatase is usually low.

Bone marrow (BM) study by myelogram or biopsy shows granulocytic hyperplasia. Other nonspecific biopsy findings include reticulin fibrosis and vascularization.

The final diagnosis is made by searching for the Ph chromosome, with karyotype analysis, preferably in a BM sample, using G-band staining. In urgent situations, the BCR/ABL rearrangement can be tested using Fish, a fast and specific technique in which molecular probes are used to identify chromosomal anomalies.

The PCR technique is most frequently used to detect BCR-ABL rearrangements.

Prognostic analysis can be performed using several indexes, of which the Sokal prognostic score is the most common, taking into account four variables:

• spleen size;
• percentage of blasts;
• age; and
• platelet count (> 700,000/mm3).

Historically, until 1950, the main therapeutic resource for the treatment of CML was radiotherapy. In 1953, Galton successfully introduced oral busulfan and, in 1972, hydroxyurea became the main drug used in the management of CML, producing hematologic control with few side effects.

However, these therapeutic measures, despite producing clinical and hematological control of patients, do not alter the natural history of the disease represented by the evolution to the accelerated and blastic phases, with consequent death.

Bone marrow transplantation (BMT) was the only curable treatment. Today, it is practically limited to a few specific cases.

Since the approval in 2000 of the first tyrosine kinase inhibitor, imatinib, this drug has become the first-line treatment of choice in CML.

These drugs represent one of the greatest therapeutic advances in the management of CML. And they were the basis for other so-called targeted therapies in other tumors.

The experience gained with this product, which acts at the molecular level, has shown how knowledge of the biology and pathophysiology of a disease can be useful in developing a therapeutic action.

Today, other drugs can be used in the treatment of CML, either in the first line or in resistant patients or in patients with mutations. We can mention Dasatinib, Nilotinib, Bosutinib and recently Ponatinib and Ascimetinib.

We can say that patients who respond to these medications can have a normal life expectancy and studies are showing that people with strict responses for more than four years and under surveillance can have their medication suspended.

For me, who participated in multicenter studies with so-called first and second generation drugs, it is a privilege to see such an important change in medicine.

This content was originally published in Chronic myeloid leukemia: see what is known about the disease on the CNN Brasil website.

Source: CNN Brasil