Chronic myeloid leukemia (CML) is a clonal myeloproliferative neoplasm characterized by uncontrolled proliferation of myeloid cells due to the presence of the BCR-ABL1 fusion gene, resulting from the Philadelphia chromosome (t(9;22)(q34;q11)).

The BCR-ABL1 gene encodes a constitutively active tyrosine kinase that promotes abnormal proliferation and survival of myeloid cells.

CML progresses through three clinical phases:

• Chronic phase

• Accelerated phase

• Blast crisis

Without effective treatment, CML may progress from a relatively stable chronic disease to an aggressive acute leukemia-like condition.

Epidemiology

CML accounts for approximately 15% of adult leukemias.

Epidemiological characteristics include:

• Occurs mainly in adults

• Median age at diagnosis is around 50–60 years

• Slight male predominance

• Rare in children

• Incidence increases with advancing age

Risk factors

Radiation exposure

Previous exposure to high-dose ionizing radiation increases the risk of developing CML.

Age

Risk increases with increasing age.

Genetic abnormalities

The major abnormality is:

• Philadelphia chromosome

• BCR-ABL1 fusion gene

Environmental factors

Most cases occur without an identifiable risk factor.

Pathophysiology

CML develops due to acquisition of the Philadelphia chromosome, resulting in formation of the BCR-ABL1 fusion gene.

The BCR-ABL1 protein has abnormal tyrosine kinase activity causing:

1. Increased proliferation of myeloid precursor cells

2. Reduced apoptosis of abnormal cells

3. Expansion of granulocytic cell lines

4. Progressive accumulation of leukemic cells

Disease progression occurs through:

Chronic phase

• Increased mature and immature myeloid cells

• Blast cells <10%

Accelerated phase

• Increasing blast cells

• Blast cells 10–19%

• Increasing genetic instability

Blast crisis

• Blast cells ≥20%

• Behaves similarly to acute leukemia

Clinical presentation

Many patients are diagnosed incidentally following abnormal blood counts.

Clinical manifestations are related to:

• Increased leukocyte production

• Splenic enlargement

• Disease progression

Symptoms

Symptoms due to increased cell production

• Fatigue

• Weakness

• Weight loss

• Fever

• Night sweats

Symptoms due to splenomegaly

• Abdominal discomfort

• Left upper quadrant fullness

• Early satiety

Symptoms due to advanced disease

• Bone pain

• Increasing fatigue

• Recurrent infections

• Bleeding symptoms

Clinical signs

General examination

• Pallor

• Fever

• Weight loss

• Reduced performance status

Abdominal examination

• Splenomegaly

• Hepatomegaly

Hematological findings

May include:

• Marked leukocytosis

• Anaemia

• Thrombocytosis or thrombocytopenia in advanced disease

Differential diagnosis

• Leukemoid reaction due to severe infection or inflammation

• Acute myeloid leukemia

• Other myeloproliferative neoplasms

• Chronic neutrophilic leukemia

• Primary myelofibrosis

Diagnostic criteria

Diagnosis of CML is confirmed by demonstrating:

• Persistent leukocytosis with myeloid proliferation

• Presence of BCR-ABL1 fusion gene

Disease phase classification:

Chronic phase

• Blast cells <10%

Accelerated phase

• Blast cells 10–19%

Blast crisis

• Blast cells ≥20%

Investigations

Laboratory investigations

Full blood count (FBC)

May show:

• Marked leukocytosis

• Anaemia

• Platelet abnormalities

Peripheral blood film

May demonstrate:

• Increased granulocytic cells at different maturation stages

• Increased basophils

• Increased eosinophils

Renal and liver function tests

Including:

• Urea

• Creatinine

• Liver enzymes

Performed before treatment initiation and during monitoring.

Molecular and cytogenetic investigations

BCR-ABL1 analysis

Performed using:

• Polymerase chain reaction (PCR)

• Fluorescence in situ hybridization (FISH)

Used for:

• Diagnosis confirmation

• Monitoring treatment response

Philadelphia chromosome analysis

Used to identify the characteristic chromosomal abnormality.

Staging and classification

CML is classified into:

1. Chronic phase

2. Accelerated phase

3. Blast crisis

Classification is based mainly on:

• Percentage of blast cells

• Blood counts

• Clinical progression

• Molecular findings

Management

Management depends on:

• Presence of BCR-ABL1 mutation

• Disease phase

• Treatment response

• Patient factors

The main goals are:

• Achieve molecular remission

• Prevent progression to blast crisis

• Maintain long-term disease control

Management includes:

1. Targeted therapy for BCR-ABL1 positive disease

2. Cytoreductive therapy when indicated

3. Supportive care

4. Monitoring of treatment response

Non-pharmacological treatment

Supportive care

Includes:

• Adequate hydration

• Monitoring for complications of high white cell count

• Blood transfusion when clinically indicated according to severity of anaemia

Monitoring

Regular monitoring includes:

• Full blood count

• BCR-ABL1 molecular monitoring

• Assessment for disease progression

Stem cell transplantation

Allogeneic hematopoietic stem cell transplantation may be considered in:

• Resistant disease

• Advanced disease phases

• Failure of multiple tyrosine kinase inhibitors

Pharmacological treatment

BCR-ABL1 positive CML

First-line treatment is with tyrosine kinase inhibitors (TKIs).

Chronic phase CML

Characterized by blast cells <10%.

Imatinib – 400 mg – oral – once daily – continuous treatment

Treatment continues until inadequate response, intolerance, or progression.

Accelerated phase CML

Characterized by blast cells 10–19%.

Imatinib – 600–800 mg/day – oral – divided into two doses – until chronic phase is achieved

After achieving chronic phase:

Imatinib – 400 mg – oral – once daily – continuous treatment

Blast crisis CML

Characterized by blast cells ≥20%.

Management depends on previous treatment exposure:

• Patients not previously treated with TKIs are managed similarly to accelerated phase

• Patients already receiving TKIs are treated according to acute leukemia protocols

Second-line TKIs include:

• Nilotinib

• Dasatinib

• Bosutinib

• Ponatinib

These are administered orally according to specialist hematology protocols.

BCR-ABL1 negative disease

When BCR-ABL1 is not detected, cytoreductive therapy may be used.

Hydroxyurea – 40 mg/kg – oral – once daily

Dose adjustment:

• Dose may range according to white blood cell count response

Supportive therapy

Patients with high tumour burden, marked leukocytosis, or those starting cytoreductive therapy should receive prophylaxis against hyperuricemia and tumour lysis syndrome.

Allopurinol – 300 mg – oral – once daily – continued according to risk and treatment response

Additional supportive measures include:

• Adequate hydration should be maintained

• Monitor serum uric acid, renal function, and electrolytes

• Blood transfusion is indicated according to the severity of anaemia

Management according to underlying cause

CML with BCR-ABL1 positivity

• Initiate tyrosine kinase inhibitor therapy

• Monitor molecular response using BCR-ABL1 levels

• Escalate therapy or change TKI if treatment failure occurs

CML with progression to blast crisis

Management follows acute leukemia treatment principles and may include:

• Intensive chemotherapy

• Tyrosine kinase inhibitors

• Consideration of allogeneic stem cell transplantation

Referral

All suspected and confirmed CML patients should be referred to a specialist hematology centre.

Urgent referral indications

• Very high white blood cell count with symptoms

• Suspected blast crisis

• Severe anaemia or bleeding

• Rapid disease progression

• Failure of tyrosine kinase inhibitor therapy

Complications

Disease-related complications

• Progression to accelerated phase

• Blast crisis

• Splenic rupture

• Severe anaemia

• Bleeding complications

Treatment-related complications

• Cytopenias

• Gastrointestinal symptoms

• Fluid retention

• Cardiovascular complications

• Drug intolerance

Prognosis

Prognosis has significantly improved with tyrosine kinase inhibitor therapy.

Outcome depends on:

• Disease phase at diagnosis

• Response to treatment

• BCR-ABL1 molecular response

• Presence of resistance mutations

Patients diagnosed in chronic phase and responding well to TKIs may have near-normal life expectancy.

Prevention

There are no established methods for preventing CML.

Measures include:

• Avoid unnecessary exposure to ionizing radiation

• Reduce occupational exposure to carcinogenic substances

• Early evaluation of persistent unexplained blood count abnormalities