Chronic myeloid leukemia (CML…)

Chronic myeloid leukemia (CML) belongs to the group of myeloproliferative neoplasms. It is a malignancy of the hematopoietic stem cells with excessive proliferation of the myeloid lineage (especially granulocytes). It is caused by a cytogenetic aberration (Philadelphia chromosome 22) that results in the formation of a BCR-ABL fusion gene. The increased activity of this gene's product – a tyrosine kinase – promotes unregulated proliferation of myeloid progenitor cells, which eventually differentiate into mature cells. CML has three distinct clinical phases. The chronic phase is characterized by nonspecific symptoms (fever, weight loss, night sweats) and splenomegaly and can persist for up to 10 years. The accelerated phase is characterized by complications secondary to the suppression of the other cell lines (thrombocytopenia, anemia, recurrent infections). The clinical picture of the terminal phase, blast crisis, resembles that of acute leukemia. Important diagnostic features are severe leukocytosis (> 500,000/μl), basophilia, and extreme splenomegaly. The most important therapeutic principle is targeted therapy with imatinib, which selectively inhibits BCR-ABL tyrosine kinase. This drug has revolutionized CML treatment and greatly improved the prognosis of CML.

• Sex: ♂ > ♀
• Incidence: : peak incidence is 50–60 years

References:^[1]

Epidemiological data refers to the US, unless otherwise specified.

• Idiopathic (in most cases)
• Ionizing radiation (e.g., secondary to therapeutic radiation)
• Aromatic hydrocarbons (especially benzene)

References:^[2]

Philadelphia chromosome

• Reciprocal translocation between chromosome 9 and chromosome 22 → formation of the Philadelphia chromosome t(9;22) → fusion of the ABL1 gene (chromosome 9) with the BCR gene (chromosome 22) → formation of the BCR-ABL gene → encodes a BCR-ABL non-receptor tyrosine kinase with increased enzyme activity
• Result: inhibits physiologic apoptosis and increases mitotic rate → uncontrolled proliferation of functional granulocytes

Malignancy	Detection of Philadelphia translocation
CML	> 90% of patients
ALL	∼ 20% of adults ∼ 5% of children
AML	< 2% of patients

Genetic changes and clinical course

• Additional chromosomal changes and mutations of tumor suppressor genes and oncogenes (p53, Rb1, or Ras), which emerge during the course of the disease, are responsible for the progression from chronic to accelerated phase and, ultimately, the transition to acute leukemia.

References:^[3][2][1]

Chronic phase

• Can persist for up to 10 years and is often subclinical
• When symptomatic, features include:
  • Weight loss, fever, night sweats, fatigue
  • Splenomegaly: abdominal discomfort in the left upper quadrant
  • Lymphadenopathy is not typical in CML.

Unlike AML, CML is not characterized by recurrent infections during early stages, since the granulocytes are still fully functional.

Accelerated phase

• Erythrocytopenia: anemia
• Neutropenia: infection and fever
• Extreme pleocytosis
  • Infarctions: splenic and myocardial infarctions, retinal vessel occlusion
  • Leukemic priapism
  • Terminal phase: myelofibrosis
• Extreme splenomegaly : palpable in lower left quadrant or pelvic cavity

Blast crisis

The blast crisis is the terminal stage of CML.

• Symptoms resemble those of acute leukemia.
• Rapid progression of bone marrow failure → pancytopenia, bone pain
• Severe malaise
• Subtypes :
  • Myeloid blast crisis → AML (⅔ of cases)
  • Lymphoid blast crisis → ALL (⅓ of cases)

References:^[2][4]

Peripheral blood analysis

• CBC and blood smear
  • Leukocytosis with midstage progenitor cells (e.g., myelocytes, metamyelocytes) and mature cells (e.g., neutrophils, myelocytes)
  • Basophilia and eosinophilia
  • Blasts can indicate transition to the accelerated phase.
  • Thrombocytosis

CML causes the most severe leukocytosis (> 500,000/μl) of all forms of leukemia. Increasing basophilia is a sign of acceleration.

• Cytochemistry: ↓ leukocyte alkaline phosphatase (LAP) versus a leukemoid reaction
• Cytogenetics: confirmation of BCR-ABL (Philadelphia chromosome) fusion gene

Low LAP is a distinct feature of CML that distinguishes it from all other forms of leukemia!

Bone marrow

• Hyperplastic myelopoiesis: predominantly granulocytosis
• Elevated granulocytic precursor cells (especially myelocytes and promyelocytes)

WHO classification of the CML phases

CML Phase	Blast count in peripheral blood and bone marrow
Chronic	< 10%
Accelerated	10–19%
Blast Crisis	≥ 20%

References:^[2][1][5][6]

Disease	CBC and peripheral blood smear	LAP score	Genetics/cause
Polycythemia vera	Erythrocytosis Thrombocytosis Leukocytosis	↑	JAK2 mutation in 95% of cases
Primary myelofibrosis	Progressive pancytopenia Dacryocytes	↑	JAK2 mutation in up to 60% of cases
Essential thrombocythemia	Isolated thrombocytosis	↑	JAK2 mutation in 50% of cases
Chronic myeloid leukemia	Extreme leukocytosis Basophilia	↓	Philadelphia chromosome
Leukemoid reaction	Leukocytosis	↑	No mutation Typically secondary to infections or drugs (e.g., steroids) Associated with certain solid tumors (e.g., lung and kidney cancer)

References:^{[7][8][9][10][11]}

The differential diagnoses listed here are not exhaustive.

• Targeted therapy: first-line for chronic and accelerated phase
  • Tyrosine kinase inhibitors: e.g., imatinib, dasatinib, nilotinib
    • Mechanism of action: selectively inhibit the enzyme tyrosine kinase by binding to its active ATP site → no transfer of phosphate (from ATP) to tyrosine residues on the enzyme's substrates (i.e., cell signaling proteins of the BCR-ABL1 pathway) → inhibits proliferation and induces apoptosis of malignant cells that carry the mutant tyrosine kinase
    • Adverse effects include: fluid retention, pulmonary edema, QT prolongation, nausea, vomiting, diarrhea, and pancytopenia
  • Lifelong treatment
• Allogeneic stem cell transplantation: if targeted therapy is not successful or in young patients without any major comorbidities (the only curative option)
• Cell count normalization: supportive therapy if targeted therapy fails
  • Hydroxyurea
• Blast phase: acute leukemia treatment

References:^[12][13]