• Clinical science

Chronic myeloid leukemia (CML…)

Summary

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.



Epidemiology

  • Sex: >
  • Peak incidence: 50–60 years

References:[1]

Epidemiological data refers to the US, unless otherwise specified.

Etiology

References:[2]

Pathophysiology

Philadelphia chromosome

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]

Clinical features

Chronic phase

The early stage of CML, in contrast to AML, is not characterized by recurrent infections! The granulocytes produced are fully functional.

Accelerated phase

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]

Diagnostics

Peripheral blood analysis

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)
  • 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]

Differential diagnoses

Disease CBC and peripheral blood smear LAP score Genetics / Cause
Polycythemia vera
  • JAK2 mutation in 95% of cases
Osteomyelofibrosis
  • JAK2 mutation in up to 60% of cases
Essential thrombocythemia
  • JAK2 mutation in 50% of cases
Chronic myeloid leukemia
Leukemoid reaction
  • 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.

Treatment

References:[12][13]

Prognosis

  • Survival rate without treatment:
    • Chronic phase: 3.5–5 years
    • Blast phase: 3–6 months
  • In most patients, life expectancy can be markedly improved through targeted therapy with imatinib. In some cases, it even results in molecular remission.

References:[12][2]