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 (up to > 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.

Philadelphia chromosome

• Reciprocal translocation between chromosome 9 and chromosome 22 → formation of the Philadelphia chromosome t(9;22) → fusion of the ABL gene with the BCR gene on 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 functioning 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 clinically unremarkable
• Weight loss, fever, night sweats, fatigue
• Splenomegaly: abdominal discomfort in the left upper quadrant
• Swollen lymph nodes are not typical in CML.

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

Accelerated phase

• Erythrocytopenia: anemia
• Thrombocytopenia: petechial bleeding
• 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
  • Extreme leukocytosis with midstage progenitor cells (e.g., myelocytes, metamyelocytes)
• 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)
• 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 and, initially, megakaryocytosis
• Elevated granulocytic precursor cells (especially myelocytes and promyelocytes)
• Occasional dwarf megakaryocytes ≈ size of an erythrocyte (∼ 7.5 μm)

WHO classification of the CML phases

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

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

• Targeted therapy: first-line for chronic and accelerated phase
  • Tyrosine kinase inhibitors: imatinib, nilotinib, dasatinib Nilotinib and dasatinib are new inhibitors that have shown an advantage over imatinib in some studies. Further research is necessary to prove clinical efficacy and safety; the FDA has approved the newer TKIs for the treatment of newly diagnosed CML and CML resistant to initial treatment with imatinib.
    • Selectively inhibit the enzyme tyrosine kinase → binds to the active site for ATP on the abnormal BCR-ABL tyrosine kinase → inactivated enzyme → no transfer of phosphate (from ATP) to tyrosine residues (phosphorylation) on substrates of the abnormal enzyme → inhibits proliferation and induces apoptosis of cells with the BCR-ABL mutation
  • 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]