Chronic Myeloid Leukemia

Pathophysiology

• CML is a clonal myeloproliferative neoplasm of hematopoietic stem cells.
• Caused by the BCR-ABL fusion gene, resulting from a reciprocal translocation between chromosomes 9 and 22 → called the Philadelphia chromosome (t(9;22)(q34;q11)).
• BCR-ABL encodes a constitutively active tyrosine kinase → uncontrolled myeloid proliferation.

Phases of CML

• Chronic Phase (CP) – ~85% of cases at diagnosis
  • Asymptomatic or mild symptoms
  • <10% blasts in blood or bone marrow
• Accelerated Phase (AP)
  • Worsening symptoms, rising WBC
  • 10–19% blasts or new cytogenetic abnormalities
• Blast Crisis (BC)
  • Resembles acute leukemia
  • ≥20% blasts in blood or bone marrow
  • Poor prognosis

Clinical Presentation

• Often asymptomatic, discovered on routine labs
• Fatigue, weight loss, early satiety (from splenomegaly), night sweats
• Splenomegaly (common finding)
• Symptoms of hyperviscosity (e.g., headache, blurred vision) in some

Diagnostic Workup

• CBC:
  • Elevated WBC (often >100,000/μL)
  • Anemia and thrombocytosis may be present
• Peripheral blood smear:
  • Left shift with all stages of granulocyte maturation
  • Basophilia and eosinophilia
• Bone marrow biopsy:
  • Hypercellular marrow with granulocytic proliferation
• Cytogenetics and Molecular Testing:
  • FISH or karyotyping for Philadelphia chromosome
  • RT-PCR to detect BCR-ABL transcripts (used for diagnosis and monitoring)

Treatment Options

Goal: achieve complete molecular response (CMR)

• Tyrosine Kinase Inhibitors (TKIs) – first-line therapy
  • Imatinib (1st gen): targets BCR-ABL
  • Dasatinib, Nilotinib (2nd gen): used if resistant/intolerant to imatinib
  • Ponatinib: used in T315I mutation (resistant mutation)
  • Monitor BCR-ABL levels via qRT-PCR every 3–6 months
• Stem Cell Transplant:
  • For patients resistant to multiple TKIs or in blast crisis
• Supportive Care:
  • Cytoreduction (e.g., hydroxyurea) for very high WBC at diagnosis
  • Allopurinol to prevent tumor lysis syndrome