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Chronic Myeloid Leukemia (CML)

  • CML is a myeloproliferative disorder (MPD)
    • Clonal stem cell disorders in which regulation of proliferation is impaired, but differentiation and maturation are generally maintained
    • Characterised by ↑cell counts – but the increase consist mostly of mature cells
  • Different MPDs feature a predominant increase in a single cell line

Epidemiology

  • MC in older adults – but can occur at any age
  • Possible link to ionizing radiation

Pathophysiology

  • Caused by reciprocal translocation between C9 long arm and C22 long arm – t(9;22)
    • Philadelphia chromosome
  • Results in BCR-ABL fusion gene – which codes for the fusion protein p210
    • The normal abl gene codes for a TK enzyme
    • But the p210 protein coded by BCR-ABL is more potent TK – acts as an oncogene
  • 3 phases
    • Chronic, accelerated, Blast crisis

Clinical features

  • Mostly discovered as incidental finding
  • Fatigue, lethargy, LGF, weight loss
  • LUQ discomfort – due to splenomegaly
  • Gout – due to hyperuricemia
  • Hyperviscosity due to leukostasis

Diagnosis

  • ↑WCC – 25,000 – >300,000/μl
  • Mild anemia
  • Thrombocytosis
  • Blood smear – characteristic (see table + pic)
  • ↑LDH + UA + B12
  • ↓ LAP
    • But can be ↑in infection, treatment or progression to accelerated/blast phase
    • Normal LAP score – 20-100
    • Also ↓LAP in PNH
  • Bone marrow (see table)
  • Cytogenetics
    • Ph chromosome – 85% of cases
    • If case appears to lack Ph then test for t(9;22) and bcr/abl
      • t(9;22) – detected by FISH
      • bcr/abl rearrangement – detected by PCR
    • 9% cases are Ph –ve (poor prognosis)
  • Sokal score – prognosis

Differential diagnosis

  • Other MPDs – especially ET
    • confirm dx by cytogenetics – if Ph present then dx is CML

Disease course

Chronic phase – most patients diagnosed in this phase

  • lasts for 3-4 years
  • 5% of pts transform within 1st year

Accelerated phase

  • Gradual ↑ in blasts in blood/BM, ↑in basophils in blood, or ↑in fibrosis in marrow
  • Systemic sx – fever, WL, night sweats
  • Short phase – pts either transform to blast crisis or die

Blast crisis

  • Defined by presence of >30% blasts in blood/BM
  • Mean survival is <3 months

Treatment

Cytotoxic chemotherapy – Switch drug if loss of response

  • Hydroxyurea – 2g/d
    • DOC to control WCC and systemic symptoms
  • Interferon-a – for pts with chronic phase CML
    • Decreases proportion of cells in BM that carry Ph chromosome
    • SE – flu-like symptoms, athralgia, myalgia, impotence, WL
  • BMT – only curative treatment
    • Treatment of choice in young pts – BMT should be considered as soon as CML is diagnosed
  • TK inhibitors – imatinib [400mg]
  • Allopurinol [300mg] – treatment for gout
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