Chronic Myelogenous Leukemia - CML

Chronic Myelogenous Leukemia - CML

 

Chronic myelogenous leukemia (CML) is a pluripotential stem cell disease accounting for 15% of all leukemias.

Epidemiology

  • Incidence – 1-2/100,000 per year in U.S.
  • Age – peak >50 years but may be seen in all age groups including children
  • Gender – affects more males than females (1.5:1.0)
    • Females have a survival advantage

Risk Factors

  • Exposure to significant quantities of ionizing radiation
  • Benzene or alkylating agents

Pathophysiology

  • A clonal expansion of stem cells arising from a translocation between chromosomes 9 and 22 (Philadelphia chromosome)
  • This translocation causes a fusion of the abl gene and bcr gene
  • This abl-bcr fusion codes for proteins that possess unusual tyrosine-kinase acuity
    • Type of mutation determines resistance to therapy
  • Mechanism of treatment resistance and relapse
    • Treatment of choice is imatinib mesylate (an abl kinase inhibitor); however, resistance to this drug can develop
    • Relapse after effective chemotherapy occurs mainly as a result of outgrowth of leukemic subclones that are resistant to currently used tyrosine kinase inhibitors
      • Presence of mutations in bcr/abl kinase is the most common cause of imatinib resistance leading to relapse
    • Using different drugs may induce a more permanent remission if it is known a mutation is present

Clinical Presentation

  • 20-40% are asymptomatic – disease diagnosed by routine blood count
  • Insidious onset with vague signs and symptoms – weight loss, fatigue, splenomegaly and fever
  • Thromboses with vasoocclusive disease – cerebral vascular accident, myocardial infarction, visual disturbances
  • 10% present with de novo blast crisis
  • Splenomegaly, leukocytosis with small numbers of myeloid blasts but full range of myeloid maturation, normochromic normocytic anemia, thrombocytosis
  • Lymphadenopathy is unusual

Diagnosis

  • Laboratory testing
    • Presumptive diagnosis from blood cell counts and examination of the blood film
      • Leukocyte alkatine phosphatase can be used to differentiate cause of neutrophilia – lower score more consistent with CML
    • Hallmark is the t(9,22) (q34; q11.2) translocation with shortened 22q (Philadelphia chromosome) or detection of a bcr/abl fusion transcript by qualitative PCR testing
      • t(9,22) translocation may be found occasionally in acute lymphocytic leukemia (ALL) and acute myelogenous leukemia (AML) and, in some cases, may reflect CML blast crisis in a previously unrecognized CML
      • Present in 90-95% of patients with CML
    • Disease resistance testing should be performed if patient is unresponsive or appears to be less responsive to treatment
      • bcr/abl mutation analysis by sequencing detects greater than 90% of abl mutations that may lead to imatinib resistance
      • Resistance testing should only be performed initially in patients with accelerated phase disease when these mutations are frequent
      • Not performed routinely prior to first therapy
      • Low incidence of these mutations in chronic-phase patients receiving Imatinib as first-line therapy

Differential Diagnosis

  • Other myeloproliferative disorders
    • Polycythemia vera
    • Idiopathic myelofibrosis
    • Essential thrombocythemia
  • Leukemoid reactions
    • Infection
    • Pancreatitis
    • Other cancers
  • Acute leukemia

Disease Monitoring

  • Detection of residual disease with quantitative bcr/abl t(9;22)

See Also