Leukemia, Chronic Myeloid

Key Features

Essentials of Diagnosis

• Elevated white blood count (WBC)

• Left-shifted myeloid series but low percentage of promyelocytes and blasts

• Presence of bcr/abl gene (Philadelphia chromosome)

General Considerations

• Myeloproliferative disorder characterized by overproduction of myeloid cells

• Associated with characteristic chromosomal abnormality, the Philadelphia chromosome, a reciprocal translocation between long arms of chromosomes 9 and 22

• Translocated portion of 9q contains abl, a protooncogene, which is received on 22q, at the break point cluster (bcr) site

• The fusion gene bcr/abl produces a novel protein that possesses tyrosine kinase activity, leading to leukemia

• Disease may progress from chronic phase to accelerated phase and to blast crisis

• Progression is often associated with added chromosomal defects superimposed on the Philadelphia chromosome

• Blast crisis chronic myeloid leukemia (CML) is morphologically indistinguishable from acute leukemia

Demographics

• CML occurs mainly in middle age; median age at presentation is 50 years

Clinical Findings

Symptoms and Signs

• Fatigue, night sweats, and low-grade fevers

• Abdominal fullness related to splenomegaly

• Leukostasis clinical syndrome (blurred vision, respiratory distress, and/or priapism) is rare

• Sternal tenderness

• Fever in absence of infection, bone pain, and splenomegaly may mark disease acceleration

Differential Diagnosis

• Reactive leukocytosis resulting from infection, inflammation, or cancer

• Other myeloproliferative disorder: essential thrombocytosis, polycythemia vera, or myelofibrosis

Diagnosis

Laboratory Tests

• Median WBC at diagnosis is 150,000/mcL, although some cases are discovered when WBC is only modestly increased

• In the rare cases of the leukostasis clinical syndrome, WBC usually > 500,000/mcL

• Hematocrit is usually normal at presentation

• Platelet count may be normal or elevated (sometimes strikingly elevated)

• Basophilia and eosinophilia may be present

• Peripheral blood smear

  • Myeloid series left-shifted with mature forms dominating

  • Blasts usually < 5%

  • Red blood cell (RBC) morphology normal; nucleated RBCs rarely seen

• The diagnosis is confirmed by finding the Philadelphia chromosome (bcr/abl gene) in peripheral blood

• Progressive anemia and thrombocytopenia occur in accelerated and blast phases, and percentage of blasts in blood and bone marrow increases

Diagnostic Procedures

• Bone marrow aspirate and biopsy: hypercellular, with left-shifted myelopoiesis is not diagnostic, but distinguishes chronic phase from more advanced disease

• Cytogenetics in bone marrow may show abnormalities in addition to the Philadelphia chromosome

• When blasts comprise > 20% of bone marrow cells, blast phase of CML is diagnosed

Treatment

Medications

• Imatinib mesylate, 400 mg orally once daily

  • Results in nearly universal (98%) hematologic control of chronic phase disease

  • Rate of a major molecular response is ~30% at 1 year

• Dasatinib and nilotinib

  • Increase the ...