Wallach's Interpretation of Diagnostic Tests: Pathways to Arriving at a Clinical Diagnosis (348 page)

CML is a myeloproliferative neoplasm characterized by the dysregulated production and uncontrolled proliferation originating in an abnormal pluripotential bone marrow stem cell. It is consistently associated with the BCR-ABL1 fusion gene. It results in an increase of myeloid cells, and, to a lesser extent, erythroid and platelets in the peripheral blood, and marked hyperplasia in the bone marrow. CML is induced by a chimeric gene that results from the fusion of the ABL1 gene on chromosome 9 with the BCR gene on chromosome 22, leading to the formation of a new leukemia-specific fusion gene that codes for a constitutionally activated protein tyrosine kinase. The Philadelphia (Ph) chromosome is the abnormal chromosome 22, reflecting the 95% of cases where the translocation between chromosomes 9 and 22 is balanced.

If untreated, CML progresses from the chronic phase to acute leukemia (blastic transformation) within 3–5 years, frequently with an intermediate “accelerated” phase. It may also present in the accelerated or blastic phase when first diagnosed.

   Who Should Be Suspected?

Patients found to have persistent, and not otherwise explained, myeloid leukocytosis. Patients with fatigue, anorexia, weight loss, excessive sweating, early satiety, abdominal fullness due to splenomegaly, and bleeding episodes.

   Laboratory Findings

Chronic Phase

   
CBC
:

   WBC count is markedly elevated, usually 50,000–300,000/μL, predominantly neutrophils, bands, metamyelocytes, and myelocytes. The presence of a greater percentage of myelocytes than metamyelocytes (leukemic hiatus or myelocyte bulge) is a classic finding. Blasts account for <2% of cells. Basophilia is nearly always present. Eosinophilia may also be present. Absolute monocytosis is usually present but absolute lymphocytes are normal.

   Hct/Hb may be normal or slightly decreased or increased; if anemia is present, it is normochromic, normocytic. Normoblasts are usually seen on the peripheral blood smear (PBS). Reticulocyte count is <3%.

   Platelets may be normal, but in approximately 50% of cases, they are elevated. Occasionally, the platelets may be decreased, especially as the disease progresses. Large platelets (megathrombocytes) may be conspicuous.

   
Bone marrow

   Hyperplastic, with increase mainly in the myelocytic line, increased myeloid-to-erythroid ratio.

   Myeloblasts are <5%. Increase in basophils and eosinophils, including immature forms. Megakaryocytes may be increased. Small megakaryocytes with hypolobulated nuclei are commonly found. Increases in reticulin fibrosis and vascularity are frequently found.

   
Cytogenetics

Demonstration of t(9,22)(q34;q11) involving BCR-ABL1 genes is the gold standard for diagnosis. Approximately 5% of CML patients do not demonstrate the t(9;22) by karyotyping but demonstrate the BCR-ABL1 gene fusion by FISH or real-time PCR techniques.
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Patients may have variant complex translocations involving other chromosome or other cryptic translocations, but all result in the formation of the Ph chromosome with the BCR-ABL1 rearrangement. Patients whose cells lack evidence of BCR-ABL1 gene fusion by FISH or RT-PCR do not have CML. The V617F JAK2 mutation is absent.

   
Immunostains
: Leukocyte (neutrophil) alkaline phosphatase (LAP) (NAP): Low or absent LAP is not necessary for diagnosis in Philadelphia chromosome–positive patients. Nevertheless, it may be helpful for the rapid differentiation of CML from leukemoid reactions or other myeloproliferative neoplasms, while results of cytogenetic studies are pending.