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BCR-ABL1-POSITIVE CHRONIC MYELOGENOUS LEUKEMIA

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  • BCR-ABL1–positive chronic myelogenous leukemia (CML) results from a somatic mutation in a pluripotential lymphohematopoietic cell, yielding a fusion oncogene (BCR-ABL1).

  • CML is characterized by granulocytic leukocytosis, granulocytic immaturity, basophilia, anemia, and often thrombocytosis in the blood, intense leukemic granulocytic precursor expansion in the marrow, and splenomegaly.

  • The natural history of the disease is to evolve into an accelerated phase in which cytopenias develop and response to chronic phase therapy is lost; either the chronic or accelerated phase can undergo further clonal evolution to acute leukemia.

  • This natural history has been modified significantly by the introduction of inhibitors of the constitutive kinase activity of the BCR-ABL1 oncoprotein.

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ETIOLOGY

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  • Exposure to high-dose ionizing radiation increases the incidence of BCR-ABL1–positive CML, with a mode of increased incidence that ranges from 4 to 11 years in different exposed populations.

  • Obesity may be an endogenous risk factor.

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PATHOGENESIS

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Genetic Abnormality

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  • BCR-ABL1–positive CML is the result of an acquired genetic abnormality that induces a malignant transformation of a single pluripotential lymphohematopoietic cell.

  • The proximate cause is a translocation between chromosome 9 and 22 [t(9;22)]. This alteration juxtaposes a portion of the ABL proto-oncogene from chromosome 9 to a portion of the BCR gene on chromosome 22.

  • The resulting gene fusion, BCR-ABL1, creates an oncogene that encodes an elongated protein tyrosine phosphokinase (usually p210) that is constitutively expressed. This mutant protein disrupts cell signal pathways and results in the malignant transformation.

  • The genetic alteration is present in erythroid, neutrophilic, eosinophilic, basophilic, monocytic, megakaryocytic, and marrow B- and T-lymphocytic cells, consistent with its origin in a pluripotential lymphohematopoietic cell.

  • The designation Philadelphia (Ph) chromosome specifically refers to chromosome 22 with a shortened long arm (22q-) and is evident by light microscopy of cell metaphase preparations in approximately 90% of cases. Fluorescence in situ hybridization (FISH) can identify the fusion BCR-ABL1 gene in approximately 96% of cases. Approximately 4% of cases with a blood and marrow phenotype indistinguishable from BCR-ABL1 CML do not have rearrangement in the BCR gene.

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Hematopoietic Abnormalities

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  • There is a marked expansion of granulocytic progenitors and a decreased sensitivity of the progenitors to regulation resulting in an inexorable increase in white cell count and decrease in hemoglobin concentration.

  • Megakaryocytopoiesis is often expanded. Erythropoiesis is usually moderately deficient.

  • Function of the neutrophils and platelets is nearly normal; infection and bleeding are not a feature of the chronic phase.

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EPIDEMIOLOGY

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  • BCR-ABL1–positive CML accounts for approximately 15% of all cases of leukemia and approximately 3% of childhood leukemias in the United States.

  • Males are affected at approximately 1.5 times the rate of females.

  • The age-specific incidence rate increases exponentially from late adolescence (0.2 cases/100,000) to octogenarians (10 cases/100,000).

  • Familial occurrence is vanishingly rare, and there is no ...

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