Chapter 46: The Chronic Myelogenous Leukemias

BCR-ABL1-POSITIVE CHRONIC MYELOGENOUS LEUKEMIA

• 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.

ETIOLOGY

• 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.

PATHOGENESIS

Genetic Abnormality

• 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.

Hematopoietic Abnormalities

• 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.

EPIDEMIOLOGY

• 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 ...