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Chronic myeloid leukemia (CML) is a pluripotent hematopoietic stem cell disorder leading to myeloproliferation and its attendant consequences. The BCR–ABL rearrangement, the pathognomonic molecular abnormality in CML, imparts a proliferative and survival advantage to the malignant clone leading to accumulation of leukemic cells. Patients may present with characteristic clinical findings caused by large numbers of circulating and bone marrow myeloid cells, such as splenomegaly, leukocytosis, or even isolated thrombocytosis. Often, patients are asymptomatic at diagnosis and are discovered only incidentally to have the disease in the setting of a routine complete blood count performed for an unrelated reason. A plethora of exciting discoveries have taken place in the understanding of the biology of the disease and in advancement of therapy for CML. The elucidation of this disease entity at the molecular level and the dramatic impact of the first truly targeted therapy, imatinib mesylate, has served to single out the CML story as the model for modern molecular medicine and the era of personalized targeted therapy.

In 2010, in the United States, an estimated 4870 cases of CML will be diagnosed and 440 patients will die of the disease; there has been little change in the incidence of CML over the preceding decades, but the mortality has been greatly reduced. CML is exceedingly rare in children, with a median age at diagnosis of 67 years and the incidence increasing with age (1). There is a mild male predominance in incidence of the disease with a ratio of 1.3-2.2:1 (2). There are no known hereditary, familial, geographic, or ethnic associations.

The exact mechanism that initiates and induces the translocation represented by the Philadelphia (Ph) chromosome, the initiating molecular event in CML, is incompletely understood. BCR–ABL is only present in hematopoietic cells, but it has been found using very sensitive PCR methods in the hematopoietic cells of 25 to 30% of healthy normal volunteers (3,4). This raises interesting questions about the role of the gene product in the development of the disease, and the need for a yet unknown "second hit" (5). There does not appear to be any chemical or infectious associations with the development of the disease, although an increased risk has been noted with exposure to ionizing radiation (6).

CML is the paradigm of a neoplastic process defined by one cytogenetic or molecular abnormality—the Ph chromosome. This is a balanced translocation between the long arms of chromosomes 9 and 22, t(9,22)(q34,q11.2) (7). The Ph chromosome is detectable in 90 to 95% of patients with the clinical and laboratory features of CML. Among the remaining 5 to 10%, the molecular rearrangement characteristic of CML (BCR–ABL) can be identified in 30 to 50% by sensitive methods of detection. The remaining cases, collectively referred to as true Ph-negative CML or atypical CML, are a heterogeneous group of disorders of unknown biology and with poor prognosis. The ...

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