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Chronic myeloid leukemia (CML) is a myeloproliferative disorder of pluripotent hematopoietic stem cells, characterized by the molecular BCR-ABL1 rearrangement, which drives a proliferative and survival advantage of the leukemic clone. About 30% to 50% of patients with CML are asymptomatic at diagnosis and are incidentally diagnosed during routine examination. Patients may also present with characteristic clinical findings secondary to large numbers of myeloid circulating progenitors, leading to splenomegaly, leukocytosis, or even isolated thrombocytosis. The landscape of CML has had a dramatic course, with a host of findings that have elucidated the biology and molecular pathology of the disease. The understanding of the molecular events led to the creation of the first targeted therapy—imatinib mesylate. Its impact on therapy and survival propelled CML as a model for modern molecular medicine in the fast-developing era of personalized targeted therapy.
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EPIDEMIOLOGY AND ETIOLOGY
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The incidence of CML is 1 to 2 cases per 100,000 adults with a slight male predominance and rising incidence with age, accounting for approximately 15% of newly diagnosed cases of leukemia in adults (1). Chronic myeloid leukemia is uncommon in children, with a median age at diagnosis of 67 years. There are no known hereditary, geographic, familial, or ethnic associations. No chemical or infectious associations have been established, although an increased risk has been linked with exposure to ionizing radiation (2).
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In 2014, in the United States, an estimated 6,000 cases of CML were diagnosed. Since 2000, the year of introduction of imatinib, the annual mortality in CML has decreased from 10% to 20% to 1% to 2%. Consequently, the prevalence of CML in the United States, which was estimated at about 25,000 to 30,000 cases in 2000, has increased to an estimated 80,000 to 100,000+ cases in 2015 and will reach a plateau of about 180,000 cases by 2030 (3). The overall survival (OS) of patients over the recent decade has greatly improved. The exact mechanism of initiation of the defining molecular event in CML—Philadelphia (Ph) chromosome translocation—remains elusive.
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BIOLOGY OF CHRONIC MYELOID LEUKEMIA
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Chronic myeloid leukemia is defined by a unique cytogenetic and/or molecular abnormality—the Ph chromosome—originating in a pluripotent stem cell, with a balanced translocation between the long arms of chromosomes 9 and 22, t(9,22)(q34,q11.2) (4). Detectable by routine cytogenetics or by fluorescent in situ hybridization (FISH), the Ph chromosome is noted in 90% to 95% of patients with the clinical and laboratory features of CML. In the remaining 5% to 10% of patients, the molecular BCR-ABL1 rearrangement can be recognized with high-sensitivity reverse transcriptase polymerase chain reaction (RT-PCR). All remaining cases with unknown biology deemed as true Ph-negative CML or atypical CML carry a poor prognosis. The Ph chromosome joins the proto-oncogene c-abl from chromosome 9 to the breakpoint cluster region (BCR) gene in chromosome 22, generating a novel fusion ...