The Biology of Chronic Myelogenous Leukemia: Implications for Imatinib Therapy Ricardo H. Alvarez, a Hagop Kantarjian, b and Jorge E. Cortes b Chronic myelogenous leukemia (CML) results from the neoplastic transformation of prim- itive hematopoietic stem cells, and has been classified as a myeloproliferative disorder. The hallmark of CML is the presence of a balanced translocation between the long arms of chromosomes 9 and 22, t(9;22)(q34;q11.2), which is known as the Philadelphia (Ph) chromosome. This translocation results in the formation of the bcr-abl fusion gene, which, in turn, is translated into a chimeric Bcr-Abl protein with deregulated tyrosine kinase activity. Constitutive Bcr-Abl expression has been shown to be necessary and sufficient for the transformed phenotype of CML cells. CML is unique among human cancers in that a single genetic defect, the Ph chromosome, is responsible for the transformed phenotype. Since this discovery more than 40 years ago, our understanding of the clinical course, therapy, and prognosis of patients with CML has changed significantly. These changes have culminated in the emergence of imatinib, the first rationally designed, molecularly targeted therapy for human malignancy. In this review, the authors describe the molecular biology of CML and the development of imatinib as a therapeutic agent for the treatment of CML. Semin Hematol 44(suppl 1):S4-S14 © 2007 Elsevier Inc. All rights reserved. Incidence and Epidemiology The annual incidence of chronic myelogenous leukemia (CML) is estimated to be approximately 1.5 cases per 100,000 people, and CML accounts for approximately 15% of all patients with leukemia. 1,2 Roughly 4,500 new cases of CML will be diagnosed in 2006 out of a total of 35,070 new cases of leukemia in the United States, and it is estimated that 600 patients will die of CML this year. According to Surveil- lance, Epidemiology, and End Results (SEER) and Medical Research Council, UK (MRC) data, the median age of patients with CML is 67 years. However, most patients who partici- pate in clinical trials are 50 to 60 years old, with a median age of approximately 53 years, whereas patients in bone marrow transplantation (BMT) studies are even younger, with a me- dian age of approximately 40 years. In the era of imatinib therapy for CML, the annual mortality rate has been reduced from between 15% to 20% down to 2%, and the estimated median survival is expected to exceed 20 years based on the current data. Thus, the prevalence of CML in the United States in the next decade may exceed 100,000 to 140,000 cases. 2 Etiology In the great majority of patients with CML, causative factors are unknown. Some associations with genetic and environmental factors have been reported, but in most cases, no such factors can be identified. There are no known hereditary, familial, geo- graphic, ethnic, or economic associations with CML; therefore, the disease is not preventable nor does it appear to be heritable. Although the most common type of leukemia following radia- tion exposure is acute myelogenous leukemia (AML), an excess of CML has also been observed in studies following the atom bomb explosions in Japan in 1945, as well as in earlier studies of radiologists and of patients with ankylosing spondylitis treated with radiation therapy. 3 No association has been established with infectious agents. Clinical Manifestations and Natural History In the clinical setting, CML is characterized by a biphasic or triphasic course that includes a chronic phase (CP), an inter- a Division of Cancer Medicine, The University of Texas M.D. Anderson Can- cer Center, Houston, TX. b Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX. Address correspondence to Jorge E. Cortes, MD, Professor of Medicine, Department of Leukemia, Unit 428, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030- 4009. E-mail: jcortes@mdanderson.org S4 0037-1963/07/$-see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1053/j.seminhematol.2006.12.007