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Ph+ CML Information
Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) is a myeloproliferative disease characterized by the presence of the abnormal Philadelphia chromosome (Ph) in hematopoietic stem cells. CML was the first human disease in which a specific abnormality of the karyotype was linked to leukemogenesis.1, 2
The Philadelphia chromosome results from a reciprocal translocation of sections of chromosomes 9 and 22. This translocation fuses portions of the bcr and abl genes, resulting in the bcr-abl oncogene that encodes the Bcr-Abl fusion protein.1, 2 This protein possesses a constitutively activated tyrosine kinase domain, which phosphorylates intracellular proteins involved in stimulating signal transduction pathways that promote cell proliferation, suppress apoptosis, and diminish cell adhesion.2, 3 Evidence confirms that this unregulated activity of the Abl tyrosine kinase in Bcr-Abl is the cause of Ph+ CML. For this reason, the Bcr-Abl tyrosine kinase domain remains ideal for a targeted therapeutic approach.3, 4.
Three phases of progressively worsening disease are recognized in Ph+ CML: chronic phase, accelerated phase and blast phase.5, 6, 7 (See Table 1.) Most cases (85 percent) of Ph+ CML are diagnosed in the chronic phase. Frequently, the diagnosis is made incidentally after a routine blood test.1, 2
Imatinib remains the gold standard of treatment for newly diagnosed Ph+ CML patients. The 5-year rates of complete cytogenetic response and overall survival for patients originally randomized to imatinib in the IRIS trial are 87% and 89%, respectively.8 However, a small percentage of patients either fail to response to imatinib or lose their response over time.9 Still other patients must discontinue imatinib due to severe or intolerable side effects.10
Tasigna®, which is based on the chemical structure of imatinib mesylate, was designed to meet the needs of adult Ph+ CML patients who are resistant to or intolerant of imatinib.11
1. Faderl S, Talpaz M, Estrov Z, et al. "The Biology of Chronic Myeloid Leukemia." N Engl J Med. 1999;341: 164-72.
2. Sawyers CL. Chronic myeloid leukemia. N Engl J Med. 1999;340:1330-1340.
3. Ren R. Mechanisms of BCR-ABL in the pathogenesis of chronic myelogenous leukaemia. Nat Rev Cancer. 2005;5:172-183.
4. Hughes T, Branford S. "Molecular Monitoring of Bcr–Abl as a Guide to Clinical Management in Chronic Myeloid Leukemia," Blood. 2006: 20:29-41.
5. Faderl S, Kantarjian HM, Talpaz M. Chronic myelogenous leukemia: update on biology and treatment. Oncology (Williston Park). 1999;13:169-180.
6. Kantarjian HM, Giles FJ, O’Brien SM, Talpaz M. Clinical course and therapy of chronic myelogenous leukemia with interferon-alpha and chemotherapy. Biol Ther Chronic Myelogenous Leukemia. 1998;12:31-80.
7. Spiers AS. Clinical manifestations of chronic granulocytic leukemia. Semin Oncol. 1995;22:380-395.
8. Druker BJ, Guilhot F, O'Brien SG, et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med. 2006;355:2408-2417.
9. Shah, Neil. "Loss of Response to Imatinib: Mechanics and Management." Hematology (2005): 183-87
10. Deininger MW, O’Brien SG, Ford JM, Druker BJ. Practical management of patients with chronic myeloid leukemia receiving imatinib. J Clin Oncol. 2003;21:1637-1647.
11. Weisberg E, Manley PW, Breitenstein W, et al. Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl. Cancer Cell. 2005;7:129-141.
