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}

Typical CML Laboratory Parameters by Phase of Disease

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

Sources:

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.