Targeting Bcr–Abl In CML: Tyrosine Kinase Inhibitors | CML Alliance
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Targeting Bcr-Abl in Ph+ CMLTargeting Bcr-Abl in Ph+ CML

The World Health Organization classifies CML as a myeloproliferative disease characterized by the presence of the Ph+ chromosome or the BCR-ABL fusion oncogene.1

To see a video of the BCR-ABL role in Ph+ CML, click here.

The hallmark of CML, the Ph+ chromosome, produces the constitutive activation of the Bcr-Abl tyrosine kinase, an abnormal protein within the leukemic cell.2 It has been shown that Bcr-Abl is the single, definitive cause of Ph+ CML and remains the key cause of the disease throughout the chronic phase (CP).2 Therefore, maintaining effective suppression of Bcr-Abl can reduce the risk of progression to advanced stages of disease, where Bcr-Abl–independent mechanisms may begin to play a role.3

Work began in early 1990 on the discovery of Bcr-Abl tyrosine kinase inhibitors (TKIs) by researchers at Novartis (then Ciba-Geigy), who ultimately produced GLIVEC® (imatinib), the first TKI to reach the clinic. By targeting Bcr-Abl, the specific cause of Ph+ CML, GLIVEC® produced significant improvements in efficacy and tolerability for patients with Ph+ CML.4

Since Ph+ CML-CP is a single-target disease, it was determined that multitargeted agents were unlikely to provide additional benefit in this setting, and a growing body of evidence suggested that they may produce unnecessary off-target adverse effects when compared with agents that target Bcr-Abl.5,6

GLIVEC® quickly became the new standard of care in Ph+ CML and a leading model for research in oncology.4 Novartis continued its research in the field of targeted therapies in CML and developed nilotinib, now known as TASIGNA®. A highly specific and potent inhibitor of Bcr-Abl, TASIGNA® was rationally designed to bind more effectively to Bcr-Abl than GLIVEC®.2 In fact, TASIGNA® is up to 20 to 50 times more potent than GLIVEC®.7


Next: Ph+ CML Response Goals


Note: Before prescribing, please read full European Summary of Product Characteristics.

References

  1. Vardiman JW, Harris NL, Brunning RD. The World Health Organization (WHO) classification of the myeloid neoplasms. Blood. 2002;100(7):2292-2302.
  2. Manley PW, Cowan-Jacob SW, Mestan J. Advances in the structural biology, design and clinical development of BCR-ABL kinase inhibitors for the treatment of chronic myeloid leukemia. Biochim Biophys Acta. 2005;1754(1-2):3-13.
  3. Shah NP, Nicoll JM, Nagar B, et al. Multiple BCR-ABL kinase domain mutations confer polyclonal resistance to the tyrosine kinase inhibitor imatinib (STI571) in chronic phase and blast crisis chronic myeloid leukemia. Cancer Cell. 2002;2(2):117-125.
  4. Druker BJ. Perspectives on the development of a molecularly targeted agent. Cancer Cell. 2002;1(1):31-36.
  5. Burgess MR, Skaggs BJ, Shah NP, Lee FY, Sawyers CL. Comparative analysis of two clinically active BCR-ABL kinase inhibitors reveals the role of conformation-specific binding in resistance. Proc Natl Acad Sci U S A. 2005;102(9):3395-3400.
  6. Giles FJ, O’Dwyer M, Swords R. Class effects of tyrosine kinase inhibitors in the treatment of chronic myeloid leukemia. Leukemia. 2009;23(10):1698-1707.
  7. The NCCN Chronic Myelogenous Leukemia Clinical Practice Guidelines in Oncology (Version 2.2011). © 2010 National Comprehensive Cancer Network, Inc. http://www.nccn.org. Accessed November 2, 2010. To view the most recent and complete version of the guidelines, go online to www.nccn.org.