Resistant mutations in CML and Ph+ALL – role of ponatinib
Geoffrey D Miller, Benjamin J Bruno, Carol S LimDepartment of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, University of Utah, Salt Lake City, Utah, USAAbstract: In 2012, ponatinib (Iclusig®), an orally available pan-BCR-ABL tyrosine kinase inhibitor (TKI) developed by A...
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| Autores principales: | , , |
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| Formato: | article |
| Lenguaje: | EN |
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Dove Medical Press
2014
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| Acceso en línea: | https://doaj.org/article/939d6749dec244ae887b2379e66cb7ef |
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| Sumario: | Geoffrey D Miller, Benjamin J Bruno, Carol S LimDepartment of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, University of Utah, Salt Lake City, Utah, USAAbstract: In 2012, ponatinib (Iclusig®), an orally available pan-BCR-ABL tyrosine kinase inhibitor (TKI) developed by ARIAD Pharmaceuticals, Inc., was approved by the US Food and Drug Administration for use in resistant or intolerant chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL). Ponatinib is the only approved TKI capable of inhibiting BCR-ABL with the gatekeeper T315I kinase domain mutation, known to be the cause for 20% of resistant or relapsed CML cases. In 2013, ponatinib sales were temporarily suspended due to serious side effects seen in nearly 12% of the patient population. These side effects are thought to stem from the potent nature and pan-activity of this TKI. ARIAD Pharmaceuticals, Inc. has since been permitted to resume sales and marketing of ponatinib to a limited patient population with an expanded black box warning. In the following review, the use of ponatinib in CML and Ph+ALL will be discussed. Mechanisms of resistance in CML are discussed, which provide insight and background into the need for this third generation TKI, followed by the molecular design and pharmacology of ponatinib, which lead to its success as a therapeutic. Finally, the efficacy, safety, and tolerability of ponatinib will be highlighted, including summaries of the important clinical trials involving ponatinib as well as its current place in therapy.Keywords: BCR-ABL, T315I, Ph+ALL, PACE trial, EPIC trial, ARIAD, compound mutations |
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