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The development of agents targeting the BCR-ABL tyrosine kinase as Philadelphia chromosome-positive acute lymphoblastic leukemia treatment

ABSTRACT Introduction: In Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL), the BCR-ABL translocation is the main transforming event; consequently, it is targeted by ABL-tyrosine kinase inhibitors (TKIs), the first of which to be identified was imatinib mesylate. There are now four newer TKIs, three so-called second-generation inhibitors and one third generation inhibitor, all of which are more potent than imatinib in in vitro assays. Areas covered: This paper reviews the current knowledge on the function of BCR-ABL. Furthermore, this paper highlights the impact of this knowledge on the development of a targeted therapy approach in Ph+ ALL and the obstacles for the successful treatment with these drugs. Expert opinion: Identifying key components involved in disease pathogenesis may lead to new approaches that might overcome resistance mediated to the BCR-ABL TKIs. In a near future, the authors believe that monoclonal antibodies and immunotherapy should also be combined with TKIs and up-front chemotherapy for the successful treatment of ALL.