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Curr Hematol Malig Rep. 2015 Jun;10(2):158-66. doi: 10.1007/s11899-015-0248-3.

Chronic myeloid leukemia: advances in understanding disease biology and mechanisms of resistance to tyrosine kinase inhibitors.

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Division of Hematology and Medical Oncology, Oregon Health & Science University Knight Cancer Institute, Portland, OR, USA.


The successful implementation of tyrosine kinase inhibitors (TKIs) for the treatment of chronic myeloid leukemia (CML) remains a flagship for molecularly targeted therapy in cancer. This focused review highlights critical elements of the underlying biology of CML and provides a summary of the molecular mechanisms that lead to TKI resistance: BCR-ABL1 mutation-based resistance and therapy escape through alternative pathway activation despite inhibition of BCR-ABL1 tyrosine kinase activity. We direct attention to the most current manifestations of these issues, including emergence of pan-TKI-resistant BCR-ABL1 compound mutants, new strategies for identification and therapeutic targeting of alternative pathways, and the exciting, controversial topic of cessation of TKI therapy leading to durable treatment-free remissions for a subset of patients. Further gains in our understanding of the biology of Philadelphia chromosome-positive (Ph-positive) leukemia and mechanisms of resistance to BCR-ABL1 TKIs will benefit patients and also provide a blueprint for similar discovery in other cancers.

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