Seminars in hematology
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Seminars in hematology · Jan 2007
ReviewResistance to targeted therapy in chronic myelogenous leukemia.
The advent of the Bcr-Abl selective tyrosine kinase inhibitor imatinib mesylate (Glivec, Gleevec, Novartis, East Hanover, NJ) has substantially changed the treatment landscape for chronic myelogenous leukemia (CML). However, some patients, primarily those with advanced disease, are either initially refractory to imatinib or eventually develop imatinib resistance. Imatinib resistance or intolerance frequently depends on the re-emergence of Bcr-Abl kinase activity, but can also indicate Bcr-Abl-independent disease progression. ⋯ Early mutation detection may aid in risk stratification and molecular-based treatment decisions. To overcome imatinib-resistant disease, novel tyrosine kinase inhibitors with activity against imatinib-resistant mutations and/or with inhibition of alternative pathways, such as Src activation, have recently been developed. Additional strategies include imatinib dose escalation, combination therapy, and treatment interruption to stop clonal selection of resistant cells.
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Seminars in hematology · Jan 2007
ReviewNew targeted therapies for chronic myelogenous leukemia: opportunities to overcome imatinib resistance.
The advent of tyrosine kinase inhibitors (TKIs) has ushered in a new era in the management of chronic myelogenous leukemia (CML). Imatinib, the first TKI to be approved for the treatment of CML and the current standard first-line therapy, has significantly improved the prognosis of patients with CML. Nevertheless, a minority of patients in chronic-phase CML and even more patients with advanced-phase disease demonstrate resistance to imatinib or develop resistance during treatment. ⋯ These include: dasatinib, a potent dual Bcr-Abl and Src inhibitor; nilotinib, a selective, potent Bcr-Abl inhibitor; bosutinib (SKI-606) and INNO-406 (NS-187), which are both Src-Abl inhibitors; and others. Combination therapy is also being explored concurrently using agents that affect a variety of oncogenic pathways and immune modulation. Herein, we review some of these strategies, particularly those for which clinical data are currently available.