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Pilot study of bortezomib for patients with imatinib-refractory chronic myeloid leukemia in chronic or accelerated phase.

Clinical lymphoma, myeloma & leukemia

pharmacology, Pyrimidines, therapeutic use, Pyrazines, Proteasome Inhibitors, Protease Inhibitors, Piperazines, Pilot Projects, Middle Aged, Male, mortality, drug therapy, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Humans, Female, Drug Resistance, Boronic Acids, Benzamides, metabolism, drug effects, Basophils, Apoptosis, Aged

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      Proteasome inhibitors are anticancer compounds that disrupt the proteolytic activity of the proteasome and lead to tumor cell growth arrest and apoptosis. Bortezomib is a proteasome inhibitor that is currently approved for use in multiple myeloma (MM) and mantle-cell lymphoma. It induces apoptosis of chronic myeloid leukemia (CML) cells in vitro, but the activity of bortezomib in patients with imatinib-resistant CML is unknown. We conducted a pilot trial to evaluate the activity of single-agent bortezomib in CML. Seven patients with imatinib-refractory CML were treated with bortezomib at a dose of 1.5 mg/m2 on days 1, 4, 8, and 11 every 3 weeks. The median number of cycles received was 2. No patient had a hematologic or cytogenetic response. Three patients had a temporary decrease in basophil counts associated with therapy with bortezomib. Six patients experienced grade 3/4 nonhematologic toxicities. Bortezomib had minimal efficacy and considerable toxicity in patients with imatinib-refractory CML. Further studies should focus on alternative approaches to using proteasome inhibitors in the treatment of CML, such as in combination with tyrosine kinase inhibitors (TKIs) or as a strategy to eradicate leukemic stem cells. Copyright © 2011. Published by Elsevier Inc.

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