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Childhood Acute Myeloid Leukemia/Other Myeloid Malignancies Treatment (PDQ®): Treatment - Health Professional Information [NCI] - Chronic Myelogenous Leukemia

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The introduction of the tyrosine kinase inhibitor (TKI) imatinib mesylate (Gleevec) as a therapeutic drug targeted at inhibiting the BCR-ABL fusion kinase revolutionized the treatment of patients with CML for both children and adults.[9] As most data for the use of TKIs for CML is from adult clinical trials, the adult experience is initially described, followed by a description of the more limited experience for children.

Treatment of CML in Adults with TKIs

Imatinib mesylate is a potent inhibitor of the ABL tyrosine kinase, and also of PDGF receptors (alpha and beta) and KIT. Imatinib mesylate treatment achieves clinical, cytogenetic, and molecular remissions (as defined by the absence of BCR-ABL fusion transcripts) in a high proportion of CML patients treated in chronic phase.[10] Imatinib mesylate replaced the use of alpha-interferon in the initial treatment of CML based on the results of a large phase III trial comparing imatinib mesylate with interferon plus cytarabine (IRIS).[11,12] Patients receiving imatinib mesylate had higher complete cytogenetic response rates (76% vs. 14% at 18 months) [11] and the rate of treatment failure diminished over time, from 3.3% and 7.5% in the first and second years of imatinib mesylate treatment, respectively, to less than 1% by the fifth year of treatment.[12] After censoring for patients who died from causes unrelated to CML or transplantation, the overall estimated survival rate for patients randomly assigned to imatinib mesylate was 95% at 60 months.[12]

Guidelines for imatinib mesylate treatment have been developed for adults with CML based on patient response to treatment, including the timing of achieving complete hematologic response, complete cytogenetic response, and major molecular response (defined as attainment of a 3-log reduction in BCR-ABL/control gene ratio).[13,14,15] The identification of BCR-ABL kinase domain mutations at the time of failure or of suboptimal response to imatinib mesylate treatment also has clinical implications,[16] as there are alternative BCR-ABL kinase inhibitors (e.g., dasatinib and nilotinib) that maintain their activity against some (but not all) mutations that confer resistance to imatinib mesylate.[13,17,18] Poor adherence is a major reason for loss of complete cytogenetic response and imatinib mesylate failure for adult CML patients on long-term therapy.[19]

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