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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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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]

Two additional TKIs have received regulatory approval for the frontline chronic phase CML indication, nilotinib and dasatinib. Dasatinib was approved on the basis of a phase III trial comparing dasatinib (100 mg daily) with imatinib mesylate (400 mg daily).[20] Similarly, nilotinib (at a dose of either 300 mg or 400 mg twice daily) was compared in a phase III trial with imatinib mesylate (400 mg daily).[21] For both agents, superiority over imatinib mesylate was demonstrated for complete cytogenetic response rate and for major molecular response rate, which has led to the use of these agents as first-line therapy in adults with CML. These agents have not been extensively tested in children yet. Additional follow-up will be required to demonstrate the impact of these agents on clinical endpoints such as progression to accelerated/blast phase and overall survival.

Although imatinib mesylate is an active treatment for CML, there is limited evidence that it is curative. Most adults with CML treated with imatinib mesylate continue to have BCR-ABL transcripts detectable by highly sensitive molecular methods, although the rate of molecular complete remission does increase with duration of therapy.[22,23] Six of 12 adults with molecularly undetectable disease who stopped imatinib mesylate lost their molecular remission within 18 months of treatment cessation.[24,25,26] In the STIM (Stop Imatinib) trial, 100 patients older than 18 years and in complete molecular remission for at least 2 years had imatinib mesylate stopped. Of these patients, 41% maintained a complete molecular remission at 24 months.[27] Further research is required before cessation of imatinib mesylate or other BCR-ABL targeted therapy for selected patients with CML in molecular remission can be recommended as a standard clinical practice.

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WebMD Public Information from the National Cancer Institute

Last Updated: February 25, 2014
This information is not intended to replace the advice of a doctor. Healthwise disclaims any liability for the decisions you make based on this information.
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