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). 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). 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. 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.
Treatment of CML in Children
Imatinib mesylate has shown a high level of activity in children with CML that is comparable to that observed in adults, with approximately 75% achieving a complete cytogenetic response and with approximately 20% showing an unsatisfactory response to imatinib.[28,29,30,30,30,31] The pharmacokinetics of imatinib mesylate in children appears consistent with prior results in adults. Doses of imatinib mesylate used in phase II trials for children with CML have been 260 mg/m2 to 340 mg/m2, which provide comparable drug exposures as the adult flat doses of 400 mg to 600 mg.[30,31] Because there are no pediatric-specific data regarding optimal timing of monitoring for BCR-ABL transcript levels and for the presence of BCR-ABL kinase domain mutations, the monitoring guidelines described above for adults with CML are reasonable to utilize.