The development of
Bcr-Abl tyrosine kinase inhibitors has dramatically changed the prognosis of patients with newly diagnosed
chronic myeloid leukemia (CML). Standard-dose
imatinib (400 mg/day in chronic phase, 600 mg/day in advanced CML) now dominates the management of this disease, producing considerably higher hematologic, cytogenetic, and molecular response rates than seen with previous
drug therapies. However, although many patients respond well to standard-dose
imatinib initially, some patients do not achieve adequate levels of response or discontinue
therapy because of resistance. One approach to improving treatment response with first-line
imatinib may be to increase the
imatinib dose (800 mg/day), although recent trial data indicate that overall increases in response rates may be modest. Newer
Bcr-Abl tyrosine kinase inhibitors can induce responses in patients with all phases of
imatinib-resistant CML, even those with
imatinib-resistant mutations in the BCR-ABL gene. Furthermore, in initial studies, first-line
dasatinib or
nilotinib treatment has produced response rates that compare favorably with historical controls treated with
imatinib, although confirmation is required from head-to-head clinical trials. Future clinical approaches may include
drug combinations, which may allow quiescent
leukemia stem cells to be eradicated. Further improvements in
drug treatment for first-line CML are expected during the next few years.