A Critical Review of Trials of First-Line BCR-ABL Inhibitor Treatment in Patients With Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase

Abstract

The characteristic expression of the constitutively active oncoprotein, BCR-ABL tyrosine kinase, inchronic myeloid leukemia (CML) was the basis for the development of BCR-ABL tyrosine kinase inhibitors for treatment. Three BCR-ABL inhibitors, imatinib, nilotinib, and dasatinib, have been approved by the US Food and Drug Administration for first-line treatment of patients with newly diagnosed CML in chronic phase (CML-CP). This article reviews the key phase III clinical trials supporting the use of first-line imatinib, nilotinib, and dasatinib in patients with CML-CP, as well as findings of supportive phase II studies. At the time of its approval in 2001,imatinib induced unprecedented response rates in patients with CML-CP; however, resistance and intolerance to imatinib prevent 20% to 30% of patients from deriving full therapeutic benefit. Nilotinib and dasatinib, both approved in 2010 for first-line CML-CP treatment, are more potent than imatinib and less susceptible to imatinib resistance mechanisms. Comparative clinical trials of each agent with imatinib have shown that they are associated withsignificantly deeper and more rapid responses than standard-dose imatinib, without compromising safety. Given that evidence suggests achievement of an early response is predictive of improved long-term outcomes, earlier use of these compounds may lead to more rapid, deeper responses corresponding with improvements in patient outcome. Although future studies will benefit from more uniform definitions of end points and methods ofanalysis, data from published studies of first-line BCR-ABL inhibitor treatment for patients with newly diagnosed CML-CP support the use of dasatinib or nilotinib in place of imatinib.