Toward a cure for chronic myeloid leukemia.

A diagnosis of chronic myeloid leukemia (CML) remains unwelcome news. Thanks to imatinib, however, the majority of newly diagnosed patients with chronic phase CML achieve a complete cytogenetic response (CCyR) and can expect longterm survival, often without major side effects (1). Unfortunately, these responses are not equivalent to a cure because residual leukemia cells persist even in patients who become negative by reverse transcription-PCR, and recurrence of active leukemia is common upon imatinib cessation. The mechanisms that allow CML stem cells to survive in the presence of drug are largely unknown, and it is currently unclear how these cells can be specifically targeted to achieve disease eradication (reviewed in ref. 2). For patients with advanced phase CML or Philadelphia chromosome–positive acute lymphoblastic leukemia, the agenda is different: imatinib responses are mostly transient, and eligible patients are advised to proceed to allograft, using imatinib as a bridge. For those without a transplant option, the long-term outlook remains grim. We begin with an update on second-generation inhibitors for patients with resistance or intolerance to imatinib, including challenges such as pan-resistant BCR-ABL mutations and BCRABL–independent progression in advanced disease. We then examine current strategies for achieving disease eradication by targeting CML stem cells.