John M. Goldman, DM, FRCP, FRCPath, FMedSci

Is it reasonable to start all new CML patients on treatment with imatinib alone and continue the drug indefinitely in those who fare well, or should one start treatment with one of the newer agents or possibly with imatinib in combination with another anti-CML agent in order to secure the best possible outcome for an individual patient?

Molecular discoveries and clinical advances over the past few decades have made the treatment of chronic myeloid leukemia (CML) one of the great success stories of modern medicine. Before the 1980s, the focus was on maintaining normal white blood cell counts with agents such as hydroxyurea and busulfan. With the use of interferon, treatment strategies turned more toward cytogenetic remission. In 1998, targeted therapy was introduced to this setting with the first studies of imatinib mesylate. Since then, treatment objectives have shifted toward the attainment of molecular remission. In this review, we consider the variety of approaches to treating CML, efforts to minimize treatment failures, and possible future directions in therapy.

Until recently, the standard treatment for newly diagnosed patientswith chronic myeloid leukemia (CML) in chronic phase who were noteligible for allogeneic stem cell transplant was interferon-alfa alone orin combination with low-dose cytarabine. Moreover, about 20% to 25%of patients who were relatively young and had suitable HLA-matcheddonors have in recent years been offered treatment by allogeneic stemcell transplantation, a procedure that can cure CML but is associatedwith an appreciable risk of morbidity and mortality. However, followingthe recognition in the 1980s that the p210 oncoprotein encoded bythe BCR-ABL fusion gene on the Philadelphia chromosome had greatlyenhanced tyrosine kinase activity and was probably the initiating eventin the chronic phase of CML, much effort was directed toward developmentof drugs that would selectively inhibit this kinase activity. In 1998these efforts culminated in the first clinical use of imatinib mesylate(Gleevec), which has since been shown to produce impressive results intreatment of patients with CML in chronic phase. In previously untreatedpatients, the incidence of complete cytogenetic responses exceeds80%, and the majority of responses appear thus far to be durable.Imatinib also proved active in patients with accelerated phase and blasticphase disease, but in most of these cases, the benefits have been relativelyshort-lived. The advent of imatinib has thus necessitated a fundamentalreappraisal of the approach to the initial management of CML.