Targeted small-molecule drugs have revolutionized treatment of chronic myeloid leukemia (CML) during the last decade. These agents interrupt a constitutively active BCR-ABL, the causative agent for CML, by interfering with adenosine 5′ triphosphate–dependent ABL tyrosine kinase. Although the efficacy of tyrosine kinase inhibitors (TKIs) has resulted in overall survival of greater than 90%, TKIs are not curative. Moreover, no currently approved TKIs are effective against the T315I BCR-ABL variant. However, a new generation of TKIs with activity against T315I is on the horizon. We will highlight the clinical utility of historical CML therapeutics, those used today (first- and second-generation TKIs), and discuss treatment modalities that are under development. Recent advances have illuminated the complexity of CML, especially within the marrow microenvironment. We contend that the key to curing CML will involve strategies beyond targeting BCR-ABL because primitive human CML stem cells are not dependent on BCR-ABL. Ultimately, drug combinations or exploiting synthetic lethality may transform responses into definitive cures for CML.
From the Departments of *Pharmacology and Toxicology, †Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, and ‡Division of Hematology and Hematologic Malignancies, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT.
Conflicts of Interest and Source of Funding: The authors are supported by National Institutes of Health (grants HL082978-01 and CA04963920A2 to Dr Deininger and grant CA129528 to Dr Lim) and by the Leukemia and Lymphoma Society (grant 7036-01 to Dr Deininger). David Woessner was supported in part by a grant to the University of Utah from the Howard Hughes Medical Institute through the Med into Grad Initiative. Dr Deininger is a scholar in clinical research of the Leukemia and Lymphoma Society.
Reprints: Michael W. Deininger, MD, PhD, 2000 Circle of Hope, Room 4280, Salt Lake City, UT 84112-5550. E-mail: Michael.Deininger@hci.utah.edu.