March 2009 ■ COMMUNITY ONCOLOGY 113 Volume 6/Number 3 Review Article Commun Oncol 2009;6:113–125 © 2009 Elsevier Inc. All rights reserved. Identifying and treating imatinib failure in chronic myelogenous leukemia: a practical review of treatment guidelines and available agents Stuart L. Goldberg, MD, and Aisha Masood, MD Division of Leukemia, The John Theurer Cancer Center at Hackensack University Medical Center, Hackensack, NJ The tyrosine kinase inhibitor imatinib has revolutionized the treatment of chronic myelogenous leukemia (CML) by selectively targeting the gene product of the Philadelphia chromosome, BCR-ABL, thereby halting disease progression. Although most patients respond to imatinib and achieve prolonged remission, the development of imatinib resistance has emerged as a major clinical issue. Resistance can be either primary, occurring at treatment initiation when patients fail to obtain important predictive milestones, or secondary, occurring during the course of therapy when patients experience a loss of response or disease progression. Two recently approved tyrosine kinase inhibitors, the dual BCR- ABL and SRC inhibitor dasatinib and the imatinib analog nilotinib, have shown substantial activity among patients with resistance or intolerance to imatinib. Given these new options, identification of nonresponders has become increasingly important to ensure earliest administration of appropriate therapy. Here, we review recommendations for identifying and treating patients with chronic-phase CML who have experienced failure of first-line imatinib. Manuscript received July 23, 2008; accepted December 23, 2008. Correspondence to: Stuart L. Goldberg, MD, John Theurer Can- cer Center at Hackensack University Medical Center, 20 Pros- pect Avenue, Suite 400, Hackensack, NJ 07601; telephone: 201- 996-5900; fax: 201-996-9246; e-mail: sgoldberg@humed.com. C hronic myelogenous leukemia (CML) is a clonal myeloprolifera- tive disorder of hematologic stem cells accounting for 15% of adult leukemias in the United States. 1 CML usually progresses through three phases: a largely asymptomatic chronic phase (CP), a tran- sitional accelerated phase (AP), and a rapidly fatal blast phase (BP) also known as blast crisis (BC). If the disease is left untreated, the time to progression from CP to BP is typically 3–5 years. 2 The defining molecular aberration in CML is the Philadelphia chromosome (Ph), which arises from the exchange of genetic material between chromosomes 9 and 22. The resulting fusion gene product, BCR-ABL, is a constitutively active oncogenic tyrosine kinase and is believed to be the causative molecule under- lying the pathogenesis of CML. 3,4 The treatment of newly diagnosed CP CML has changed dramatically in the past several years. Standard-dose cytotoxic chemotherapy agents, in- cluding hydroxyurea and busulfan, improved he- matologic counts but did not significantly prolong survival. The biologic modifier interferon was able to suppress expression of the Philadelphia chromo- some and thus improve survival in a small propor- tion of patients. 5,6 For younger patients, allogene- ic stem cell transplantation (SCT) emerged as the curative treatment option. However, SCT is as- sociated with considerable risks of early mortality and prolonged morbidity. 7 A European Group for Blood and Marrow Transplantation (EBMT) scor- ing system, utilizing the age of the patient, interval from diagnosis to transplant, phase of CML dis- ease, donor-recipient sex match, and related versus other donor type, has been able to separate CML transplant outcomes into five distinct groupings, with 5-year survival rates ranging from 22% to 72%. This scoring system may be useful in advising patients about their transplantation options. 8 Imatinib (Gleevec) was the first BCR-ABL– targeted therapy approved for use in CML and has revolutionized its treatment. 9 This tyrosine kinase inhibitor (TKI) binds to the inactive conformation of the BCR-ABL fusion protein, blocking the bind- ing of adenosine triphosphate and thereby inhibit-