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Hematologic Malignancies Chronic Myeloid Leukemia Chronic Myeloid Leukemia— What Else is there Beyond Protein Kinase Inhibitors? Elias Jabbour, MD Associate Professor, Leukemia Department, MD Anderson Cancer Center, Houston, Texas, US Abstract Chronic myeloid leukemia (CML) is induced by the BCR-ABL oncogene. The advent of BCR-ABL tyrosine kinase inhibitors (TKIs) has redefined treatment goals in CML starting with imatinib and followed by the newer TKI inhibitors including dasatinib, nilotinib, bosutinib, and ponatinib. However, a significant proportion of patients do not achieve a satisfactory response to TKIs and resistance remains an unmet need in the in the treatment of CML. Furthermore, disease eradication with TKIs may pose a significant challenge: minimal residual disease (MRD) remains detectable following treatment with these agents. Recently, several new molecular targets have been proposed in CML, and several drugs are in clinical development. Omacetaxine, a protein translation inhibitor, has shown the potential to substantially reduce MRD in animal models and has demonstrated clinical activity in phase II clinical trials regardless of patients’ BCR-ABL T313I mutation status. The broad range of therapeutic effects associated with interferon may reduce resistance and relapse, and has resulted in a resurgence of interest in this therapy. In addition, several other therapeutic targets are currently undergoing clinical investigation. Keywords Chronic myeloid leukemia, imatinib, omacetaxine, tyrosine kinase inhibitors Disclosure: Elias Jabbour, MD, has received consultancy fees from Ariad, BMS, Novartis, Pfizer, and TEVA. Acknowledgments : Technical editorial assistance was provided by Katrina Mountfort from Touch Medical Media, London, UK. Received: September 23, 2013 Accepted: November 25, 2013 Citation: Oncology & Hematology Review, 2014;10(2):97–102 Correspondence: Elias Jabbour, MD, Leukemia Department, MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, US. E: Support: The development and publication of this article has been supported by TEVA. TEVA provided the idea for this article and a Medical Accuracy review. The views and opinions expressed are from the author and not necessarily those of TEVA. Chronic myelogenous (or myeloid) leukemia (CML) is a myeloproliferative disorder characterized by increased and unregulated growth of granulocytes, leading to high white blood cell counts and splenomegaly. It was estimated that 5,430 adults in the US would be diagnosed with CML in 2012 and 610 would die of the disease. 1 In the absence of intervention, CML typically begins in the chronic phase, and over the course of several years progresses to an accelerated phase and finally to a blast or acute phase. The latter is the terminal phase of CML and clinically behaves like an acute leukemia. Until recently, interferon alpha (IFN-a) and allogeneic stem cell transplantation (SCT) formed the mainstay of treatment in CML. However, the utility of both is limited by adverse effects (AEs). 2,3 CML is associated with a characteristic chromosomal translocation called the Philadelphia chromosome, which results in the expression of a tyrosine kinase molecule: the breakpoint cluster region–Abelson (BCR-ABL) protein. 4 The high prevalence of this protein makes it an attractive molecular target for therapeutic approaches to CML. In the last decade, the development of tyrosine kinase inhibitors (TKIs) that inhibit signaling on the BCR–ABL protein has dramatically improved outcomes for patients with CML. Before the US Food and Drug Administration (FDA) approval of imatinib in 2003, median survival was around 4 to 5 years from diagnosis. Current estimates of life expectancy in patients that respond to TKIs are similar to that of the general population. 5 © To u ch MEd ica l MEdia 201 4 However, despite the success of TKIs, drug resistance is an unmet need in the treatment of CML. Furthermore, full molecular remission (MoR) (i.e. to become negative for BCR-ABL) is rarely achieved with TKI inhibitors. This article aims to review the use of TKIs and examine alternative therapeutic targets with the potential to eradicate minimal residual disease (MRD). Available Tyrosine Kinase Inhibitor Therapies for Chronic Myeloid Leukemia Current FDA-approved treatment options for CML are summarized in Table 1. Based on the results of the International Randomized Study of Interferon and STI571 (IRIS) trial in 2003, in which imatinib demonstrated superiority over IFN-a plus low-dose cytarabine in terms of hematologic and cytogenetic responses, tolerability, and the likelihood of progression to accelerated-phase or blast-crisis CML, 6 imatinib replaced IFN-a as the standard of care in CML. It has achieved rates of complete cytogenetic response (CCyR) of more than 40  % in patients after failure of IFN and more than 80 % in newly diagnosed patients. 7 Its use has been associated with positive long-term outcomes. 8,9 However, significant proportions (10– 20  %) of patients do not achieve a satisfactory response to imatinib and discontinue therapy; a further 10–15 % will achieve a satisfactory response but subsequently acquire resistance to imatinib. 7,10,11 A significant number of patients develop AEs on imatinib therapy that cannot be managed 97