Chronic Myeloid Leukemia— What Else is there Beyond Protein Kinase Inhibitors?

Oncology & Hematology Review, 2014;10(2):97–102

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: ejabbour@mdanderson.org
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-α) 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

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-α 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-α 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 through dose reduction or symptomatic treatment.11 Common AEs include neutropenia, thrombocytopenia, anemia, and elevated liver enzymes.12 Uncommon or delayed AEs may include renal and dermatologic problems.13 imatinib has also been associated with cardiac adverse reactions related to c-ABL inhibition, suggesting that such AEs may be common to all TKIs.14 Response rates and the durability of responses to imatinib are dependent on the stage of disease at which treatment is initiated (see Figure 1).7

The second-generation TKIs dasatinib and nilotinib have higher binding affinity than imatinib to kinase domains of BCR-ABL and received FDA approval as second-line treatments in 2006 and 2007, respectively, and in the first-line treatment setting in 2010, after clinical trials data demonstrated their superior efficacy and safety.15,16 However, in spite of the advantages of dasatinib and nilotinib, treatment with these agents has been associated with AEs requiring dose interruptions and reductions.17,18 In 2012, bosutinib, a second-generation inhibitor of ABL and Src family kinases, was approved by the FDA as a second-line treatment option for adult patients with previously treated CML, following two phase I/II clinical trials.19,20 Bosutinib inhibits wild-type BCR-ABL and most imatinibresistant BCR-ABL mutations, except for V299L, F317V, and T315I, and is characterized by low hematologic toxicity and few AEs. Bosutinib has also demonstrated efficacy in the third-line treatment setting.19 However, in a phase III trial that compared bosutinib with imatinib in the first-line treatment setting, bosutinib did not meet its primary end-point of CCR at 12 months, despite the observed higher major molecular response (MMR) rate at 12 months, faster times to CCR and MMR, fewer on-treatment transformations to accelerated/blast phase, and fewer CML-related deaths with bosutinib compared with imatinib.21

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Keywords: Chronic myeloid leukemia, imatinib, omacetaxine, tyrosine kinase inhibitors