Targeted chronic myeloid leukemia therapy: Seeking a cure

Hematology/Oncology/BMT, Indiana University Cancer Center, 550 North University Boulevard, Indianapolis, IN 46202, USA.
American journal of health-system pharmacy: AJHP: official journal of the American Society of Health-System Pharmacists (Impact Factor: 1.88). 01/2008; 64(24 Suppl 15):S9-15. DOI: 10.2146/ajhp070482
Source: PubMed


This article focuses on imatinib, how it has altered CML therapy, clinical trials that are the basis for its efficacy, and adverse effects associated with its current clinical use.
Maintaining patients with CML in chronic phase (CP) yields the prospect of improved long-term survival. As recently as 1993, CML was limited to treatment with standard cytoreductive therapies. These therapies provide temporary disease control but do not alter progression to advanced disease with a median survival ranging 45 to 55 months from diagnosis. In the 1990s, immunologically based therapy with interferon alpha (IFNalpha) therapy was shown to be superior to cytoreductive therapies with a median survival of 60 to 90 months. Allogeneic hematopoietic stem cell transplant (HSCT) has offered curative potential for patients with CML; however, the median age of diagnosis of 55 years, the lack of suitable donors, and the morbidity of the procedure precludes widespread applicability of this treatment. Imatinib, the first approved tyrosine kinase inhibitor, functions by blocking the ATP binding site on the BCR-ABL kinase. It was first shown to be efficacious in patients who failed IFNalpha and then tested as a front line therapy (the International Randomized Study of Interferon [IRIS] trial). The five year follow up on the IRIS trial found that the responses were durable with progression free survival estimated at 93%. Imatinib has been found to have a lower rate of hematologic response and shorter duration of response in patients with advanced disease. Currently patients in blast crisis (BC) have the option to undergo a number of induction chemotherapies, such as etoposide, cytarabine, carboplatin (VAC) with the hope of temporarily restoring the patient to CP in preparation for HSCT. Imatinib, when administered at the standard dose of 400 mg/day is relatively well tolerated with major toxicities limited to myelo-suppression, edema, GI upset, rash, and muscle pain. Many of these toxicities are managed by decreasing the dose until the toxicity resolves. Imatinib is an inhibitor of cytochrome P450 enzymes necessitating careful monitoring of concomitant medications metabolized by these enzymes. Resistance may develop to imatinib most often caused by the evolution of mutations blocking imatinib interactions with the BCR-ABL adenosine triphosphate (ATP) binding site. The second generation BCR-ABL inhibitor, dasatinib, can block the activity of many of these mutations; however, the T315I mutation, at present, is resistant to all available kinase inhibitors. Experimental drugs that block this mutation are just entering phase two clinical trials.
The development of therapeutic agents targeting BCR-ABL has revolutionized the treatment of chronic myeloid leukemia (CML). Imatinib has successfully allowed CML patients to remain in CP for at least five years in 90% of patients. Dasatinib has activity against a number of Imatinib-resistant mutants providing an additional therapeutic option for these patients.

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    • "In CML cells, the kinase domain of Bcr-abl is phosphorylated at tyrosine residues and activated by ATP binding. Imatinib mesylate mimics ATP and inhibits its binding to the tyrosine kinase domain of Bcr-abl (Fausel, 2007). Different studies demonstrated that patients with accelerated or blast crisis phases can show resistance to imatinib (Gorre et al., 2001; Sawyers et al., 2002). "
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    ABSTRACT: Chronic myeloid leukemia (CML) is characterized by the accumulation of Philadelphia chromosome-positive (Ph+) myeloid cells. Ph+ cells occur via a reciprocal translocation between the long arms of chromosomes 9 and 22 resulting in constitutively active Bcr-abl fusion protein. Tyrosine kinase inhibitors (TKIs) are used against the kinase activity of Bcr-abl fusion protein for the effective treatment of CML. However, the development of drug resistance, directed by different genetic mechanisms, is the major problem of clinical applications of TKIs. These mechanisms include mutations in the TKI binding site of Bcr-abl, overexpression of Bcr-abl, overexpression of ATP binding cassette transporters, aberrant ceramide metabolism, inhibition of apoptosis, and changes in expression levels of microRNAs. Recently, many studies have focused on understanding the molecular mechanisms of drug resistance in cancer while targeting therapies providing reversal of resistance. Cancer stem cells also have roles in tumor initiation, maintenance, progression, metastasis, and drug resistance. Uncovering the mechanisms of drug resistance can provide more efficient treatment of cancer since these findings may provide novel targets for a complete cure. In this review, we discuss recent findings on the mechanisms of multidrug resistance and its reversal in CML.
    Turkish Journal of Biology 11/2014; DOI:10.3906/biy-1405-21 · 1.34 Impact Factor
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    • "This translates into a chimeric protein with constitutive tyrosine kinase activity that phosphorylates target proteins, leading to the expansion of hematopoietic stem and progenitor cells. The introduction of imatinib that binds to the kinase domain of BCR-ABL as a tyrosine kinase inhibitor remains the first line of therapy for CML patients [1] [2] [3] [4]. Despite the high efficiency of imatinib, approximately 30 % of patients develop resistance to it [5]. "

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    • "Large-scale clinical trials have proven imatinib has high and persistent efficacy in treating CML [17]. However, 25% of patients with imatinib monotherapy show primary refractory disease and drug resistance [18]. Several clinical studies have shown some advantages of the combination of imatinib and IFNα [19]. "
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    ABSTRACT: Background H3K9 methylation is one of the essential histone post-translational modifications for heterochromatin formation and transcriptional repression. Recently, several studies have demonstrated that H3K9 methylation negatively regulates the type I interferon response. Results We report the application of EHMT1 and EHMT2 specific chemical inhibitors to sensitize CML cell lines to interferon and imatinib treatments. Inhibition of EHMT1 and EHMT2 with BIX01294 enhances the cytotoxicity of IFNα2a in four CML cell lines, K562, KCL22, BV173 and KT1 cells. Chromatin immunoprecipitation assay shows that BIX01294 treatment enhances type I interferon response by reducing H3K9me2 at the promoters of interferon-stimulated genes. Additionally, BIX01294 treatment augments IFNα2a- and imatinib-mediated apoptosis in CML cell lines. Moreover, our data suggest that the expression level of EHMT1 and EHMT2 inversely correlates with the type I interferon responsiveness in CML cell lines. Conclusions Our study sheds light on the role of EHMT1 and EHMT2 as potential targets in improving the efficacy of standard treatments of CML.
    PLoS ONE 07/2014; 9(7):e103915. DOI:10.1371/journal.pone.0103915 · 3.23 Impact Factor
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