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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    • "The breakpoints in the BCR gene has been shown to be clustered in three regions, (a) a 5.8 kb region spanning exons 12-16 (e12-e16), called the major breakpoint cluster region (M-bcr) that codes a 210 kDa chimeric protein (p210), (b) a 55 kb sequence of the first intron (e1-e2) called the minor breakpoint cluster region (m-bcr) that encodes a 190 kDa chimeric protein (p190) and finally intron 19, called μ-bcr forming a resultant fusion transcript of 230 kDa protein (p230) (Fausel, 2007; Yuan et al., 2014). "
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    ABSTRACT: Chronic myeloid leukemia (CML) is a stem cell disorder characterized by unrestricted proliferation of the myeloid series that occurs due to the BCR-ABL fusion oncogene as a result of reciprocal translocation t(9;22) (q34;q11). This discovery has made this particular domain a target for future efforts to cure CML. Imatinib revolutionized the treatment options for CML and gave encouraging results both in case of safety as well as tolerability profile as compared to agents such as hydroxyurea or busulfan given before Imatinib. However, about 2-4% of patients show resistance and mutations have been found to be one of the reasons for its development. European Leukemianet gives recommendations for BCR-ABL mutational analysis along with other tyrosine kinase inhibitors (TKIs) that should be administered according to the mutations harbored in a patient. The following overview gives recommendations for monitoring patients on the basis of their mutational status.
    Full-text · Article · Dec 2015 · Asian Pacific journal of cancer prevention: APJCP
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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.
    Full-text · Article · Nov 2014 · Turkish Journal of Biology
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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]. "

    Full-text · Dataset · Oct 2014
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