Targeted chronic myeloid leukemia therapy: Seeking a cure
ABSTRACT 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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ABSTRACT: The authors used cancer registry data to assess the incidence rate of second primary cancers among chronic myeloid leukemia (CML) patients and the long-term survival of CML patients before the introduction of tyrosine kinase inhibitors. In the Swedish Cancer Registry, the authors identified 2,753 adult CML patients diagnosed between 1970 and 1995 who were followed through December 2007. Standardized incidence ratios (SIRs) and relative survival ratios were computed. With a total of 145 subsequent primary malignancies, an increased incidence rate of second malignancy was found for stomach cancer (SIR = 2.76, 95% confidence interval (CI): 1.33, 5.08), skin cancer (SIR = 5.36, 95% CI: 3.18, 8.47), urogenital tract cancer (SIR = 1.61, 95% CI: 1.15, 2.21), and lymphoid leukemia (SIR = 5.53, 95% CI: 1.79, 12.89). Long-term relative survival figures showed that CML was related, in the era prior to the introduction of imatinib, to a very steep decline in survival (2 years from diagnosis, relative survival = 51%, 95% CI: 49, 53). This was in spite of a marginal improvement after 1985, possibly related to the introduction of interferon-α for treatment. These estimates constitute a relevant reference for future studies and a benchmark for comparisons with prognosis in CML patients after chronic use of tyrosine kinase inhibitors.American journal of epidemiology 11/2010; 172(9):1028-33. DOI:10.1093/aje/kwq262 · 4.98 Impact Factor
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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 · 1.22 Impact Factor
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ABSTRACT: Drug development groups are close to discovering another pot of gold-a therapeutic target-similar to the success of imatinib (Gleevec) in the field of cancer biology. Modern molecular biology has improved cancer therapy through the identification of more pharmaceutically viable targets, and yet major problems and risks associated with late-phase cancer therapy remain. Presently, a growing number of reports have initiated a discussion about the benefits of metabolic regulation in cancers. The Warburg effect, a great discovery approximately 70 years ago, addresses the "universality" of cancer characteristics. For instance, most cancer cells prefer aerobic glycolysis instead of mitochondrial respiration. Recently, cancer metabolism has been explained not only by metabolites but also through modern molecular and chemical biological techniques. Scientists are seeking context-dependent universality among cancer types according to metabolic and enzymatic pathway signatures. This review presents current cancer metabolism studies and discusses future directions in cancer therapy targeting bio-energetics, bio-anabolism, and autophagy, emphasizing the important contribution of cancer metabolism in cancer therapy.Biomolecules and Therapeutics 03/2015; 23(2):99-109. DOI:10.4062/biomolther.2015.013 · 0.84 Impact Factor