Comparison of the clinical outcomes of nilotinib and dasatinib therapies in newly diagnosed patients in the chronic phase of chronic myeloid leukemia: a retrospective analysis
Noriyoshi IriyamaKeiji SugimotoEriko SatoTomoiku TakakuMichihide TokuhiraTomonori NakazatoMaho IshikawaHiroyuki FujitaIsao FujiokaYuta KimuraNorio AsouMasahiro KizakiNorio KomatsuYoshihiro HattaTatsuya Kawaguchi
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Hematology
Imatinib Mesylate
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Introductions: Dasatinib is indicated as a first line, second line and third line tyrosine kinase inhibitor (TKI) in chronic myeloid leukemia (CML). In our center it is used as a second line or third line therapy in BCR-ABL gene positive CML.
Methods: It is a retrospective observational therapy done from June 2015 to May 2018. The purpose of the study is to see the response rates using the second line and third line dasatinib after failing or not tolerating imatinib alone or following a sequential therapy with imatinib and nilotinib.
Results: A total of 31 (male 56.3%) patients were included in our study. In eighteen patients it was used as a second line TKI and in 13 a third line TKI. Complete Hematologic Response (CHR) was achieved in 93.55%. Best optimal responses were 46.66% and 61.53% in second and third line dasatinib respectively. Major Molecular Response (MMR) was achieved in 35.71% (26.66% and 46.14% in second line and third line dasatinib respectively). For both the groups, the overall survival was 92% and 94 % at 20 months and the event free survival was 70% at 10 months.
Conclusions: Dasatinib is effective in achieving MMR and inducing survival benefit in the patients who failed imatinib alone and imatinib and nilotinib.
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Treatment with the tyrosine kinase inhibitor imatinib is the standard of care for newly diagnosed patients with chronic myeloid leukemia. In recent years, several second-generation inhibitors - such as dasatinib and nilotinib - have become available: these promise to overcome some of the mutations associated with acquired resistance to imatinib. Despite eliciting similar clinical responses, the molecular effects of these agents on different subpopulations of leukemic cells remain incompletely understood. Furthermore, the consequences of using high-dose imatinib therapy have not been investigated in detail. Here we utilized clinical data from patients treated with dasatinib, nilotinib, or high-dose imatinib, together with a statistical data analysis and mathematical modeling approach, to investigate the molecular treatment response of leukemic cells to these agents. We found that these drugs elicit very similar responses if administered front-line. However, patients display significantly different kinetics when treated second-line, both in terms of differences between front-line and second-line treatment for the same drug, and among agents when used as second-line. We then utilized a mathematical framework describing the behavior of four differentiation levels of leukemic cells during therapy to predict the treatment response kinetics for the different cohorts of patients. The dynamics of BCR-ABL1 clearance observed in our study suggest that the use of standard or high-dose imatinib or a second-generation tyrosine kinase inhibitor such as nilotinib or dasatinib elicits similar responses when administered as front-line therapy for patients with chronic myeloid leukemia in chronic phase.
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Chronic myeloid leukemia (CML) originates from a hematopoietic stem cell carrying the Philadelphia (Ph) chromosome and oncogenic BCR-ABL1 fusion gene. The first tyrosine-kinase inhibitor (TKI) imatinib was introduced to clinical practice 10 years ago, and it radically improved the outcome of CML patients. The rare patients that are imatinib resistant or intolerant can be treated with second generation TKIs such as dasatinib or nilotinib. As second generation TKIs appear to be more effective than imatinib and well tolerated, they may become standard first-line treatment for CML. The major future aim in CML is curative drug therapy.
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BackgroundResearch into chronic myeloid leukemia (CML) is increasingly focused on the problem of imatinib failure. Dasatinib and nilotinib are both active in chronic- and accelerated-phase CML, including patients with imatinib-resistant or intolerant disease.MethodsThis paper reviews advances in tailoring tyrosine kinase inhibition therapy according to patient risk profiles as well as hematologic, cytogenetic, and molecular responses, BCRABL mutation status, and emerging predictive factors.ResultsIn addition to identifying specific tyrosine kinase mutations, clinical advances have allowed us to determine patients who are less likely to derive long-term survival benefits from imatinib.ConclusionsTreatment for CML should be individualized and, when resistance to imatinib can be predicted, therapy should be modified so that patients do not progress beyond chronic phase and respond as promptly and deeply as required to maximally reduce risk.
Imatinib Mesylate
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The Bcr-Abloncoprotein with constitutive tyrosine kinase activity plays a pivotal role in the pathogenesis of chronic myeloid leukemia (CML), therefore being an ideal target for the drug development. Imatinibmesylate, a selective tyrosine kinases inhibitor (TKI), has excellent efficacy in the treatment of chronic myeloid leukemia. It has opened the way to the development of additional TKIs against chronic myeloid leukemia, including nilotinib and dasatinib. In this study, computational methods are used to design novel imatinib derivatives and evaluated them for interaction with the Bcr-Abloncoprotein through insilico analysis by using Hyperchem 8.0, Gold 3.01 docking software. Here, from the results, it is reported that 1, 14, 26, ligands are having dock score near to imatinib and modifications to these ligands may result in better ligands than imatinib. The results of Toxicity studies also supported 1, 14, 26, better drug-likeness properties. Ligand 4 has shown higher affinity and better interaction with Bcr-Abloncoprotein than imatinib and any other newly designed molecules, but it had shown mutagenicity and irritancy.
Docking (animal)
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The chronic myeloid leukemia (CML) is a myeloproliferative neoplasm eligible for targeted therapy with tyrosine kinase inhibitors (TKI). We report in our study the therapeutic outcomes of 173 patients treated for CML in the department of hematology in Aziza Othmana hospital Tunis Tunisia. The front line treatment with Imatinib a first generation TKI has achieved a complete hematological response, a complete cytogenetical response, a major molecular response and a molecular response>4 log in respectively, 95%, 70%, 64% and 40% of patients. The switch to a second generation TKI was indicated in 40% of the patients and has improved the outcomes. The 5-year overall survival (OS) and progression free survival (PFS) were respectively 90 and 91%. Our outcomes are comparable to the reported data and seems to be very encouraging.
Myeloproliferative neoplasm
Hematology
Imatinib Mesylate
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