Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Treatment with imatinib has demonstrated high response rates and improved prognosis in chronic myelogenous leukemia. However, while the short-term response to imatinib is high, there are some concerns that the long-term response is substantially lower. Durable response with imatinib is difficult to achieve in patients with resistant disease. The use of higher doses has also been associated with increased toxicity and intolerance. Dasatinib is a new SRC-ABL-kinase inhibitor that has been developed for treating chronic myelogenous leukemia patients, across all phases of disease, who are resistant or intolerant to imatinib. This article details the existing evidence on the clinical efficacy, safety and value for money of dasatinib in the treatment of imatinib-resistant and -intolerant patients with chronic myelogenous leukemia. Dasatinib is associated with higher levels of response compared with high-dose imatinib. In addition, higher levels of response are associated with improved health outcomes in terms of both quality- and quantity-of-life years.
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PMID:Pharmacoeconomic benefits of dasatinib in the treatment of imatinib-resistant patients with chronic myelogenous leukemia. 1940 98

Tyrosine kinase inhibitors have revolutionized the treatment of chronic myeloid leukemia (CML), offering patients several targeted therapeutic options that provide the possibility of sustained remissions and prolonged survival. With the availability of imatinib, nilotinib and dasatinib, physicians must weigh the efficacy and safety profile of each agent when choosing the best therapeutic option for individual patients. Each agent targets tyrosine kinases within the cell uniquely to cause the desired antiproliferative effect. In addition to inhibiting the BCR-ABL kinase, imatinib and nilotinib target the same array of other tyrosine kinases, including c-KIT and platelet-derived growth factor receptor (PDGFR), albeit with differing potencies. While targeting BCR-ABL with the highest potency among approved agents in CML, dasatinib also targets a broad array of off-target kinases, including SRC family members, PDGFR and EPHB4. The differences in kinase inhibition profiles among these agents in vitro probably account for the differing clinical safety profiles of these agents. This paper reviews the various kinases inhibited by imatinib, nilotinib and dasatinib, and describes the potential impact of kinase inhibition on the efficacy and safety of each agent.
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PMID:Class effects of tyrosine kinase inhibitors in the treatment of chronic myeloid leukemia. 1947

PURPOSE Patients with chronic myelogenous leukemia in accelerated phase (CML-AP) that is resistant or intolerant to imatinib have limited therapeutic options. Dasatinib, a potent inhibitor of BCR-ABL and SRC-family kinases, has efficacy in patients with CML-AP who have experienced treatment failure with imatinib. We now report follow-up data from the full patient cohort of 174 patients enrolled onto a phase II trial to provide a more complete assessment of the efficacy and safety of dasatinib in this population. PATIENTS AND METHODS Patients with imatinib-resistant (n = 161) or -intolerant (n = 13) CML-AP received dasatinib 70 mg orally twice daily. Results At a median follow-up of 14.1 months (treatment duration, 0.1 to 21.7 months), major and complete hematologic responses were attained by 64% and 45% of patients, respectively, and major and complete cytogenetic responses were achieved in 39% and 32% of patients, respectively. Responses were achieved irrespective of imatinib status (resistant or intolerant), prior stem-cell transplantation, or the presence of prior BCR-ABL mutation. The 12-month progression-free survival and overall survival rates were 66% and 82%, respectively. Dasatinib was generally well tolerated; the most frequent nonhematologic severe treatment-related adverse event was diarrhea (52%; grade 3 to 4, 8%). Cytopenias were common, including grade 3 to 4 neutropenia (76%) and thrombocytopenia (82%). Pleural effusion occurred in 27% of patients (grade 3 to 4, 5%). CONCLUSION Dasatinib is effective in patients with CML-AP after imatinib treatment failure.
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PMID:Dasatinib in the treatment of chronic myeloid leukemia in accelerated phase after imatinib failure: the START a trial. 1948 85

Dasatinib is an oral potent adenosine triphosphate (ATP)-competitive inhibitor of BCR-ABL, cKIT, platelet-derived growth factor receptor, and SRC family kinases (SFKs), which has demonstrated high efficiency in patients with imatinib-resistant chronic myelogenous leukemia. Here, we show that dasatinib weakly affects platelet activation by thrombin or adenosine diphosphate but is a potent inhibitor of platelet signaling and functions initiated by collagen or FcgammaRIIA cross-linking, which require immunoreceptor tyrosine-based activation motif phosphorylation by SFKs. Accordingly, dasatinib treatment rapidly decreases the volume of thrombi formed under arterial flow conditions in whole blood from patients or mice perfused over a matrix of collagen. Moreover, treatment of mice with dasatinib increases the tail bleeding time in a dose-dependent manner. Interestingly, these effects are rapidly reversible after interruption of the treatment. Our data clearly demonstrate that, in contrast to imatinib, dasatinib affects platelet functions in vitro and in vivo, which has important implications in clinic and could explain increased risks of bleeding observed in patients. Moreover, dasatinib efficiently prevents platelet activation mediated by FcgammaRIIA cross-linking and by sera from patients with heparin-induced thrombocytopenia, suggesting that reversible antiplatelet agents acting as ATP-competitive inhibitors of SFKs may be of therapeutic interest in the treatment of this pathology.
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PMID:The new tyrosine-kinase inhibitor and anticancer drug dasatinib reversibly affects platelet activation in vitro and in vivo. 1971 76

The BCR-ABL inhibitor imatinib is standard first-line therapy for patients with chronic myeloid leukemia (CML) and has revolutionized treatment of the disease. However, resistance and intolerance to the agent have emerged as major clinical complications. Dasatinib is the first and only dual BCR-ABL/SRC family kinase inhibitor approved by the U.S. Food and Drug Administration for the treatment of patients with CML in any phase or Philadelphia chromosome-positive acute lymphoblastic leukemia who are resistant to or intolerant of imatinib. The agent is well tolerated and has shown clinical activity in such patients. As with other oral tyrosine kinase inhibitors, nonadherence to the prescribed dasatinib treatment regimen could obstruct a successful outcome. A new recommended dose of 100 mg once daily has been approved for patients with chronic phase CML. That dosing regimen, combined with appropriate management of dasatinib-related adverse events, may help patients adhere to their prescribed treatment and achieve maximum therapeutic benefit. This article highlights recent changes to the dasatinib label, including results with the 100 mg once-daily starting dose for patients with chronic phase CML, and discusses nursing strategies for the successful management of adverse events in patients receiving dasatinib.
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PMID:A once-daily dasatinib dosing strategy for chronic myeloid leukemia. 1950 90

The development of imatinib for the treatment of chronic myeloid leukemia (CML) has proven to be an example of medical success in the era of targeted therapy. However, imatinib resistance or intolerance occurs in a substantial number of patients. Additionally, patients who have progressed beyond the chronic phase of CML do relatively poorly with imatinib therapy. Mechanisms of imatinib resistance include BCR-ABL point mutations resulting in decreased imatinib binding, as well as mutation-independent causes of resistance such as SRC family kinase dysregulation, BCR-ABL gene amplification, drug influx/efflux mechanisms and other poorly understood processes. The options for therapy in these patients include stem cell transplantation, imatinib dose escalation as well as the use of second-generation tyrosine kinase inhibitors. Dasatinib is a second-generation multi-kinase inhibitor with several theoretical and mechanistic advantages over imatinib. Moreover, several studies have evaluated dasatinib in patients who have progressed on imatinib therapy with encouraging results. Other novel agents such as mTOR inhibitors, bosutinib and INNO 406 have also shown promise in this setting. Although treatment options have increased, the choice of second-line therapy in patients with CML is influenced by concerns surrounding the duration of response as well as toxicity. Consequently, there is no agreed upon optimal second-line agent. This paper reviews the current data and attempts to address these issues.
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PMID:Dasatinib in the treatment of imatinib refractory chronic myeloid leukemia. 1970 9

The introduction of the BCR-ABL inhibitor imatinib revolutionized the treatment of patients with chronic myeloid leukemia (CML). However, resistance to imatinib has become a clinically significant issue, limiting its long-term efficacy. Numerous mechanisms have been associated with imatinib resistance, including mutations to the BCR-ABL gene, increased production of BCR-ABL, and activation of BCR-ABL-independent pathways (e.g., SRC-family kinases [SFKs]). Resistance to imatinib has driven the development of second-line therapies, such as dasatinib, a dual BCR-ABL/SFK inhibitor more potent than imatinib at targeting BCR-ABL. Dasatinib is approved for the treatment of patients with imatinib-resistant and -intolerant CML and Philadelphia chromosome-positive acute lymphoblastic leukemia. Nilotinib, an analog of imatinib, more potent than its parent compound, is another approved agent for patients with imatinib-resistant or -intolerant CML in the chronic or accelerated phase. Nurses must be aware of what constitutes a requirement for treatment change and the mechanisms of resistance that inform the choice of second-line agents. Oncology nurses also must ensure that patients have been educated appropriately to understand imatinib resistance and second-line treatment options. This article explores the mechanisms and identification of resistance and treatment options for when resistance occurs, as well as nursing implications.
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PMID:Treatment of chronic myeloid leukemia following imatinib resistance: a nursing guide to second-line treatment options. 1979 9

Dasatanib, which has been approved for rescue therapy for patients with imatinib-resistant chronic myelogenous leukemia and Philadelphia chromosome positive acute lymphoblastic leukemia, is a novel, orally available multitargeted kinase inhibitor of BCR-ABL and SRC family kinases (Quintas-Cardama et al, J Clin Oncol 2007;25:3908-14). It binds to both active and inactive conformations of the ABL gene and is 325 times more potent than imatinib in inhibiting the growth of BCR/ABL cells in vitro (Morelock and Sahn, Chest 1999;116:212-21; Huggins and Sahn, Clin Chest Med 2004;25:141-53). Although dasatinib is a generally well-tolerated drug in the treatment of Philadelphia chromosome positive hematopoetic malignancies, pleural effusions have been frequently noted and have been reported in up to 35% of patients (Sahn SA. Drug-induced pleural disease. In: Camus P, Rosenow E, editors. Drug-induced iatrogenic lung disease. London: Hodder Arnold; 2009). Although there have been numerous reports of effusions, none have provided complete pleural fluid analysis; therefore, we report 2 patients with dasatinib-induced pleural effusion with complete pleural fluid analysis.
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PMID:Dasatinib-induced pleural effusions: a lymphatic network disorder? 1983 99

Resistance to the BCR-ABL tyrosine kinase inhibitor imatinib poses a pressing challenge in treating chronic myeloid leukemia (CML). This resistance is often caused by point mutations in the ABL kinase domain or by overexpression of LYN. The second-generation BCR-ABL inhibitor INNO-406 is known to inhibit most BCR-ABL mutants and LYN efficiently. Knowledge of its full target spectrum would provide the molecular basis for potential side effects or suggest novel therapeutic applications and possible combination therapies. We have performed an unbiased chemical proteomics native target profile of INNO-406 in CML cells combined with functional assays using 272 recombinant kinases thereby identifying several new INNO-406 targets. These include the kinases ZAK, DDR1/2 and various ephrin receptors. The oxidoreductase NQO2, inhibited by both imatinib and nilotinib, is not a relevant target of INNO-406. Overall, INNO-406 has an improved activity over imatinib but a slightly broader target profile than both imatinib and nilotinib. In contrast to dasatinib and bosutinib, INNO-406 does not inhibit all SRC kinases and most TEC family kinases and is therefore expected to elicit fewer side effects. Altogether, these properties may make INNO-406 a valuable component in the drug arsenal against CML.
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PMID:A comprehensive target selectivity survey of the BCR-ABL kinase inhibitor INNO-406 by kinase profiling and chemical proteomics in chronic myeloid leukemia cells. 1989 Mar 74

Imatinib is currently regarded as the best initial treatment for patients with chronic myeloid leukemia (CML). However, a significant proportion of patients who relapse, fail to respond, or develop intolerance might benefit from the use of second-generation tyrosine kinase inhibitors. In this review, we report the 2-year results in 8 clinical trials involving more than 2000 patients treated with dasatinib (phases I-III). Patients with CML who had failed to respond or were intolerant to imatinib were enrolled in a phase I trial. The positive results emanating from this study led to a series of 5 phase II trials known as START (SRC/ABL tyrosine kinase inhibition activity: research trials of dasatinib). In addition, 2 phase III dose-optimization trials have now been completed. These trials demonstrate that dasatinib offers clinical benefit to patients resistant or intolerant to imatinib, with a well-described and manageable adverse event profile.
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PMID:Dasatinib and chronic myeloid leukemia: two-year follow-up in eight clinical trials. 1995 80


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