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BACKGROUND:Dasatinib, a highly potent BCR‐ABL inhibitor, is an effective treatment for patients with chronic myeloid leukemia in chronic phase (CML CP) after resistance, suboptimal response, or intolerance to prior imatinib. In a phase 3 dose optimization trial in patients with CML CP (CA180‐034), the occurrence of pleural effusion was significantly minimized with dasatinib 100 mg once daily (QD)...
BACKGROUND:The recently developed the Src and Abelson (Abl) kinase inhibitor dasatinib has antitumor effects in epithelial and mesenchymal tumors. Preclinical data have indicated that dasatinib is metabolized primarily through cytochrome P450 3A4 (CYP3A4) and may cause QT prolongation. In light of its improved tolerability, the authors were interested in the safety of a once‐daily dasatinib regimen...
Identification of BCR‐ABL as the defining leukemogenic event in chronic myelogenous leukemia (CML) revolutionized the treatment of the disease. Imatinib, a potent BCR‐ABL inhibitor, is the standard of care for the first‐line treatment of patients with chronic‐phase CML because of its high long‐term response rates and favorable tolerability profile compared with previous standard therapies. However,...
BACKGROUND:Clonal evolution is frequently detected in patients developing resistance to imatinib. The outcome of patients with clonal evolution treated with second generation tyrosine kinase inhibitors is not known.
METHODS:The authors analyzed the outcome of 177 CML patients after second tyrosine kinase inhibitor therapy.
RESULTS:Ninety‐five patients were in chronic phase, 30 had clonal evolution,...
BACKGROUND:In a phase 3 study, the authors assessed the effects of dasatinib at doses of 140 mg once daily and 70 mg twice daily in patients who had either chronic myeloid leukemia (CML) in advanced phases or Philadelphia chromosome‐positive acute lymphoblastic leukemia and were resistant or intolerant to imatinib. In the current report, the results for patients with CML in blast phase after 2 years...
BACKGROUND:Dasatinib, an inhibitor of Src/Abl family kinases, can inhibit tumor growth of several solid tumors. However, the effect and mechanism of action of dasatinib in human ovarian cancer cells remains unknown.
METHODS:Dasatinib‐induced autophagy was determined by acridine orange staining, punctate localization of GFP‐LC3, LC3 protein blotting, and electron microscopy. Significance of beclin...
BACKGROUND:Treatment recommendations have been developed for management of patients with chronic myeloid leukemia (CML).
METHODS:A 30‐item multiple‐choice questionnaire was administered to 435 hematologists and oncohematologists in 16 Latin American countries. Physicians self‐reported their diagnostic, therapeutic, and disease management strategies.
RESULTS:Imatinib is available as initial therapy...
Tyrosine kinase inhibitor (TKI) treatment targeting breakpoint cluster region‐Abelson murine leukemia virus, the cause of chronic myeloid leukemia (CML), has revolutionized therapy for patients with this disease. The majority of patients with CML maintain favorable responses with long‐term imatinib therapy; however, the availability of the second‐generation TKIs nilotinib and dasatinib limits the...
Chronic myeloid leukemia (CML) is a progressive and often fatal myeloproliferative neoplasm. The hallmark of CML is an acquired chromosomal translocation known as the Philadelphia chromosome (Ph), which results in the synthesis of the breakpoint cluster region‐Abelson murine leukemia (BCR‐ABL) fusion oncoprotein, a constitutively active tyrosine kinase. The introduction of imatinib, a tyrosine kinase...
Data demonstrating the superiority of nilotinib over imatinib in the frontline treatment of chronic myeloid leukemia (CML) and ongoing studies with dasatinib and bosutinib are rapidly changing the treatment landscape for CML. In this review, the authors discuss currently available therapies for CML, focusing on mechanisms of resistance to imatinib and treatment strategies to overcome resistance. Relevant...
BACKGROUND:Treatment options for patients with advanced head and neck squamous cell carcinoma (HNSCC) are scarce. This phase 2 study was conducted to evaluate the safety, tolerability, pharmacokinetics, and efficacy of dasatinib in this setting.
METHODS:Patients with recurrent and/or metastatic HNSCC after platinum‐based therapy were treated with dasatinib either orally or via percutaneous feeding...
BACKGROUND:Inhibiting src kinases (non‐receptor tyrosine kinase signaling intermediates) reduces melanoma cell proliferation and invasion. Dasatinib inhibits c‐kit, PDGFβR, and EPHA2 and src kinases c‐src, c‐Yes, Lck, and Fyn. A phase 2 trial of dasatinib in melanoma was conducted to assess response rate (RR), progression‐free survival (PFS), and toxicity.
METHODS:Adults with stage 3/4 chemotherapy‐naïve...
Although imatinib has been used as frontline therapy for chronic myeloid leukemia (CML) for nearly a decade, current debate is focused on the incorporation of newer tyrosine kinase inhibitors (TKIs) at diagnosis in light of recent US Food and Drug Administration approval of nilotinib and dasatinib for initial therapy in chronic‐phase CML. Articles were identified through a PubMed search and a review...
BACKGROUND:Deletions of derivative chromosome 9 are a poor prognostic factor in patients with chronic myeloid leukemia (CML) treated with hydroxyurea, interferon, or stem cell transplantation. Imatinib may overcome the adverse prognostic impact of deletions of derivative chromosome 9.
METHODS:A study was undertaken to investigate the prognostic impact of deletions of derivative chromosome 9 in 353...
Chronic myeloid leukemia (CML) depends on the kinase activity of the BCR‐ABL1 fusion protein. This dependency has led to the development of BCR‐ABL1 inhibitors, such as imatinib, dasatinib, and nilotinib, which have proved to be highly efficacious treatments for CML. The European LeukemiaNet guidelines have established the importance of achieving a certain depth of response at different time points...
BACKGROUND:To determine the potential efficacy of targeting both the tumor and bone microenvironment in patients with castration‐resistant prostate cancer (PC), the authors conducted a phase 1‐2 trial combining docetaxel with dasatinib, an oral SRC inhibitor.
METHODS:In phase 1, 16 men received dasatinib 50 to 120 mg once daily and docetaxel 60 to 75 mg/m2 every 21 days. In phase 2, 30 additional...
In patients with chronic myeloid leukemia (CML), the hallmark Philadelphia chromosome is the marker of disease that can be detected by conventional metaphase cytogenetics, fluorescence in situ hybridization, or polymerase chain reaction. The current “gold standard” of treatment response is cytogenetic response. Cytogenetic response to imatinib is strongly associated with disease progression and survival...
The high response rates and increased survival associated with imatinib therapy prompted a paradigm shift in the management of chronic myeloid leukemia. However, 25% to 30% of imatinib‐treated patients develop drug resistance or intolerance, increasing the risk of disease progression and poor prognosis. In 2006, the European LeukemiaNet proposed criteria to identify patients with a suboptimal response...
BACKGROUNDPatients with Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL) frequently relapse on imatinib with acquisition of BCR‐ABL kinase domain (KD) mutations. To analyze the changes that second‐generation tyrosine kinase inhibitors (TKIs) have brought in mutation frequency and type, a database review was undertaken of the results of all the BCR‐ABL KD mutation analyses...
BACKGROUNDChronic use of tyrosine kinase inhibitors (TKIs) may lead to previously unrecognized adverse events. This study evaluated the incidence of acute kidney injury (AKI) and chronic kidney disease (CKD) in chronic‐phase (CP) chronic myeloid leukemia (CML) patients treated with imatinib, dasatinib, and nilotinib.
METHODSFour hundred sixty‐eight newly diagnosed CP CML patients treated with TKIs...
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