Dasatinib

Conchon, Mônika; Freitas, Carla Maria Boquimpani de Moura; Rego, Maria Aparecida do Carmo; Braga, José Wilson Ramos

doi:10.5581/1516-8484.20110034

Cited by 30 publications

(11 citation statements)

References 24 publications

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“…Based on risk factors for pleural effusion in dasatinib-treated patients described in literature, 9,11–13 retrospective multivariate analyses were performed to investigate the association between pleural effusion and baseline hypertension, age, and lymphocytosis in patients treated with dasatinib, as well as additional variables of interest including sex, region, dosing schedule (034/Dose-optimization only), baseline Euro (Hasford) risk scores (DASISION only), exposure to interferon alpha (034/Dose-optimization only), BCR-ABL1 levels, baseline parameters, major molecular response (MMR) at 12 months, line of therapy, duration of prior TKI therapy, and depth of MR at any time. Average daily dose, prior skin rash, and prior autoimmune or lung disease were assessed in the DASISION/034/Dose-optimization pooled population only.…”

Section: Resultsmentioning

confidence: 99%

Incidence, outcomes, and risk factors of pleural effusion in patients receiving dasatinib therapy for Philadelphia chromosome-positive leukemia

et al. 2018

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Dasatinib, a second-generation BCR-ABL1 tyrosine kinase inhibitor, is approved for the treatment of chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia, both as first-line therapy and after imatinib intolerance or resistance. While generally well tolerated, dasatinib has been associated with a higher risk for pleural effusions. Frequency, risk factors, and outcomes associated with pleural effusion were assessed in two phase 3 trials (DASISION and 034/Dose-optimization) and a pooled population of 11 trials that evaluated patients with chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia treated with dasatinib (including DASISION and 034/Dose-optimization). In this largest assessment of patients across the dasatinib clinical trial program (N=2712), pleural effusion developed in 6% to 9% of patients at risk annually in DASISION, and in 5% to 15% of patients at risk annually in 034/Dose-optimization. With a minimum follow-up of 5 and 7 years, drug-related pleural effusion occurred in 28% of patients in DASISION and in 33% of patients in 034/Dose-optimization, respectively. A significant risk factor identified for developing pleural effusion by a multivariate analysis was age. We found that overall responses to dasatinib, progression-free survival, and overall survival were similar in patients who developed pleural effusion and in patients who did not.

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Section: Resultsmentioning

confidence: 99%

Incidence, outcomes, and risk factors of pleural effusion in patients receiving dasatinib therapy for Philadelphia chromosome-positive leukemia

et al. 2018

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“…TEAE: Cytopenias, fluid retention, pleural effusion, dyspnea, gastrointestinal disorders, skin rash, headache and fatigue [ 63 ].…”

Section: Molecules That Inhibit Upstream Ikk Complex In Nf-κb Pathmentioning

confidence: 99%

Small Molecule NF-κB Pathway Inhibitors in Clinic

Ramadass

Vaiyapuri

Tergaonkar

2020

IJMS

129

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Nuclear factor kappa B (NF-κB) signaling is implicated in all major human chronic diseases, with its role in transcription of hundreds of gene well established in the literature. This has propelled research into targeting the NF-κB pathways for modulating expression of those genes and the diseases mediated by them. In-spite of the critical, but often promiscuous role played by this pathway and the inhibition causing adverse drug reaction, currently many biologics, macromolecules, and small molecules that modulate this pathway are in the market or in clinical trials. Furthermore, many marketed drugs that were later found to also have NF-κB targeting activity were repurposed for new therapeutic interventions. Despite the rising importance of biologics in drug discovery, small molecules got around 76% of US-FDA (Food and Drug Administration-US) approval in the last decade. This encouraged us to review information regarding clinically relevant small molecule inhibitors of the NF-κB pathway from cell surface receptor stimulation to nuclear signaling. We have also highlighted the underexplored targets in this pathway that have potential to succeed in clinic.

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“…In advanced phase patients, anemia is present in around 60% of patients undergoing treatment, and neutropenia occurs at a frequency similar to that observed for imatinib [32] . However, the use of factors that stimulate granulocyte colonies can help to reverse the latter in patients using dasatinib [31] . Rates of thrombocytopenia were 19% amongst patients that received dasatinib, compared to 10% for patients receiving imatinib [32] .…”

Section: Dasatinibmentioning

confidence: 99%

“…This drug is able to inhibit BCR-ABL, and has been utilized in adult patients with CML who present no response, or intolerance, to imatinib. It is indicated for the treatment of adults during the chronic, accelerated, or blast phases of the disease, and is considered to be a second generation tyrosine kinase inhibitor [8,31] .…”

Section: Dasatinibmentioning

confidence: 99%

Immunological implications of the use of tyrosine kinase inhibitors in chronic myeloid leukemia

et al. 2012

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Background: The treatment of chronic myeloid leukemia (CML) employs drugs known as tyrosine kinase inhibitors (TKIs). Comparative analyses of the effects of different TKIs has shown that these substances can reduce the immunogenicity of leukemic cells, and prejudice anti-tumoral immunity. Once the TKIs differ in terms of their direct influence on cells of the immunological system, the objective of this work was therefore to analyze alterations in the immunological systems of CML patients using different TKI drugs. Methodology/Principal findings:A review of the literature revealed that imatinib is considered to be the new paradigm for treatment of CML; however, use of this drug can result in inhibition of activation of immune system cells and development of resistance. Second and third generation TKIs can be used in the treatment of patients resistant to imatinib, but can have immunosuppressor effects. Nilotinib is more effective than imatinib in recently-diagnosed patients, however at high doses can induce myelosuppression and diminish cytokine production. Dasatinib was found to induce a rapid full cytogenetic response, with heightened in vivo immune-stimulation, in contrast to an immunosuppression observed in vitro. The mutated T315I phenotype of CML only shows a response to treatment with inhibitors that do not compete with ATP, involving aurora kinases that control mitosis, progression of the cellular cycle, and apoptosis induction. MK0457, which is able to act in the presence of the mutation, presents important bone marrow toxicity, while in small doses danusertib has shown anti-proliferative and pro-apoptotic activity against a wide spectrum of BCR-ABL-positive cells.Conclusions/Significance: Selection of the most suitable tyrosine kinase inhibitor in patients showing positive to the BCR-ABL mutation requires previous analysis of the phenotype and the influence of the TKI on the immunological system.

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Dasatinib

Cited by 30 publications

References 24 publications

Incidence, outcomes, and risk factors of pleural effusion in patients receiving dasatinib therapy for Philadelphia chromosome-positive leukemia

Incidence, outcomes, and risk factors of pleural effusion in patients receiving dasatinib therapy for Philadelphia chromosome-positive leukemia

Small Molecule NF-κB Pathway Inhibitors in Clinic

Immunological implications of the use of tyrosine kinase inhibitors in chronic myeloid leukemia

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