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https://www.readbyqxmd.com/read/29643105/a-next-generation-sequencing-based-assay-for-minimal-residual-disease-assessment-in-aml-patients-with-flt3-itd-mutations
#1
Mark J Levis, Alexander E Perl, Jessica K Altman, Christopher D Gocke, Erkut Bahceci, Jason Hill, Chaofeng Liu, Zhiyi Xie, Andrew R Carson, Valerie McClain, Timothy T Stenzel, Jeffrey E Miller
Internal tandem duplications in fms-like tyrosine kinase 3 ( FLT3- ITDs) are common in acute myeloid leukemia (AML) and confer a poor prognosis. A sensitive and specific assay for the detection of minimal residual disease (MRD) in FLT3- ITD mutated AML could guide therapy decisions. Existing assays for MRD in FLT3- ITD AML have not been particularly useful because of limited sensitivity. We developed a sensitive and specific MRD assay for FLT3- ITD mutations using next-generation sequencing. The initial validation of this assay was performed by spiking fixed amounts of mutant DNA into wild-type DNA to establish a sensitivity of detection equivalent to ≥1 FLT3- ITD-containing cell in 10 000, with a minimum input of 100 000 cell equivalents of DNA...
April 24, 2018: Blood Advances
https://www.readbyqxmd.com/read/29507660/flt3-itd-induces-expression-of-pim-kinases-through-stat5-to-confer-resistance-to-the-pi3k-akt-pathway-inhibitors-on-leukemic-cells-by-enhancing-the-mtorc1-mcl-1-pathway
#2
Keigo Okada, Ayako Nogami, Shinya Ishida, Hiroki Akiyama, Cheng Chen, Yoshihiro Umezawa, Osamu Miura
FLT3-ITD is the most frequent tyrosine kinase mutation in acute myeloid leukemia (AML) associated with poor prognosis. We previously reported that activation of STAT5 confers resistance to PI3K/Akt inhibitors on the FLT3-ITD-positive AML cell line MV4-11 and 32D cells driven by FLT3-ITD (32D/ITD) but not by FLT3 mutated in the tyrosine kinase domain (32D/TKD). Here, we report the involvement of Pim kinases expressed through STAT5 activation in acquisition of this resistance. The specific pan-Pim kinase inhibitor AZD1208 as well as PIM447 in combination with the PI3K inhibitor GDC-0941 or the Akt inhibitor MK-2206 cooperatively downregulated the mTORC1/4EBP1 pathway, formation of the eIF4E/eIF4G complex, and Mcl-1 expression leading to activation of Bak and Bax to induce caspase-dependent apoptosis synergistically in these cells...
February 6, 2018: Oncotarget
https://www.readbyqxmd.com/read/29498296/asp2215-in-the-treatment-of-relapsed-refractory-acute-myeloid-leukemia-with-flt3-mutation-background-and-design-of-the-admiral-trial
#3
Claudia M Gorcea, John Burthem, Eleni Tholouli
Acute myeloid leukemia (AML) is a heterogeneous disease with cure rates of only 30-40% in patients <60 years old. Cytogenetic and molecular markers have improved our understanding of the different prognostic entities in AML. FLT3 mutations are present in 30-40% of AML cases, conferring a poor prognosis with reduced survival. AXL activates FLT3, impacting adversely on outcome. Both FLT3 and AXL constitute promising molecular targets. ASP2215 (gilteritinib) is a novel, dual FLT3/AXL inhibitor with promising early phase trial data (NCT02014558)...
March 2, 2018: Future Oncology
https://www.readbyqxmd.com/read/28687566/the-flt3-inhibitor-gilteritinib-has-activity-in-patients-with-aml
#4
(no author information available yet)
Gilteritinib was well tolerated in a phase I/II dose-escalation and dose-expansion study.
July 7, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28645776/selective-inhibition-of-flt3-by-gilteritinib-in-relapsed-or-refractory-acute-myeloid-leukaemia-a-multicentre-first-in-human-open-label-phase-1-2-study
#5
MULTICENTER STUDY
Alexander E Perl, Jessica K Altman, Jorge Cortes, Catherine Smith, Mark Litzow, Maria R Baer, David Claxton, Harry P Erba, Stan Gill, Stuart Goldberg, Joseph G Jurcic, Richard A Larson, Chaofeng Liu, Ellen Ritchie, Gary Schiller, Alexander I Spira, Stephen A Strickland, Raoul Tibes, Celalettin Ustun, Eunice S Wang, Robert Stuart, Christoph Röllig, Andreas Neubauer, Giovanni Martinelli, Erkut Bahceci, Mark Levis
BACKGROUND: Internal tandem duplication mutations in FLT3 are common in acute myeloid leukaemia and are associated with rapid relapse and short overall survival. The clinical benefit of FLT3 inhibitors in patients with acute myeloid leukaemia has been limited by rapid generation of resistance mutations, particularly in codon Asp835 (D835). We aimed to assess the highly selective oral FLT3 inhibitor gilteritinib in patients with relapsed or refractory acute myeloid leukaemia. METHODS: In this phase 1-2 trial, we enrolled patients aged 18 years or older with acute myeloid leukaemia who either were refractory to induction therapy or had relapsed after achieving remission with previous treatment...
August 2017: Lancet Oncology
https://www.readbyqxmd.com/read/28516360/gilteritinib-a-flt3-axl-inhibitor-shows-antileukemic-activity-in-mouse-models-of-flt3-mutated-acute-myeloid-leukemia
#6
Masamichi Mori, Naoki Kaneko, Yoko Ueno, Masaki Yamada, Ruriko Tanaka, Rika Saito, Itsuro Shimada, Kenichi Mori, Sadao Kuromitsu
Advances in the understanding of the molecular basis for acute myeloid leukemia (AML) have generated new potential targets for treatment. Fms-like tyrosine kinase 3 (FLT3) is one of the most frequently mutated genes in AML and mutations in this gene are associated with poor overall survival. AXL plays a role in the activation of FLT3 and has been implicated in the pathogenesis of AML. The studies reported here evaluated the ability of a novel FLT3/AXL inhibitor, gilteritinib, to block mutated FLT3 in cellular and animal models of AML...
October 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28000291/the-role-of-flt3-inhibitors-in-the-treatment-of-flt3-mutated-acute-myeloid-leukemia
#7
REVIEW
Amir T Fathi, Yi-Bin Chen
FLT3 mutations are present in about one-third of patients with acute myeloid leukemia (AML). Several FLT3 inhibitors have been used in clinical trials, and these include midostaurin, sorafenib, quizartinib, crenolanib, and gilteritinib. Monotherapy with early tyrosine kinase inhibitors (TKIs) did not have much success; however, later generation agents have shown more promising results. Combination with conventional chemotherapy may have benefit as evidenced by recently presented results, and data from ongoing trials are eagerly awaited...
April 2017: European Journal of Haematology
https://www.readbyqxmd.com/read/27908881/preclinical-studies-of-gilteritinib-a-next-generation-flt3-inhibitor
#8
LETTER
Lauren Y Lee, Daniela Hernandez, Trivikram Rajkhowa, Samuel C Smith, Jayant Ranganathan Raman, Bao Nguyen, Donald Small, Mark Levis
No abstract text is available yet for this article.
January 12, 2017: Blood
https://www.readbyqxmd.com/read/27775694/inhibition-of-flt3-in-aml-a-focus-on-sorafenib
#9
REVIEW
A Antar, Z K Otrock, J El-Cheikh, M A Kharfan-Dabaja, G Battipaglia, R Mahfouz, M Mohty, A Bazarbachi
FMS-like tyrosine kinase 3 (FLT3) is one of the most commonly mutated genes in AML. FLT3 is mutated in ~30% of patients with AML, either by internal tandem duplications (FLT3-ITD) of the juxta-membrane domain or by a point mutation, usually involving the tyrosine kinase domain. Several FLT3 tyrosine kinase inhibitors are being evaluated in multiple studies aiming at improving outcomes. The most widely used is sorafenib, a potent multikinase inhibitor approved for hepatocellular carcinoma and renal cell carcinoma...
March 2017: Bone Marrow Transplantation
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