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sorafenib AML

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https://www.readbyqxmd.com/read/27908881/pre-clinical-studies-of-gilteritinib-a-next-generation-flt3-inhibitor
#1
Lauren Y Lee, Daniela Hernandez, Trivikram Rajkhowa, Samuel C Smith, Jayant Ranganathan Raman, Bao Nguyen, Donald Small, Mark Levis
Activating mutations in the receptor tyrosine kinase FLT3 comprise approximately one-third of genetic lesions in acute myeloid leukemia (AML) and are associated with a poor prognosis. Internal tandem duplication (FLT3-ITD) mutations in particular are associated with a high relapse rate. Although FLT3 tyrosine kinase inhibitors (TKIs) appear to improve clinical outcomes for patients with FLT3-ITD AML, the development of early-generation FLT3 TKIs has been impeded by several obstacles such as low potency and selectivity, myelosuppression, and the emergence of resistance-conferring point mutations...
December 1, 2016: Blood
https://www.readbyqxmd.com/read/27893163/sorafenib-and-azacitidine-as-salvage-therapy-for-relapse-of-flt3-itd-mutated-aml-after-allo-sct
#2
Christina Rautenberg, Kathrin Nachtkamp, Ariane Dienst, Pia Verena Schmidt, Claudia Heyn, Mustafa Kondakci, Ulrich Germing, Rainer Haas, Guido Kobbe, Thomas Schroeder
OBJECTIVE: Patients with acute myeloid leukemia (AML) carrying FLT3-ITD mutations (FLT3-ITD+) who relapse after allogeneic 3transplantation (allo-SCT) have a very dismal prognosis with the currently available treatment options. METHODS: We treated 8 patients with FLT3-ITD+ AML who had relapsed in median 91 days (range, 28 - 249) following allo-SCT with a combination of the multikinase inhibitor Sorafenib and the DNA methyltransferase inhibitor Azacitidine (Aza)...
November 28, 2016: European Journal of Haematology
https://www.readbyqxmd.com/read/27863389/nt1721-a-novel-epidithiodiketopiperazine-exhibits-potent-in-vitro-and-in-vivo-efficacy-against-acute-myeloid-leukemia
#3
Claudia M Kowolik, Min Lin, Jun Xie, Larry E Overman, David A Horne
Acute myeloid leukemia (AML) is an aggressive malignancy characterized by heterogeneous genetic and epigenetic changes in hematopoietic progenitors that lead to abnormal self-renewal and proliferation. Despite high initial remission rates, prognosis remains poor for most AML patients, especially for those harboring internal tandem duplication (ITD) mutations in the fms-related tyrosine kinase-3 (FLT3). Here, we report that a novel epidithiodiketopiperazine, NT1721, potently decreased the cell viability of FLT3-ITD+ AML cell lines, displaying IC50 values in the low nanomolar range, while leaving normal CD34+ bone marrow cells largely unaffected...
November 15, 2016: Oncotarget
https://www.readbyqxmd.com/read/27835920/-acute-myeloid-leukemia
#4
Jan Braess
Acute myeloid leukemia (AML) has been genetically characterized extensively and can now be subdivided into 9 to 11 pathogenetically different subtypes according to their profile of driver mutations. In clinical practice karyotyping and molecular analysis of NPM1, cEBPa and FLT3-ITD are required for treatment stratification and potentially genotype specific treatment. Some markers such as NPM1 not only offer prognostic information but can also serve as markers of minimal residual disease and thus have the potential to guide therapy in the future...
November 2016: Deutsche Medizinische Wochenschrift
https://www.readbyqxmd.com/read/27778197/outcome-of-flt3-itd-positive-acute-myeloid-leukemia-impact-of-allogeneic-stem-cell-transplantation-and-tyrosine-kinase-inhibitor-treatment
#5
Maximilian Fleischmann, Ulf Schnetzke, Karin G Schrenk, Volker Schmidt, Herbert G Sayer, Inken Hilgendorf, Andreas Hochhaus, Sebastian Scholl
BACKGROUND: Activating mutations of the receptor tyrosine kinase FLT3 (fms-related tyrosine kinase 3) reflect the most frequent molecular aberration in acute myeloid leukemia (AML). In particular, FLT3 internal tandem duplications (FLT3-ITD) are characterized by an unfavorable prognosis and allogeneic stem cell transplantation (allogeneic SCT) in first complete remission is recommended. In case of imminent or frank relapse following allogeneic SCT, treatment with FLT3 tyrosine kinase inhibitors (TKI) constitutes a promising clinical approach to induce hematologic remission without conventional chemotherapy...
October 24, 2016: Journal of Cancer Research and Clinical Oncology
https://www.readbyqxmd.com/read/27775694/inhibition-of-flt3-in-aml-a-focus-on-sorafenib
#6
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...
October 24, 2016: Bone Marrow Transplantation
https://www.readbyqxmd.com/read/27708062/homoharringtonine-omacetaxine-mepesuccinate-as-an-adjunct-for-flt3-itd-acute-myeloid-leukemia
#7
Stephen S Y Lam, Eric S K Ho, Bai-Liang He, Wui-Wing Wong, Chae-Yin Cher, Nelson K L Ng, Cheuk-Him Man, Harinder Gill, Alice M S Cheung, Ho-Wan Ip, Chi-Chiu So, Jerome Tamburini, Chi Wai Eric So, Dona N Ho, Chun-Hang Au, Tsun-Leung Chan, Edmond S K Ma, Raymond Liang, Yok-Lam Kwong, Anskar Y H Leung
An in vitro drug-screening platform on patient samples was developed and validated to design personalized treatment for relapsed/refractory acute myeloid leukemia (AML). Unbiased clustering and correlation showed that homoharringtonine (HHT), also known as omacetaxine mepesuccinate, exhibited preferential antileukemia effect against AML carrying internal tandem duplication of fms-like tyrosine kinase 3 (FLT3-ITD). It worked synergistically with FLT3 inhibitors to suppress leukemia growth in vitro and in xenograft mouse models...
October 5, 2016: Science Translational Medicine
https://www.readbyqxmd.com/read/27571118/sorafenib-therapy-for-pediatric-acute-myeloid-leukemia-with-fms-like-tyrosine-kinase-3-internal-tandem-duplication-mutations-2-case-reports
#8
Shinya Osone, Toshihiko Imamura, Takuyo Kanayama, Yusuke Tsuma, Sachiko Kawashima-Goto, Takuya Nakatani, Atsuya Sugimoto, Akari Takai, Mitsuru Miyachi, Shinichi Tamura, Hiroyuki Ishida, Hajime Hosoi
Sorafenib is a promising agent for treating pediatric refractory acute myeloid leukemia (AML) exhibiting FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD); however, its optimal use needs to be established. We report 2 cases of refractory pediatric FLT3-ITD-positive AML treated with sorafenib. Case 1 underwent stem cell transplantation (SCT) without entering remission, despite the use of chemotherapy. This patient relapsed despite receiving post-SCT sorafenib. Chemotherapy combined with sorafenib successfully achieved complete remission in case 2...
August 26, 2016: Journal of Pediatric Hematology/oncology
https://www.readbyqxmd.com/read/27450971/flt3-inhibitors-for-treating-acute-myeloid-leukemia
#9
Mona Hassanein, Muhamad H Almahayni, Syed O Ahmed, Sameh Gaballa, Riad El Fakih
FLT3 (Fms-like tyrosine kinase 3) inhibitors are tyrosine kinase inhibitors. The first-generation FLT3 inhibitors were developed several years ago and include midostaurin, lestaurtinib, sunitinib, and sorafenib. They are relatively nonspecific for FLT3, with other potential targets that include platelet-derived growth factor receptor, vascular endothelial growth factor receptor, KIT, and Janus kinase 2. The second-generation inhibitors, including quizartinib, crenolanib, PLX3397, and ASP2215, are more potent and selective than the first-generation inhibitors...
June 25, 2016: Clinical Lymphoma, Myeloma & Leukemia
https://www.readbyqxmd.com/read/27434660/haematopoietic-cell-transplantation-with-and-without-sorafenib-maintenance-for-patients-with-flt3-itd-acute-myeloid-leukaemia-in-first-complete-remission
#10
Andrew M Brunner, Shuli Li, Amir T Fathi, Martha Wadleigh, Vincent T Ho, Kerry Collier, Christine Connolly, Karen K Ballen, Corey S Cutler, Bimalangshu R Dey, Areej El-Jawahri, Sarah Nikiforow, Steven L McAfee, John Koreth, Daniel J Deangelo, Edwin P Alyea, Joseph H Antin, Thomas R Spitzer, Richard M Stone, Robert J Soiffer, Yi-Bin Chen
We performed a retrospective study analysing the effect of sorafenib, an oral fms-Like Tyrosine Kinase 3 (FLT3)/multikinase inhibitor, as post-transplant maintenance in adult patients with FLT3-internal tandem duplication (ITD) acute myeloid leukaemia (AML). We identified consecutive patients with FLT3-ITD AML diagnosed between 2008 and 2014 who received haematopoietic cell transplantation (HCT) in first complete remission (CR1). Post-HCT initiation of sorafenib (yes/no) was evaluated as a time-varying covariate in the overall survival/progression-free survival (OS/PFS) analysis and we performed a landmark analysis of controls alive without relapse at the median date of sorafenib initiation...
November 2016: British Journal of Haematology
https://www.readbyqxmd.com/read/27408351/the-successful-complete-remission-induction-by-sorafenib-monotherapy-in-a-flt3-d835y-positive-patient-with-refractory-acute-monocytic-leukemia
#11
Yanhua Yue, Song Jin, Ting Xu, Jin Zhou, Liang Ma, Hongjie Shen, Depei Wu, Suning Chen, Miao Miao
Sorafenib has been shown to be active in AML patients with FLT3-ITD. However, the effect of sorafenib in AML patients with FLT-TKD has never been well determined. Moreover, acquisition of secondary FLT3 TKD mutations, mainly at D835 (D835F/H/V/Y), are recognized as the major mechanisms of resistance of AML patients with FLT3-ITD to sorafenib. It has been reported that sorafenib induced death of cells that expressed the FLT3-ITD or FLT3-D835G but not cells that expressed the FLT3-D835Y point mutant or wild-type FLT3 in vitro...
June 2016: Indian Journal of Hematology & Blood Transfusion
https://www.readbyqxmd.com/read/27329844/activation-of-protein-phosphatase-2a-in-flt3-acute-myeloid-leukemia-cells-enhances-the-cytotoxicity-of-flt3-tyrosine-kinase-inhibitors
#12
Amanda M Smith, Matthew D Dun, Erwin M Lee, Celeste Harrison, Richard Kahl, Hayley Flanagan, Nikita Panicker, Baratali Mashkani, Anthony S Don, Jonathan Morris, Hamish Toop, Richard B Lock, Jason A Powell, Daniel Thomas, Mark A Guthridge, Andrew Moore, Leonie K Ashman, Kathryn A Skelding, Anoop Enjeti, Nicole M Verrills
Constitutive activation of the receptor tyrosine kinase Fms-like tyrosine kinase 3 (FLT3), via co-expression of its ligand or by genetic mutation, is common in acute myeloid leukemia (AML). In this study we show that FLT3 activation inhibits the activity of the tumor suppressor, protein phosphatase 2A (PP2A). Using BaF3 cells transduced with wildtype or mutant FLT3, we show that FLT3-induced PP2A inhibition sensitizes cells to the pharmacological PP2A activators, FTY720 and AAL(S). FTY720 and AAL(S) induced cell death and inhibited colony formation of FLT3 activated cells...
June 18, 2016: Oncotarget
https://www.readbyqxmd.com/read/27248172/integrin-alphavbeta3-enhances-%C3%AE-catenin-signaling-in-acute-myeloid-leukemia-harboring-fms-like-tyrosine-kinase-3-internal-tandem-duplication-mutations-implications-for-microenvironment-influence-on-sorafenib-sensitivity
#13
Hai Yi, Dongfeng Zeng, Zhaohua Shen, Jun Liao, Xiaoguo Wang, Yao Liu, Xi Zhang, Peiyan Kong
Binding of leukemia cells to the bone marrow extracellular matrix (ECM) through integrins might influence drug response and the survival of acute myeloid leukemia (AML). However, the functions of integrin in AML are needed to be clarified. Data from The Cancer Genome Atlas (TCGA) were retrieved and integrin β3 (ITGB3) expression and prognostic significance for AML were analyzed. Integrin alphavbeta3 (αvβ3) in sorafenib sensitivity and signaling pathway of FLT3-ITD AML cells was evaluated in vitro. The level of ITGB3 expression was positively correlated with risk stratification and prognosis of AML patients, especially in cytogenetic-normal patients with Fms-like tyrosine kinase-3 internal tandem duplication (FLT3-ITD) mutation...
May 26, 2016: Oncotarget
https://www.readbyqxmd.com/read/27150998/-clinical-efficacy-of-sorafenib-combined-with-low-dose-cytarabine-for-treating-patients-with-flt3-relapsed-and-refractory-acute-myeloid-leukemia
#14
Xiao-Shu Liu, Hui Long, Yu-Xian Huang, Jian-Hui Xu, Jun-Yu Zhu, Qing-Feng DU, Bing-Yi Wu
OBJECTIVE: To study the efficacy and safety of sorafenib combined with low dose cytarabine for treating patients with FLT3(+) relapsed and refractory acute myeloid leukemia (FLT3(+) RR-AML). METHODS: Seven patients with FLT3(+) RR-AML were treated with sorafenib and low dose cytarabine. The curative rate and adverse effects were observed in these patients. RESULTS: Out of 7 RR-AML patients after treatment, 5 patients achieved complete remission (CR), 2 patients achieved partial remission (PR), and the overall response rate (ORR) after one course of therapy was 100%...
April 2016: Zhongguo Shi Yan Xue Ye Xue za Zhi
https://www.readbyqxmd.com/read/27132990/metabolic-alterations-and-drug-sensitivity-of-tyrosine-kinase-inhibitor-resistant-leukemia-cells-with-a-flt3-itd-mutation
#15
Amin Huang, Huai-Qiang Ju, Kaiyan Liu, Guilian Zhan, Daolu Liu, Shijun Wen, Guillermo Garcia-Manero, Peng Huang, Yumin Hu
Internal tandem duplication (ITD) of the juxtamembrane region of FMS-like tyrosine kinase-3 (FLT3) receptor is a common type of mutation in adult acute myeloid leukemia (AML), and patient response to FLT3 inhibitors appears to be transient due to the emergence of drug resistance. We established two sorafenib-resistant cell lines carrying FLT3/ITD mutations, including the murine BaF3/ITD-R and human MV4-11-R cell lines. Gene expression profile analysis of the resistant and parental cells suggests that the highest ranked molecular and cellular functions of the differentially expressed genes are related to mitochondrial dysfunction...
July 28, 2016: Cancer Letters
https://www.readbyqxmd.com/read/27093991/-sorafenib-as-salvage-therapy-in-refractory-relapsed-acute-myeloid-leukemia-with-positive-flt3-mutation
#16
Yu Zhang, Li Xuan, Zhiping Fan, Fen Huang, Qianli Jiang, Na Xu, Ya Gao, Jing Sun, Qifa Liu
OBJECTIVE: To analyze the effect of sorafenib as salvage therapy used before and/or after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in refractory relapsed FLT3-positive acute myeloid leukemia (AML). METHODS: A total of 16 patients with refractory relapsed FLT3-positive AML, including 10 refractory relapsed pre-transplantation and 6 relapsed after allo-HSCT, were enrolled in this retrospective study. Sorafenib treatment protocols included sorafenib in combination with chemotherapy inducing remission, and sorafenib monotherapy as mauntenance treatment after complete remission (CR)...
April 2016: Zhonghua Xue Ye Xue za Zhi, Zhonghua Xueyexue Zazhi
https://www.readbyqxmd.com/read/27030618/-improved-clinical-outcome-of-acute-myeloid-leukemia-with-flt3-itd-mutation-treated-with-sorafenib
#17
B Gu, G H Chen, H J Shen, X Ma, C C Fu, Y Han, X W Tang, M Miao, H Y Qiu, A N Sun, D P Wu
OBJECTIVE: To analyze the efficacy of sorafenib on the treatment of patients diagnosed as acute myeloid leukemia(AML) with FLT3-ITD mutation. METHODS: From January 2012 to February 2015, 42 cases of AML with FLT3-ITD mutation according to MICM (morphology, immunology, cytogenetics and molecular) diagnosis system in our hospital were retrospectively analyzed. Thirty-two cases were refractory to chemotherapy or relapsed, who were treated with sorafenib or combined with chemotherapy...
April 1, 2016: Zhonghua Nei Ke za Zhi [Chinese Journal of Internal Medicine]
https://www.readbyqxmd.com/read/26999641/aberrant-activation-of-the-pi3k-mtor-pathway-promotes-resistance-to-sorafenib-in-aml
#18
O Lindblad, E Cordero, A Puissant, L Macaulay, A Ramos, N N Kabir, J Sun, J Vallon-Christersson, K Haraldsson, M T Hemann, Å Borg, F Levander, K Stegmaier, K Pietras, L Rönnstrand, J U Kazi
Therapy directed against oncogenic FLT3 has been shown to induce response in patients with acute myeloid leukemia (AML), but these responses are almost always transient. To address the mechanism of FLT3 inhibitor resistance, we generated two resistant AML cell lines by sustained treatment with the FLT3 inhibitor sorafenib. Parental cell lines carry the FLT3-ITD (tandem duplication) mutation and are highly responsive to FLT3 inhibitors, whereas resistant cell lines display resistance to multiple FLT3 inhibitors...
September 29, 2016: Oncogene
https://www.readbyqxmd.com/read/26884901/sorafenib-in-combination-with-low-dose-homoharringtonine-as-a-salvage-therapy-in-primary-refractory-flt3-itd-positive-aml-a-case-report-and-review-of-literature
#19
REVIEW
Gaixiang Xu, Liping Mao, Hui Liu, Min Yang, Jie Jin, Wenbin Qian
The presence of internal tandem duplications (ITD) in the Fms-related tyrosine kinase 3 receptor (FLT3) has been associated with a poor prognosis in acute myeloid leukemia (AML). Over the past decade, FLT3 is a promising target in FLT3-ITD-positive AML. Sorafenib which is one of the commonly focused FLT3 inhibitors may improve outcome, but only few patients display long-term responses in previously reported cases, prompting the search for underlying resistance mechanisms and therapeutic strategies to overcome them...
2015: International Journal of Clinical and Experimental Medicine
https://www.readbyqxmd.com/read/26842729/abcc4-is-a-determinant-of-cytarabine-induced-cytotoxicity-and-myelosuppression
#20
C D Drenberg, S Hu, L Li, D R Buelow, S J Orwick, A A Gibson, J D Schuetz, A Sparreboom, S D Baker
Resistance to cytarabine remains a major challenge in the treatment of acute myeloid leukemia (AML). Based on previous studies implicating ABCC4/MRP4 in the transport of nucleosides, we hypothesized that cytarabine is sensitive to ABCC4-mediated efflux, thereby decreasing its cytotoxic response against AML blasts. The uptake of cytarabine and its monophosphate metabolite was found to be facilitated in ABCC4-expressing vesicles and intracellular retention was significantly impaired by overexpression of human ABCC4 or mouse Abcc4 (P < 0...
February 2016: Clinical and Translational Science
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