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Flt3-itd

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https://www.readbyqxmd.com/read/29139135/phase-1-study-of-quizartinib-in-combination-with-induction-and-consolidation-chemotherapy-in-patients-with-newly-diagnosed-acute-myeloid-leukemia
#1
Jessica K Altman, James M Foran, Keith W Pratz, Denise Trone, Jorge E Cortes, Martin S Tallman
Novel therapies have potential to improve outcomes in patients with acute myeloid leukemia (AML) harboring FLT3-ITD mutations that have high risk of relapse and poor survival following standard of care (SOC) cytarabine/anthracycline-based induction/consolidation chemotherapy. Quizartinib is a selective and highly potent FLT3 inhibitor that has shown strong single-agent activity in relapsed or refractory (R/R) AML. This phase 1, open-label, sequential group dose-escalation trial (NCT 01390337) is the first evaluating safety and tolerability of quizartinib in combination with SOC chemotherapy in newly diagnosed AML (ndAML)...
November 15, 2017: American Journal of Hematology
https://www.readbyqxmd.com/read/29100302/a-tyrosine-kinase-stat5-mir21-pdcd4-regulatory-axis-in-chronic-and-acute-myeloid-leukemia-cells
#2
Anne-Sophie Espadinha, Valérie Prouzet-Mauléon, Stéphane Claverol, Valérie Lagarde, Marc Bonneu, François-Xavier Mahon, Bruno Cardinaud
MicroRNAs (miRNAs) are regulators of several key patho-physiological processes, including cell cycle and apoptosis. Using microarray-based miRNA profiling in K562 cells, a model of chronic myeloid leukemia (CML), we found that the oncoprotein BCR-ABL1 regulates the expression of miR-21, an "onco-microRNA", found to be overexpressed in several cancers. This effect relies on the presence of two STAT binding sites on the promoter of miR-21, and on the phosphorylation status of STAT5, a transcription factor activated by the kinase activity of BCR-ABL1...
September 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/29095060/emerging-molecular-predictive-and-prognostic-factors-in-acute-myeloid-leukemia
#3
Shannon R McCurdy, Mark J Levis
Recurrent cytogenetic abnormalities have provided the backbone for prognosticating acute myeloid leukemia and predicting response to consolidative therapies for decades. However, more than 45% of acute myeloid leukemia patients have normal cytogenetics on both karyotype and fluorescence in situ hybridization at diagnosis. Increasingly utilized next-generation sequencing has led to the discovery of numerous recurrent molecular mutations in acute myeloid leukemia, which can currently be identified in 97.3% of patients...
November 2, 2017: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/29090473/results-of-a-phase-1-study-of-quizartinib-as-maintenance-therapy-in-subjects-with-acute-myeloid-leukemia-in-remission-following-allogeneic-hematopoietic-stem-cell-transplant
#4
Brenda M Sandmaier, Samer Khaled, Betül Oran, Guy Gammon, Denise Trone, Olga Frankfurt
FLT3-ITD-mutated acute myeloid leukemia (AML) has very high risk of relapse and is associated with poor outcome following allogeneic hematopoietic-cell transplant (allo-HCT). This two-part, phase 1, multicenter, open-label, sequential-group, dose-escalation study aimed to determine dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), and safety/tolerability of quizartinib, a selective and highly potent FLT3 inhibitor, when administered as maintenance therapy after allo-HCT. Thirteen subjects with documented FLT3-ITD-mutated AML in morphological remission following allo-HCT received one of two quizartinib dihydrochloride dose levels (DL): 40 mg/d (DL1; n = 7) and 60 mg/d (DL2; n = 6), administered orally in 28-day cycles for up to 24 cycles...
November 1, 2017: American Journal of Hematology
https://www.readbyqxmd.com/read/29079128/dnmt3a-r882-mutation-features-and-prognostic-effect-in-acute-myeloid-leukemia-in-coexistent-with-npm1-and-flt3-mutations
#5
Dushyant Kumar, Anurag Mehta, Manoj Kumar Panigrahi, Sukanta Nath, Kandarpa Kumar Saikia
OBJECTIVE/BACKGROUND: In the absence of high-risk cytogenetic, DNMT3A mutation status has an impact on outcome in the presence of FLT3 and/or NPM1. In this study, we focus on the features and effect of DNMT3A (R882) mutation in acute myeloid leukemia (AML) in the presence or absence of NPM1 and FLT3 mutations. METHODS: A total of 174 cytogenetically normal (CN)-AML cases were analyzed for NPM1, FLT3, and DNMT3A mutations. For NPM1 mutation detection, we used the pyrosequencing technique; for FLT3 mutations, polymerase chain reaction and RFLP with ECO-RV techniques were used, and for DNMT3A mutation analysis, we used Sanger sequencing and RFLP techniques...
October 18, 2017: Hematology/oncology and Stem Cell Therapy
https://www.readbyqxmd.com/read/29074603/concurrent-inhibition-of-pim-and-flt3-kinases-enhances-apoptosis-of-flt3-itd-acute-myeloid-leukemia-cells-through-increased-mcl-1-proteasomal-degradation
#6
Shivani Kapoor, Karthika Natarajan, Patrick R Baldwin, Kshama A Doshi, Rena G Lapidus, Trevor J Mathias, Mario Scarpa, Rossana Trotta, Eduardo Davila, Manfred Kraus, Dennis Huszar, Adriana E Tron, Danilo Perrotti, Maria R Baer
PURPOSE: fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) is present in 30% of acute myeloid leukemia (AML), and these patients have short disease-free survival. FLT3 inhibitors have limited and transient clinical activity, and concurrent treatment with inhibitors of parallel or downstream signaling may improve responses. The oncogenic serine/threonine kinase Pim-1 is upregulated downstream of FLT3-ITD and also promotes its signaling in a positive feedback loop, suggesting benefit of combined Pim and FLT3 inhibition...
October 26, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29070697/overcoming-mutational-complexity-in-acute-myeloid-leukemia-by-inhibition-of-critical-pathways
#7
Yoriko Saito, Yoshiki Mochizuki, Ikuko Ogahara, Takashi Watanabe, Leah Hogdal, Shinsuke Takagi, Kaori Sato, Akiko Kaneko, Hiroshi Kajita, Naoyuki Uchida, Takehiro Fukami, Leonard D Shultz, Shuichi Taniguchi, Osamu Ohara, Anthony G Letai, Fumihiko Ishikawa
Numerous variant alleles are associated with human acute myeloid leukemia (AML). However, the same variants are also found in individuals with no hematological disease, making their functional relevance obscure. Through NOD.Cg-Prkdc(scid)Il2rg(tmlWjl)/Sz (NSG) xenotransplantation, we functionally identified preleukemic and leukemic stem cell populations present in FMS-like tyrosine kinase 3 internal tandem duplication-positive (FLT3-ITD)(+) AML patient samples. By single-cell DNA sequencing, we identified clonal structures and linked mutations with in vivo fates, distinguishing mutations permissive of nonmalignant multilineage hematopoiesis from leukemogenic mutations...
October 25, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/29069942/midostaurin-pkc412-for-the-treatment-of-newly-diagnosed-flt3-mutation-positive-acute-myeloid-leukemia
#8
Marlise R Luskin, Daniel J DeAngelo
Acute myeloid leukemia (AML) is an aggressive hematologic malignancy with inadequate treatment options. Approximately one-third of cases have a FLT3-ITD or FLT3-TKD mutation which leads to constitutive tyrosine kinase activation which contributes to leukemogenesis. The FLT3-ITD mutation is associated with a particularly poor prognosis. Midostaurin is a multi-kinase inhibitor active against the FLT3 receptor. Midostaurin was approved by the US FDA in April 2017 for treatment of newly diagnosed FLT3-mutant AML in combination with chemotherapy...
October 30, 2017: Expert Review of Hematology
https://www.readbyqxmd.com/read/29069784/high-expression-of-dedicator-of-cytokinesis-1-dock1-confers-poor-prognosis-in-acute-myeloid-leukemia
#9
Sze-Hwei Lee, Yu-Chiao Chiu, Yi-Hung Li, Chien-Chin Lin, Hsin-An Hou, Wen-Chien Chou, Hwei-Fang Tien
DOCK family genes encode evolutionarily conserved guanine nucleotide exchange factors for Rho GTPase involving multiple biological functions. Yet the patterns and prognostic significance of their expression in acute myeloid leukemia (AML) remain unexplored. Here we analyzed the expression patterns of 11 DOCK family genes in AML cells based on the array data of 347 patients from our cohort and several other published datasets. We further focused on the implications of the expression of DOCK1 since it was the only one in DOCK family to be associated with survival...
September 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/29062237/low-platelet-count-is-potentially-the-most-important-contributor-to-severe-bleeding-in-patients-newly-diagnosed-with-acute-promyelocytic-leukemia
#10
Yu-Hua Song, Peng Peng, Chun Qiao, Run Zhang, Jian-Yong Li, Hua Lu
The objective of the current study was to provide more appropriate therapeutic strategies for reducing severe hemorrhaging by assessing the recovery of abnormal coagulation indexes in patients with acute promyelocytic leukemia (APL) during induction therapy. Retrospective analyses of 112 patients newly diagnosed with APL were performed during initial treatment. In our study, the early death rate was 5.36%. Hemorrhage was the leading cause of death during the induction period (4/6). The values of white blood cell count, lactate dehydrogenase, prothrombin time (PT), fibrinogen (Fbg), hemoglobin, and bone marrow leukemic promyelocytes were significantly different in the high-risk group compared to the low/intermediate-risk groups...
2017: OncoTargets and Therapy
https://www.readbyqxmd.com/read/29062038/the-src-family-kinase-lck-cooperates-with-oncogenic-flt3-itd-in-cellular-transformation
#11
Alissa Marhäll, Julhash U Kazi, Lars Rönnstrand
The non-receptor tyrosine kinase LCK belongs to the SRC family of kinases. SRC family kinases are proto-oncogenes that have long been known to play key roles in cell proliferation, motility, morphology and survival. Here we show that LCK regulates the function of the type III receptor tyrosine kinase FLT3 in murine pro-B cells. We observed that expression of LCK significantly enhances the colony forming capacity of the constitutively active FLT3 mutant FLT3-ITD (internal tandem duplication). Furthermore, cells expressing LCK developed tumor earlier compared to cells transfected with empty control vector...
October 23, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29059168/oncogenic-flt3-itd-supports-autophagy-via-atf4-in-acute-myeloid-leukemia
#12
Q Heydt, C Larrue, E Saland, S Bertoli, J-E Sarry, A Besson, S Manenti, C Joffre, V Mansat-De Mas
In acute myeloid leukemia (AML), internal tandem duplication mutations in the FLT3 tyrosine kinase receptor (FLT3-ITD) account for up to 25% of cases and are associated with a poor outcome. In order to better target this AML subtype, a comprehensive view of how FLT3-ITD impacts AML cell biology is required. Here, we found that FLT3-ITD expression increased basal autophagy in AML cells, and that both pharmacological and genetic inhibition of the receptor reduced autophagy in primary AML samples and cell lines...
October 23, 2017: Oncogene
https://www.readbyqxmd.com/read/29055209/long-term-survival-of-sorafenib-treated-flt3-itd-positive-acute-myeloid-leukaemia-patients-relapsing%C3%A2-after-allogeneic-stem-cell-transplantation
#13
S K Metzelder, T Schroeder, M Lübbert, M Ditschkowski, K Götze, S Scholl, R G Meyer, P Dreger, N Basara, M F Fey, H R Salih, A Finck, T Pabst, A Giagounidis, G Kobbe, E Wollmer, J Finke, A Neubauer, A Burchert
BACKGROUND: Fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD)-positive acute myeloid leukaemia (AML) relapsing after allogeneic stem cell transplantation (allo-SCT) has a dismal prognosis with limited therapeutic options. FLT3-ITD kinase inhibition is a reasonable but palliative experimental treatment alternative in this situation. Information on long-term outcome is not available. METHODS: We performed a long-term follow-up analysis of a previously reported cohort of 29 FLT3-ITD-positive AML patients, which were treated in relapse after allo-SCT with sorafenib monotherapy...
October 18, 2017: European Journal of Cancer
https://www.readbyqxmd.com/read/29037944/identification-of-pyrrolo-2-3-d-pyrimidines-as-potent-hck-and-flt3-itd-dual-inhibitors
#14
Yasuko Koda, Ko Kikuzato, Junko Mikuni, Akiko Tanaka, Hitomi Yuki, Teruki Honma, Yuri Tomabechi, Mutsuko Kukimoto-Niino, Mikako Shirouzu, Fumiyuki Shirai, Hiroo Koyama
A series of novel pyrrolo[2,3-d]pyrimidines were synthesized by introducing 15 different amino acids to 7-cyclohexyl-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine. Compounds with potent activities against HCK and FLT3-ITD were evaluated in viability studies with acute myeloid leukemia cell line MV4-11. Our structure activity relationship analyses lead to the identification of compound 31, which exhibited potent HCK and FLT3-ITD inhibition and activity against the MV4-11 cell line.
November 15, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29034366/a-phase-2-study-incorporating-sorafenib-into-the-chemotherapy-for-older-adults-with-flt3-mutated-acute-myeloid-leukemia-calgb-11001
#15
Geoffrey L Uy, Sumithra J Mandrekar, Kristina Laumann, Guido Marcucci, Weiqiang Zhao, Mark J Levis, Heidi D Klepin, Maria R Baer, Bayard L Powell, Peter Westervelt, Daniel J DeAngelo, Wendy Stock, Ben Sanford, William G Blum, Clara D Bloomfield, Richard M Stone, Richard A Larson
The Cancer and Leukemia Group B (CALGB), now part of the Alliance for Clinical Trials in Oncology, conducted a multicenter, single-arm, phase 2 study in patients ≥60 years with FMS-like tyrosine kinase 3 (FLT3)-mutated acute myeloid leukemia (AML). In this study, sorafenib was added to daunorubicin and cytarabine-based induction and consolidation chemotherapy and was also continued for 12 months of maintenance therapy. The primary end point of the study was overall survival (OS) at 1 year in the FLT3 internal tandem duplication (FLT3-ITD) cohort...
January 24, 2017: Blood Advances
https://www.readbyqxmd.com/read/29027108/prognostic-value-of-genetic-mutations-in-adolescent-and-young-adults-with-acute-myeloid-leukemia
#16
Yachiyo Kuwatsuka, Daisuke Tomizawa, Rika Kihara, Yasunobu Nagata, Norio Shiba, Yuka Iijima-Yamashita, Akira Shimada, Takao Deguchi, Hayato Miyachi, Akio Tawa, Takashi Taga, Akitoshi Kinoshita, Hideki Nakayama, Nobutaka Kiyokawa, Akiko Moriya Saito, Katsuyoshi Koh, Hiroaki Goto, Yoshiyuki Kosaka, Norio Asou, Shigeki Ohtake, Shuichi Miyawaki, Yasushi Miyazaki, Toru Sakura, Yukiyasu Ozawa, Noriko Usui, Heiwa Kanamori, Yoshikazu Ito, Kiyotoshi Imai, Youko Suehiro, Shinichi Kobayashi, Kunio Kitamura, Emiko Sakaida, Seishi Ogawa, Tomoki Naoe, Yasuhide Hayashi, Keizo Horibe, Atsushi Manabe, Shuki Mizutani, Souichi Adachi, Hitoshi Kiyoi
Clinical outcomes and the genetic background of acute myeloid leukemia (AML) in adolescent and young adults (AYAs) are known to differ in younger children and older adults. To clarify the impact of genetic mutations on clinical outcomes of AYAs with AML, we analyzed data from the JPLSG AML-05 and JALSG AML201 studies. AYAs aged 15-39 years (n = 103) were included. FLT3-ITD, KIT, CEBPA, NRAS, KRAS, WT1, MLL-PTD, and NPM1 mutations were analyzed. Overall survival (OS) of the AYAs was 61% and event-free survival was 38% at 3 years...
October 12, 2017: International Journal of Hematology
https://www.readbyqxmd.com/read/28989589/aberrant-methylation-of-apaf-1-gene-in-acute-myeloid-leukemia-patients
#17
Shahrbano Rostami, Fatemeh Nadali, Reza Alibakhshi, Farhad Zaker, Nahid Nasiri, Mehrdad Payandeh, Bahram Chahardouli, Ali Maleki
Background: Acute myeloid leukemia (AML) is a heterogeneous clonal disorder characterized by immature myeloid cell proliferation and bone marrow failure. Various genetic and epigenetic factors have been found to be influential in such patients. Methylation silencing of APAF-1, a putative tumor suppressor gene (TSG), has been found in several human malignancies. In this study, we explored the association of APAF-1 methylation status with AML patients. Materials and Methods: We studied the methylation status of APAF-1 gene in 101 AML patients and 50 healthy subjects as controls...
July 1, 2017: International Journal of Hematology-oncology and Stem Cell Research
https://www.readbyqxmd.com/read/28984348/acute-myeloid-leukaemia-with-gene-mutation-a-correlation-with-haematological-and-immunophenotypic-characteristics-and-our-experience-in-a-tertiary-care-cancer-center-in-south-india
#18
Rachna Khera, Faiq Ahmed, Manasi Mundada, Lavanya Nambaru, Sudha S Murthy, Sandhya Devig, Senthil J Rajappa, Krishna Mohan Mallavarapu, A Santa, Pavan Kumar
OBJECTIVE: Molecular genetic analysis of FLT3, NPM1, and CEBPA is already the standard of care in patients with acute myeloid leukaemia (AML) and represents the most frequent genetic alterations and important diagnostic and prognostic indicators. This study was undertaken to determine the frequency of FLT3 and NPM1 gene mutations in our institution and to characterize the association between gene mutations and haematological parameters as well as immunophenotypic features. MATERIAL AND METHOD: Morphological, haematological and immunophenotypic characteristics of NPM1 and FLT3 mutations in 126 patients of de novo AML including adults and children were studied...
October 6, 2017: Türk Patoloji Dergisi
https://www.readbyqxmd.com/read/28980058/full-length-mutation-search-of-the-tp53-gene-in-acute-myeloid-leukemia-has-increased-significance-as-a-prognostic-factor
#19
Kazuki Terada, Hiroki Yamaguchi, Toshimitsu Ueki, Kensuke Usuki, Yutaka Kobayashi, Kenji Tajika, Seiji Gomi, Saiko Kurosawa, Keiki Miyadera, Taichiro Tokura, Ikuko Omori, Atushi Marumo, Yusuke Fujiwara, Shunsuke Yui, Takeshi Ryotokuji, Yoshiki Osaki, Kunihito Arai, Tomoaki Kitano, Fumiko Kosaka, Satoshi Wakita, Hayato Tamai, Takahiro Fukuda, Koiti Inokuchi
TP53 gene abnormality has been reported to be an unfavorable prognostic factor in acute myeloid leukemia (AML). However, almost all studies of TP53 gene abnormality so far have been limited to mutation searches in the DNA binding domain. As there have been few reports examining both mutation and deletion over the full-length of the TP53 gene, the clinical characteristics of TP53 gene abnormality have not yet been clearly established. In this study, TP53 gene mutation was observed in 7.3% of the total 412 de novo AML cases (33 mutations in 30 cases), with mutation outside the DNA binding domain in eight cases (27%)...
October 4, 2017: Annals of Hematology
https://www.readbyqxmd.com/read/28978861/acute-leukemia-in-adolescents-and-young-adults
#20
Daisuke Tomizawa
Both acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) are common malignant diseases in adolescents and young adults (AYAs). Recent advances in genomic studies have helped us understand the biological nature of acute leukemia in AYAs; higher frequency of Ph-like ALL and rearrangements in DUX4, ERG, MEF2D, and ZNF384 genes in AYAs with ALL and higher frequency of FLT3-ITD, NPM1, IDH1/2, DNMT3A, ASXL1, TET2, and CEBPA mutations in AYAs with AML than that in children. The pediatric-inspired regimen has become a standard treatment approach for AYAs with ALL, but optimal treatment strategy for AYAs with AML is not yet established to date...
2017: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
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