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Flt3-itd

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https://www.readbyqxmd.com/read/28632487/prospective-randomized-comparison-of-idarubicin-and-high-dose-daunorubicin-in-induction-chemotherapy-for-newly-diagnosed-acute-myeloid-leukemia
#1
Je-Hwan Lee, Hawk Kim, Young-Don Joo, Won-Sik Lee, Sung Hwa Bae, Dae Young Zang, Jihyun Kwon, Min Kyoung Kim, Junglim Lee, Gyeong Won Lee, Jung-Hee Lee, Yunsuk Choi, Dae-Young Kim, Eun-Hye Hur, Sung-Nam Lim, Sang-Min Lee, Hun Mo Ryoo, Hyo Jung Kim, Myung Soo Hyun, Kyoo-Hyung Lee
Purpose We compared two induction regimens, idarubicin (12 mg/m(2)/d for 3 days) versus high-dose daunorubicin (90 mg/m(2)/d for 3 days), in young adults with newly diagnosed acute myeloid leukemia (AML). Patients and Methods A total of 299 patients (149 randomly assigned to cytarabine plus idarubicin [AI] and 150 assigned to cytarabine plus high-dose daunorubicin [AD]) were analyzed. All patients received cytarabine (200 mg/m(2)/d for 7 days). Results Complete remission (CR) was induced in 232 patients (77...
June 20, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/28627830/flt3-itd-mutations-in-egyptian-patients-of-acute-myeloid-leukemia-correlation-with-cytogenetic-fab-subgroups-and-prognosis
#2
Shady Adnan-Awad, Ola Gaber, Soad A Eltokhy, Dalia Mourad, Mariam Amer, Eman Z Kandeel, Ihab Eldesouky
BACKGROUND: FLT3-ITD mutations are common in AML subgroups, particularly in Acute Promyelocytic Leukemia (APL). It infers poor prognosis in AML patients; however, its prognostic value in APL is still controversial. We aimed to assess the distribution and prognostic value of FLT3-ITD mutation within AML subgroups, focusing on APL. METHODS: In NCI, Cairo University, 346 newly diagnosed AML patients were included. Morphological, immunophenotypic and cytogenetic analysis were done at presentation and fixed follow-up points with monitoring in follow up visits of patients...
May 1, 2017: Clinical Laboratory
https://www.readbyqxmd.com/read/28625976/a-genome-wide-crispr-screen-identifies-genes-critical-for-resistance-to-flt3-inhibitor-ac220
#3
Panpan Hou, Chao Wu, Yuchen Wang, Rui Qi, Dheeraj Bhavanasi, Zhixiang Zuo, Cedric Dos Santos, Shuliang Chen, Yu Chen, Hong Zheng, Hong Wang, Alexander E Perl, Deyin Guo, Jian Huang
Acute myeloid leukemia (AML) is a malignant hematopoietic disease and the most common type of acute leukemia in adults. The mechanisms underlying drug resistance in AML are poorly understood. Activating mutations in FMS-like tyrosine kinase 3 (FLT3) are the most common molecular abnormality in AML. Quizartinib (AC220) is a potent and selective second-generation inhibitor of FLT3. It is in clinical trials for the treatment of relapsed or refractory FLT3-ITD-positive and -negative AML patients and as maintenance therapy...
June 16, 2017: Cancer Research
https://www.readbyqxmd.com/read/28618074/bcrp-mrna-and-flt3-itd-are-independent-poor-risk-factors-in-adult-patients-with-acute-myeloid-leukemia-and-intermediate-or-normal-karyotype
#4
B Nasilowska-Adamska, K Warzocha, I Solarska, K Borg, B Pieńkowska-Grela, A Czyż
PURPOSE: FMS-like tyrosine kinase 3- internal tandem duplication (FLT3-ITD) is aberration associated with poor prognosis in AML. We have analyzed the expression of MDR-1, MRP-1 and BCRP mRNA in relation to FLT3-ITD in 100 AML adult patients with normal and intermediate karyotype. METHODS: The RQ-PCR method was performed to assess the expression of MDR-1, MRP-1 and BCRP mRNA and the results were presented as coefficients calculated using an intermediate method according to Pfaffl's rule...
June 15, 2017: European Journal of Haematology
https://www.readbyqxmd.com/read/28616699/flt3-itd-with-dnmt3a-r882-double-mutation-is-a-poor-prognostic-factor-in-chinese-patients-with-acute-myeloid-leukemia-after-chemotherapy-or-allogeneic-hematopoietic-stem-cell-transplantation
#5
Shanhao Tang, Hongjie Shen, Xinliang Mao, Haiping Dai, Xiaming Zhu, Shengli Xue, Zixuan Ding, Jing Lu, Depei Wu, Xiaowen Tang
To investigate clinical characteristics and outcomes of transplantation in AML patients with FLT3-ITD/DNMT3A double mutation, we retrospectively analyzed 206 Chinese patients with AML after Sanger sequencing. Our analysis showed that AML patients with FLT3-ITD and DNMT3A R882 mutations had a higher white blood cell count and a lower complete remission (CR) rate after first induction chemotherapy. All 206 patients received allogeneic hematopoietic stem cell transplantation (allo-HSCT) in status of CR. These results indicate that AML patients with FLT3-ITD and DNMT3A R882 double mutation show a higher 2-year cumulative incidence of relapse (CIR), lower 2-year overall survival (OS) rate, and lower 2-year leukocyte-free survival (LFS) after allo-HSCT...
June 14, 2017: International Journal of Hematology
https://www.readbyqxmd.com/read/28596089/prkch-regulates-hematopoietic-stem-cell-function-and-predicts-poor-prognosis-in-acute-myeloid-leukemia
#6
Shaina N Porter, Jeffrey A Magee
Acute myeloid leukemia (AML) cells often co-opt normal hematopoietic stem cell (HSC) programs to drive neoplastic proliferation, and HSC-related gene expression signatures have been identified as biomarkers for poor prognosis in AML patients. We sought to identify new regulators of HSCs and AML cells from previously published HSC and leukemia stem cell (LSC) gene expression signatures. We identified PRKCH (Protein Kinase C eta) as a gene that is highly expressed in both mouse and human HSCs, as well as in LSCs from independent cohorts of AML patients...
June 5, 2017: Experimental Hematology
https://www.readbyqxmd.com/read/28592755/acute-myeloid-leukemia-developing-secondary-immune-thrombocytopenia-after-umbilical-cord-blood-transplantation
#7
Rena Matsumoto, Kazuhiro Ito, Naoko Hosono, Yasufumi Matsuda, Katsunori Tai, Ippei Sakamaki, Goh Aoki, Hirohito Yamazaki, Shinji Nakao, Takahiro Yamauchi
A 64-year-old man was diagnosed with acute myeloid leukemia M2 (FLT3-ITD-positive). After induction chemotherapy and four courses of consolidation therapy, he underwent umbilical cord blood transplantation (CBT) in his first remission. He developed acute graft-versus-host disease (skin stage 2) after successful engraftment. On post-transplantation day 147, he was admitted to the hospital suffering from pneumonia. During the treatment, drastic thrombocytopenia was observed on day 251. Both platelet-associated immunoglobulin G and platelet antibody producing B cells were detected, and he was diagnosed with immune thrombocytopenia (ITP)...
2017: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
https://www.readbyqxmd.com/read/28576946/flt3-inhibitors-in-acute-myeloid-leukemia-current-status-and-future-directions
#8
REVIEW
Maria Larrosa-Garcia, Maria R Baer
The receptor tyrosine kinase fms-like tyrosine kinase 3 (FLT3), involved in regulating survival, proliferation, and differentiation of hematopoietic stem/progenitor cells, is expressed on acute myeloid leukemia (AML) cells in most patients. Mutations of FLT3 resulting in constitutive signaling are common in AML, including internal tandem duplication (ITD) in the juxtamembrane domain in 25% of patients and point mutations in the tyrosine kinase domain in 5%. Patients with AML with FLT3-ITD have a high relapse rate and short relapse-free and overall survival after chemotherapy and after transplant...
June 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28574487/cd123-target-validation-and-preclinical-evaluation-of-adcc-activity-of-anti-cd123-antibody-csl362-in-combination-with-nks-from-aml-patients-in-remission
#9
L H Xie, M Biondo, S J Busfield, A Arruda, X Yang, G Vairo, M D Minden
Despite the heterogeneity of acute myeloid leukemia (AML), overexpression of the interleukin-3 receptor-α (CD123) on both the more differentiated leukemic blast and leukemic stem cells (LSCs) provides a therapeutic target for antibody treatment. Here we present data on the potential clinical activity of the monoclonal antibody CSL362, which binds to CD123 with high affinity. We first validated the expression of CD123 by 100% (52/52) of patient samples and the correlation of NPM1 and FLT3-ITD mutations with the high frequency of CD123 in AML...
June 2, 2017: Blood Cancer Journal
https://www.readbyqxmd.com/read/28565742/-sorafenib-in-combination-with-chemotherapy-as-first-line-therapy-for-flt3-itd-positive-acute-myeloid-leukemia
#10
Q Y Zhang, X D Wei, Q S Yin, R H Mi, F F Yuan, L Chen
Objective: To analyze the clinical features of acute myeloid leukemia patients with Fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) mutation and the therapeutic effect of sorafenib in combination with chemotherapy as first-line therapy for these patients. Methods: Clinical features and therapeutic effect were retrospectively analyzed in 53 AML patients with FLT3-ITD mutation diagnosed in Henan Cancer Hospital from January 2013 to August 2016. The biological characteristics and clinical efficacy of chemotherapy in combination with or without Sorafeinb were analyzed...
May 14, 2017: Zhonghua Xue Ye Xue za Zhi, Zhonghua Xueyexue Zazhi
https://www.readbyqxmd.com/read/28556489/factors-associated-with-risk-of-central-nervous-system-relapse-in-patients-with-non-core-binding-factor-acute-myeloid-leukemia
#11
Elias Jabbour, Naval Guastad Daver, Nicholas James Short, Xuelin Huang, Hsiang-Chun Chen, Abhishek Maiti, Farhad Ravandi, Jorge Cortes, Simon Abi Aad, Guillermo Garcia-Manero, Zeev Estrov, Tapan Kadia, Susan O'Brien, Bouthaina Dabaja, Carlos Bueso-Ramos, Paolo Strati, Carol Bivins, Sherry Pierce, Hagop Kantarjian
Central nervous system (CNS) relapse is uncommon in patients with acute myeloid leukemia (AML) with the use of high-dose cytarabine containing chemotherapy regimens. The clinical and molecular features associated with a higher risk of CNS relapse are not well defined. We assessed the incidence and outcome of CNS relapses among 1245 patients with relapsed/refractory AML referred to our institution between 2000 and 2014. CNS leukemia relapse was observed in 51 patients (4.1%). Using a multivariate regression model and after adjusting for age, FLT3-ITD mutation (OR=2...
May 27, 2017: American Journal of Hematology
https://www.readbyqxmd.com/read/28522571/flt3-and-flt3-itd-phosphorylate-and-inactivate-the-cyclin-dependent-kinase-inhibitor-p27kip1-in-acute-myeloid-leukemia
#12
Ines Peschel, Silvio R Podmirseg, Martin Taschler, Justus Duyster, Katharina S Götze, Heinz Sill, David Nachbaur, Heidelinde Jäkel, Ludger Hengst
p27Kip1 can prevent cell proliferation by inactivating cyclin-dependent kinases. This function is impaired upon phosphorylation of p27 at tyrosine residue 88. We observed that FLT3 and FLT3-ITD can directly bind and selectively phosphorylate p27 on this residue. Inhibition of FLT3-ITD in cell lines strongly reduced p27 tyrosine 88 phosphorylation and resulted in increased p27 levels and cell cycle arrest. Subsequent analysis revealed the presence of tyrosine 88 phosphorylated p27 in primary patient samples...
May 18, 2017: Haematologica
https://www.readbyqxmd.com/read/28516360/gilteritinib-a-flt3-axl-inhibitor-shows-antileukemic-activity-in-mouse-models-of-flt3-mutated-acute-myeloid-leukemia
#13
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...
May 17, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28507466/high-level-of-mir-196b-at-newly-diagnosed-pediatric-acute-myeloid-leukemia-predicts-a-poor-outcome
#14
Lihua Xu, Yang Guo, Wenying Yan, Jiannong Cen, Yuna Niu, Qing Yan, Hailong He, Chien-Shing Chen, Shaoyan Hu
Differential expression of microRNAs (miRNAs) has been implicated in leukemogenesis. We investigate the expression pattern of miR-196b. Using quantitative real-time PCR (qRT-PCR), we detected the expression of miR-196b and its correlated genes (SMC1A/MLH1) in initial pediatric AML. A significant association was observed between overexpression of miR-196b and inferior overall survival of pediatric AML (Log Rank P<0.0001). AML M4/5 subtype, high white blood cell (WBC) count at presentation, MLL rearrangement, or FLT3-ITD mutation at diagnosis and non-remission group after the first induction chemotherapy possessed higher miR-196b expression...
2017: EXCLI journal
https://www.readbyqxmd.com/read/28484171/current-diagnosis-and-treatment-for-pediatric-acute-myeloid-leukemia
#15
Norio Shiba
Acute myeloid leukemia (AML) is a complex disease caused by chromosomal aberrations, mutations, epigenetic modifications, and the deregulated expression of genes, leading to increased myeloid cell proliferation and decreased hematopoietic progenitor cell differentiation. Although most of these aberrations are correlated with prognosis, accurate risk stratification remains a challenge even after incorporating these molecular markers. Currently, some genetic mutations that allow risk stratification have been identified in adult AML, including DNMT3A and IDH1/2...
2017: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
https://www.readbyqxmd.com/read/28473620/prognostic-and-biologic-significance-of-long-non-coding-rna-profiling-in-younger-adults-with-cytogenetically-normal-acute-myeloid-leukemia
#16
Dimitrios Papaioannou, Deedra Nicolet, Stefano Volinia, Krzysztof Mrózek, Pearlly Yan, Ralf Bundschuh, Andrew J Carroll, Jessica Kohlschmidt, William Blum, Bayard L Powell, Geoffrey L Uy, Jonathan E Kolitz, Eunice S Wang, Ann-Kathrin Eisfeld, Shelley J Orwick, David M Lucas, Michael A Caligiuri, Richard M Stone, John C Byrd, Ramiro Garzon, Clara D Bloomfield
Long non-coding RNAs are a novel class of RNA molecules, which are increasingly recognized as important molecular players in solid and hematologic malignancies. Herein we investigated whether long non-coding RNA expression is associated with clinical and molecular features, as well as outcome of younger adults (aged <60 years) with de novo cytogenetically normal acute myeloid leukemia. Whole transcriptome profiling (RNA-seq) was performed in a training (n=263) and a validation set (n=114). Using the training set, we identified 24 long non-coding RNAs associated with event-free survival...
May 4, 2017: Haematologica
https://www.readbyqxmd.com/read/28470536/flt3-itd-and-its-current-role-in-acute-myeloid-leukaemia
#17
REVIEW
Francisco Alejandro Lagunas-Rangel, Venice Chávez-Valencia
FMS-like tyrosine kinase 3 (FLT3) is a proto-oncogene involved in crucial steps of haematopoiesis such as proliferation, differentiation and survival. In recent years, FLT3 has been an important marker in different haematological malignancies, highlighting in acute myeloid leukaemia, where FLT3 mutations have been associated with the clinical prognosis, treatment and survival of patients. The most common form of FLT3 mutation is an internal tandem duplication (ITD) that promotes ligand-independent auto-phosphorylation and constitutive activation of the receptor...
June 2017: Medical Oncology
https://www.readbyqxmd.com/read/28456748/reprogramming-acute-myeloid-leukemia-into-sensitivity-for-retinoic-acid-driven-differentiation
#18
REVIEW
Noortje van Gils, Han J M P Verhagen, Linda Smit
The success of all-trans retinoic acid (ATRA) therapy for acute promyelocytic leukemia (APL) provides a rationale for using retinoic acid (RA)-based therapy for other subtypes of acute myeloid leukemia (AML). Recently, several studies showed that ATRA may drive leukemic cells efficiently into differentiation and/or apoptosis in a subset of AML patients with an NPM1 mutation, an FLT3-ITD, an IDH1 mutation, and an overexpression of EVI-1. Because not all patients within these molecular subgroups respond to ATRA and clinical trials that tested ATRA response in non-APL AML patients have had disappointing results, the identification of additional biomarkers may help to identify patients who strongly respond to ATRA-based therapy...
April 27, 2017: Experimental Hematology
https://www.readbyqxmd.com/read/28450419/phosphoproteome-analysis-reveals-differential-mode-of-action-of-sorafenib-in-wildtype-and-mutated-flt3-aml-cells
#19
Catrin Roolf, Nikolaj Dybowski, Anett Sekora, Stefan Mueller, Gudrun Knuebel, Andreas Tebbe, Hugo Murua Escobar, Klaus Godl, Christian Junghanss, Christoph Schaab
Constitutively activating internal tandem duplication (ITD) alterations of the receptor tyrosine kinase FLT3 (Fms-like tyrosine kinase 3) are common in acute myeloid leukemia (AML) and classifies FLT3 as an attractive therapeutic target. So far, applications of FLT3 small molecule inhibitors have been investigated primarily in FLT3-ITD+ patients. Only recently, a prolonged event-free survival has been observed in AML patients who were treated with the multi-kinase inhibitor sorafenib in addition to standard therapy...
April 27, 2017: Molecular & Cellular Proteomics: MCP
https://www.readbyqxmd.com/read/28447422/minimal-residual-disease-in-acute-myelogenous-leukemia
#20
REVIEW
N M Cruz, N Mencia-Trinchant, D C Hassane, M L Guzman
Treatment of acute myelogenous leukemia (AML) over the past four decades remains mostly unchanged and the prognosis for the majority of patients remains poor. Most of the significant advances that have been observed are in defining cytogenetic abnormalities, as well as the genetic and epigenetic profiles of AML patients. While new cytogenetic and genetic aberrations such as the FLT3-ITD and NPM1 mutations are able to guide prognosis for the majority of patients with AML, outcomes are still dismal and relapse rates remain high...
May 2017: International Journal of Laboratory Hematology
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