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https://www.readbyqxmd.com/read/29235894/pacritinib-and-its-use-in-the-treatment-of-patients-with-myelofibrosis-who-have-thrombocytopenia
#1
Adolfo Enrique Diaz, Ruben A Mesa
The treatment landscape for myelofibrosis (MF) has reached the molecular era by targeting different pathways that are implied in this myeloproliferative neoplasm. A few years ago, the first-in-class JAK1/JAK2 inhibitor ruxolitinib, demonstrated reductions in both constitutional symptoms and splenomegaly, leading to the US FDA approval. The development or worsening of cytopenias in patients receiving ruxolitinib uncovered an unmet need that has been addressed by alternative approaches. Pacritinib, a dual JAK2 and FLT3 inhibitor which also inhibits IRAK1, has demonstrated the ability to favorably impact MF-associated splenomegaly and symptom burden, while having limited myelosuppression with manageable gastrointestinal toxicity...
December 13, 2017: Future Oncology
https://www.readbyqxmd.com/read/29231051/midostaurin-in-combination-with-standard-chemotherapy-for-treatment-of-newly-diagnosed-fms-like-tyrosine-kinase-3-flt3-mutation-positive-acute-myeloid-leukemia
#2
Miryoung Kim, Sherry Williams
OBJECTIVE: To evaluate the efficacy and safety of midostaurin in combination with standard cytarabine and daunorubicin induction and cytarabine consolidation in newly diagnosed FLT3-mutated acute myeloid leukemia (AML). DATA SOURCE: A literature search of PubMed and MEDLINE (September 2017) was performed using the terms midostaurin, PKC412, FLT3 gene, and acute myeloid leukemia. STUDY SELECTION/DATA EXTRACTION: Clinical trials evaluating the efficacy and safety of midostaurin in combination with standard cytarabine and daunorubicin induction and cytarabine consolidation were reviewed for the treatment of newly diagnosed FLT3-mutated AML...
December 1, 2017: Annals of Pharmacotherapy
https://www.readbyqxmd.com/read/29227476/the-molecular-landscape-of-pediatric-acute-myeloid-leukemia-reveals-recurrent-structural-alterations-and-age-specific-mutational-interactions
#3
Hamid Bolouri, Jason E Farrar, Timothy Triche, Rhonda E Ries, Emilia L Lim, Todd A Alonzo, Yussanne Ma, Richard Moore, Andrew J Mungall, Marco A Marra, Jinghui Zhang, Xiaotu Ma, Yu Liu, Yanling Liu, Jaime M Guidry Auvil, Tanja M Davidsen, Patee Gesuwan, Leandro C Hermida, Bodour Salhia, Stephen Capone, Giridharan Ramsingh, Christian Michel Zwaan, Sanne Noort, Stephen R Piccolo, E Anders Kolb, Alan S Gamis, Malcolm A Smith, Daniela S Gerhard, Soheil Meshinchi
We present the molecular landscape of pediatric acute myeloid leukemia (AML) and characterize nearly 1,000 participants in Children's Oncology Group (COG) AML trials. The COG-National Cancer Institute (NCI) TARGET AML initiative assessed cases by whole-genome, targeted DNA, mRNA and microRNA sequencing and CpG methylation profiling. Validated DNA variants corresponded to diverse, infrequent mutations, with fewer than 40 genes mutated in >2% of cases. In contrast, somatic structural variants, including new gene fusions and focal deletions of MBNL1, ZEB2 and ELF1, were disproportionately prevalent in young individuals as compared to adults...
December 11, 2017: Nature Medicine
https://www.readbyqxmd.com/read/29227282/hypoxia-induced-upregulation-of-bmx-kinase-mediates-therapeutic-resistance-in-acute-myeloid-leukemia
#4
Jolieke G van Oosterwijk, Daelynn R Buelow, Christina D Drenberg, Aksana Vasilyeva, Lie Li, Lei Shi, Yong-Dong Wang, David Finkelstein, Sheila A Shurtleff, Laura J Janke, Stanley Pounds, Jeffrey E Rubnitz, Hiroto Inaba, Navjotsingh Pabla, Sharyn D Baker
Oncogenic addiction to the Fms-like tyrosine kinase 3 (FLT3) is a hallmark of acute myeloid leukemia (AML) that harbors the FLT3-internal tandem duplication (FLT3-ITD) mutation. While FLT3 inhibitors like sorafenib show initial therapeutic efficacy, resistance rapidly develops through mechanisms that are incompletely understood. Here, we used RNA-Seq-based analysis of patient leukemic cells and found that upregulation of the Tec family kinase BMX occurs during sorafenib resistance. This upregulation was recapitulated in an in vivo murine FLT3-ITD-positive (FLT3-ITD+) model of sorafenib resistance...
December 11, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29214689/distinct-factors-determine-the-kinetics-of-disease-relapse-in-adults-transplanted-for-acute-myeloid-leukaemia
#5
C Craddock, J Versluis, M Labopin, G Socie, A Huynh, E Deconinck, L Volin, N Milpied, J H Bourhis, A Rambaldi, P Chevallier, D Blaise, M Manz, E Vellenga, M-C Vekemans, J Maertens, J Passweg, P Vyas, C Schmid, B Löwenberg, G Ossenkoppele, M Mohty, J J Cornelissen, A Nagler
Disease recurrence remains the major cause of death in adults with acute myeloid leukemia (AML) treated using either intensive chemotherapy (IC) or allogenic stem cell transplantation (allo-SCT). The timely delivery of maintenance drug or cellular therapies represent emerging strategies with the potential to reduce relapse after both treatment modalities, but whilst the determinants of overall relapse risk have been extensively characterized the factors determining the timing of disease recurrence have not been characterized...
December 7, 2017: Journal of Internal Medicine
https://www.readbyqxmd.com/read/29212189/quizartinib-ac220-reverses-abcg2-mediated-multidrug-resistance-in-vitro-and-in-vivo-studies
#6
Jun Li, Priyank Kumar, Nagaraju Anreddy, Yun-Kai Zhang, Yi-Jun Wang, Yanglu Chen, Tanaji T Talele, Kanav Gupta, Louis D Trombetta, Zhe-Sheng Chen
Previous reports have shown that some tyrosine kinase inhibitors (TKIs) could inhibit the ATP-binding cassette (ABC) transporters involved in multidrug resistance (MDR). Quizartinib (AC220), a potent class III receptor tyrosine kinase inhibitor (TKI), was synthesized to selectively inhibit FMS-like tyrosine kinase-3 (FLT3), a target in the treatment of acute myeloid leukemia (AML). Quizartinib is currently under clinical trials for FLT3 ITD and wild-type AML and is tested in combination with chemotherapy. While non-toxic to cell lines, quizartinib at 3 μM showed significant reversal effect on wild-type and mutant ABCG2 (R482T)-mediated MDR, and only a moderate reversal effect on mutant ABCG2 (R482G)-mediated MDR...
November 7, 2017: Oncotarget
https://www.readbyqxmd.com/read/29209657/hitting-the-snooze-button-inducing-quiescence-with-the-flt3-inhibitor-quizartinib-protects-hematopoietic-progenitors-from-chemotherapy
#7
Samuel J Taylor, Wallace Y Langdon
Myelosuppression is one of the most severe and limiting side effects of chemotherapy. Our recent work outlines a strategy to prevent chemotherapy-induced myelosuppression by administering a priming dose of the FMS-Like Tyrosine kinase 3 (FLT3) inhibitor quizartinib. Furthermore, by administering sequential quizartinib primed injections of fluorouracil (5-FU), we demonstrated a novel and effective strategy to eliminate disease in two mouse models of quizartinib resistant acute myeloid leukemia (AML).
2017: Molecular & Cellular Oncology
https://www.readbyqxmd.com/read/29209600/targeting-flt3-signaling-in-childhood-acute-myeloid-leukemia
#8
REVIEW
Amy N Sexauer, Sarah K Tasian
Acute myeloid leukemia (AML) is the second most common leukemia of childhood and is associated with high rates of chemotherapy resistance and relapse. Clinical outcomes for children with AML treated with maximally intensive multi-agent chemotherapy lag far behind those of children with the more common acute lymphoblastic leukemia, demonstrating continued need for new therapeutic approaches to decrease relapse risk and improve long-term survival. Mutations in the FMS-like tyrosine kinase-3 receptor gene (FLT3) occur in approximately 25% of children and adults with AML and are associated with particularly poor prognoses...
2017: Frontiers in Pediatrics
https://www.readbyqxmd.com/read/29206716/primary-epithelioid-angiosarcoma-of-finger-masquerading-as-epithelioid-hemangioma-report-of-a-case-and-analysis-of-mutational-pattern-in-epithelioid-hemangiomas-and-angiosarcomas-by-next-generation-sequencing
#9
Manish M Subramaniam, Nur L Salleh, Bingcheng Wu, Michelle A Rozario, HueyJin Lim, Mark E Puhaindran, Richie Soong, Victor K Lee
AIMS: We report an unusual case of epithelioid angiosarcoma (AS) mimicking an epithelioid hemangioma (EH) and analyze mutational patterns in EHs and ASs. METHODS AND RESULTS: A 58-year-old woman presented with a finger lump and metastatic lung nodules. Initial needle biopsies showed an EH, with only focal atypical histologic features. The patient underwent finger amputation and resection of lung nodules. The amputation specimen and lung nodules revealed features of AS...
January 2018: Applied Immunohistochemistry & Molecular Morphology: AIMM
https://www.readbyqxmd.com/read/29206680/immune-therapies-in-acute-myeloid-leukemia-a-focus-on-monoclonal-antibodies-and-immune-checkpoint-inhibitors
#10
Rita Assi, Hagop Kantarjian, Farhad Ravandi, Naval Daver
PURPOSE OF REVIEW: This review discusses the rationale, efficacy, and toxicity of a variety of immune approaches being evaluated in the therapy of acute myeloid leukemia (AML) including naked and conjugated monoclonal antibodies, bispecific T-cell engager antibodies, and immune checkpoint blockade via antibodies targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed-death 1 (PD-1). RECENT FINDINGS: The stellar success of immune therapies that harness the power of T cells in solid tumors and an improved understanding of the immune system in patients with hematologic malignancies have resulted in major efforts to develop immune therapies for the treatment of patients with AML...
December 4, 2017: Current Opinion in Hematology
https://www.readbyqxmd.com/read/29193057/prognostic-utility-of-six-mutated-genes-for-older-patients-with-acute-myeloid-leukemia
#11
Jinghan Wang, Zhixin Ma, Qinrong Wang, Qi Guo, Jiansong Huang, Wenjuan Yu, Huanping Wang, Jingwen Huang, Yang Washington Shao, Suning Chen, Jie Jin
Approximately 50% of older patients with acute myeloid leukemia (AML) do not obtain chromosomal abnormalities as an effective risk-stratification, and present cytogenetically normal AML (CN-AML). In order to develop a reliable prediction model for stratifying the risk of these elderly patients, we conducted a study with a discovery and validation design. As a result, we found the top 6 mutated genes in the discovery cohort of 26 case by the whole exome sequencing, and verified as recurrent mutations in the large cohort of 329 patients by sanger sequencing...
November 29, 2017: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/29191878/the-target-landscape-of-clinical-kinase-drugs
#12
Susan Klaeger, Stephanie Heinzlmeir, Mathias Wilhelm, Harald Polzer, Binje Vick, Paul-Albert Koenig, Maria Reinecke, Benjamin Ruprecht, Svenja Petzoldt, Chen Meng, Jana Zecha, Katrin Reiter, Huichao Qiao, Dominic Helm, Heiner Koch, Melanie Schoof, Giulia Canevari, Elena Casale, Stefania Re Depaolini, Annette Feuchtinger, Zhixiang Wu, Tobias Schmidt, Lars Rueckert, Wilhelm Becker, Jan Huenges, Anne-Kathrin Garz, Bjoern-Oliver Gohlke, Daniel Paul Zolg, Gian Kayser, Tonu Vooder, Robert Preissner, Hannes Hahne, Neeme Tõnisson, Karl Kramer, Katharina Götze, Florian Bassermann, Judith Schlegl, Hans-Christian Ehrlich, Stephan Aiche, Axel Walch, Philipp A Greif, Sabine Schneider, Eduard Rudolf Felder, Juergen Ruland, Guillaume Médard, Irmela Jeremias, Karsten Spiekermann, Bernhard Kuster
Kinase inhibitors are important cancer therapeutics. Polypharmacology is commonly observed, requiring thorough target deconvolution to understand drug mechanism of action. Using chemical proteomics, we analyzed the target spectrum of 243 clinically evaluated kinase drugs. The data revealed previously unknown targets for established drugs, offered a perspective on the "druggable" kinome, highlighted (non)kinase off-targets, and suggested potential therapeutic applications. Integration of phosphoproteomic data refined drug-affected pathways, identified response markers, and strengthened rationale for combination treatments...
December 1, 2017: Science
https://www.readbyqxmd.com/read/29188605/-analysis-of-prognosis-of-acute-myeloid-leukemia-patients-based-on-genetic-mutations
#13
Jinning Shi, Yu Zhu, Ming Hong, Huihui Zhao, Jianping Mao, Hui Jin, Wenjing Zhang, Ting Zhang, Yongchao Ma, Yaoyu Chen, Sixuan Qian, Jianyong Li, Chun Qiao
OBJECTIVE: To correlate the clinical features of patients with acute myeloid leukemia (AML) with mutations of FLT3-ITD, NPM1, CEBPA, c-KIT, DNMT3A and ND4 genes as well as chromosomal aberrations. METHODS: Somatic mutations of aforementioned genes in 412 newly diagnosed AML patients were detected with PCR and direct sequencing. All patients were also subjected to R-banding chromosomal analysis. The results were correlated with the clinical features and prognosis of the patients...
December 10, 2017: Zhonghua Yi Xue Yi Chuan Xue za Zhi, Zhonghua Yixue Yichuanxue Zazhi, Chinese Journal of Medical Genetics
https://www.readbyqxmd.com/read/29187377/a-novel-irreversible-flt3-inhibitor-ff-10101-shows-excellent-efficacy-against-aml-cells-with-flt3-mutations
#14
Takeshi Yamaura, Toshiyuki Nakatani, Ken Uda, Hayato Ogura, Wigyon Shin, Naoya Kurokawa, Koichi Saito, Norie Fujikawa, Tomomi Date, Masaru Takasaki, Daisuke Terada, Atsushi Hirai, Akimi Akashi, Fangli Chen, Yoshiya Adachi, Yuichi Ishikawa, Fumihiko Hayakawa, Shinji Hagiwara, Tomoki Naoe, Hitoshi Kiyoi
An activating mutation of FLT3 is the most frequent genetic alteration associated with poor prognosis in acute myeloid leukemia (AML). Although many FLT3 inhibitors have been clinically developed, no first-generation inhibitors have demonstrated clinical efficacy by monotherapy, due to poor pharmacokinetics or unfavorable safety profiles possibly associated with low selectivity against FLT3 kinase. Recently, a selective FLT3 inhibitor, quizartinib, demonstrated favorable outcomes in clinical studies. However, several resistant mutations emerged during the disease progression...
November 29, 2017: Blood
https://www.readbyqxmd.com/read/29179894/-preventative-and-therapeutic-relapse-strategies-after-allogeneic-hematopoietic-stem-cell-transplantation-guidelines-from-the-francophone-society-of-bone-marrow-transplantation-and-cellular-therapy-sfgm-tc
#15
Nabil Yafour, Florence Beckerich, Claude Eric Bulabois, Patrice Chevallier, Étienne Daguindau, Cécile Dumesnil, Thierry Guillaume, Anne Huynh, Stavroula Masouridi Levrat, Anne-Lise Menard, Mauricette Michallet, Cécile Pautas, Xavier Poiré, Aurelie Ravinet, Ibrahim Yakoub-Agha, Ali Bazarbachi
Disease relapse remains the first cause of mortality of hematological malignancies after allogeneic hematopoietic stem cell transplantation (allo-HCT). The risk of recurrence is elevated in patients with high-risk cytogenetic or molecular abnormalities, as well as when allo-HCT is performed in patients with refractory disease or with persistent molecular or radiological (PET-CT scan) residual disease. Within the frame of the 7th annual workshops of the francophone society for bone marrow transplantation and cellular therapy, the working group reviewed the literature in order to elaborate unified guidelines for the prevention and treatment of relapse after allo-HCT...
November 24, 2017: Bulletin du Cancer
https://www.readbyqxmd.com/read/29179430/dock2-a-novel-flt3-itd-leukemia-drug-target
#16
EDITORIAL
Min Wu, Donald Small, Amy S Duffield
No abstract text is available yet for this article.
October 24, 2017: Oncotarget
https://www.readbyqxmd.com/read/29175091/phosphoprotein-dige-profiles-reflects-blast-differentiation-cytogenetic-risk-stratification-flt3-npm1-mutations-and-therapy-response-in-acute-myeloid-leukaemia
#17
Rakel Brendsdal Forthun, Elise Aasebø, Josef Daniel Rasinger, Siv Lise Bedringaas, Frode Berven, Frode Selheim, Øystein Bruserud, Bjørn Tore Gjertsen
Acute myeloid leukaemia (AML) is an aggressive blood cancer characterized by a distinct block in differentiation of myeloid progenitors, recurrent chromosomal translocations and gene mutations of which >50% involve signal transduction through dysregulated kinases and phosphatases. In search for novel protein biomarkers for disease stratification we investigated the phosphoproteome in leukaemic cells from 62 AML patients at time of diagnosis using immobilized metal-affinity chromatography, protein separation by two-dimensional differential gel electrophoresis (2D-DIGE) and mass spectrometry before validation by selected reaction monitoring (SRM)...
November 21, 2017: Journal of Proteomics
https://www.readbyqxmd.com/read/29172682/impact-of-specimen-heterogeneity-on-biomarkers-in-repository-samples-from-patients-with-acute-myeloid-leukemia-a-swog-report
#18
Era L Pogosova-Agadjanyan, Anna Moseley, Megan Othus, Frederick R Appelbaum, Thomas R Chauncey, I-Ming L Chen, Harry P Erba, John E Godwin, Min Fang, Kenneth J Kopecky, Alan F List, Galina L Pogosov, Jerald P Radich, Cheryl L Willman, Brent L Wood, Soheil Meshinchi, Derek L Stirewalt
INTRODUCTION: Current prognostic models for acute myeloid leukemia (AML) are inconsistent at predicting clinical outcomes for individual patients. Variability in the quality of specimens utilized for biomarker discovery and validation may contribute to this prognostic inconsistency. METHODS: We evaluated the impact of sample heterogeneity on prognostic biomarkers and methods to mitigate any adverse effects of this heterogeneity in 240 cryopreserved bone marrow and peripheral blood specimens from AML patients enrolled on SWOG (Southwest Oncology Group) trials...
November 27, 2017: Biopreservation and Biobanking
https://www.readbyqxmd.com/read/29172276/flt3-itd-npm1-and-dnmt3a-gene-mutations-and-risk-factors-in-normal-karyotype-acute-myeloid-leukemia-and-myelodysplastic-syndrome-patients-in-upper-northern-thailand
#19
Piyanan Mevatee, Adisak Tantiworawit, Patrinee Traisathit, Chaniporn Puaninta, Umnat Mevatee, Sirinda Angsuchawan, Kanokkan Bumroongkit
Objective: Approximately 40-45% of AML and MDS patients have a cytogenetically normal karyotype (CN-AML and CN-MDS). The frequency and types of gene mutations in these cases may differ among various populations. The objective of this study was to identify frequencies and types of FLT3-ITD, NPM1, and DNMT3A mutations, and associations of them with clinical data and risk factors in CN-AML and CN-MDS cases in upper Northern Thailand. Methods: Bone marrow samples of 40 CN-AML and 60 CN-MDS patients were analyzed for gene mutations by direct sequencing...
November 26, 2017: Asian Pacific Journal of Cancer Prevention: APJCP
https://www.readbyqxmd.com/read/29168461/study-of-stem-cell-homing-self-renewal-marker-gene-profile-of-ex-vivo-expanded-human-cd34-cells-manipulated-with-a-mixture-of-cytokines-stromal-cell-derived-factor-1
#20
Jyoti Kode, Navin Khattry, Ashish Bakshi, Vasanti Amrutkar, Bhausaheb Bagal, Rohini Karandikar, Pallavi Rane, Nobutaka Fujii, Shubhada Chiplunkar
BACKGROUND & OBJECTIVES: Next generation transplantation medicine aims to develop stimulating cocktail for increased ex vivo expansion of primitive hematopoietic stem and progenitor cells (HSPC). The present study was done to evaluate the cocktail GF (Thrombopoietin + Stem Cell factor + Flt3-ligand) and homing-defining molecule Stromal cell-derived factor 1 (SDF1) for HSPC ex vivo expansion. METHODS: Peripheral blood stem cell (n=74) harvests were analysed for CD34hiCD45lo HSPC...
July 2017: Indian Journal of Medical Research
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