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Aml relapse treatment

Nan Yang, Zhenyang Gu, Zhanxiang Liu, Wenrong Huang, Shuhong Wang, Lili Wang, Chunji Gao
Multi-kinase inhibitor sorafenib showed dramatic effects in acute myeloid leukemia (AML) cells harboring fms-related tyrosine kinase 3-internal tandem duplication(FLT3-ITD) mutation. However, little is known about its therapeutic effects and underlying mechanisms on AML without this mutation. In this report, sorafenib monotherapy was utilized as a salvage treatment in two relapse/refractory AML patients without FLT3-ITD mutation. A central nervous system(CNS) relapsed patient exhibited significant shrink of tumor volume, the other patient with refractory AML, arising from chronic myelomonocytic leukemia, achieved hematological improvements...
March 7, 2018: Anti-cancer Agents in Medicinal Chemistry
Xiaoqin Feng, He Lan, Yongsheng Ruan, Chunfu Li
OBJECTIVES: This meta-analysis evaluated the impact of granulocyte colony-stimulating factor (G-CSF) added to chemotherapy on treatment outcomes including survival and disease recurrence in patients with acute myeloid leukemia (AML). METHODS: Medline, Cochrane, EMBASE, and Google Scholar databases were searched until 19 September 2016 using search terms. Studies that investigated patients with AML who underwent stem-cell transplantation were included. RESULTS: The overall analysis revealed a significant improvement in overall survival (OS) (P = ...
March 8, 2018: Hematology (Amsterdam, Netherlands)
Jessica C Petrov, Masayuki Wada, Kevin G Pinz, Lulu E Yan, Kevin H Chen, Xiao Shuai, Hua Liu, Xi Chen, Lai-Han Leung, Huda Salman, Nabil Hagag, Fang Liu, Xun Jiang, Yupo Ma
Acute myeloid leukemia (AML) bears heterogeneous cells that can consequently offset killing by single-CAR-based therapy, which results in disease relapse. Leukemic stem cells (LSCs) associated with CD123 expression comprise a rare population that also plays an important role in disease progression and relapse. Here, we report on the robust anti-tumor activity of a compound CAR (cCAR) T-cell possessing discrete scFv domains targeting two different AML antigens, CD123, and CD33, simultaneously. We determined that the resulting cCAR T-cells possessed consistent, potent, and directed cytotoxicity against each target antigen population...
February 25, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
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
Francesco Buccisano, Luca Maurillo, Maria Ilaria Del Principe, Ambra Di Veroli, Eleonora De Bellis, Annalisa Biagi, Anangiulia Zizzari, Valentina Rossi, Vito Rapisarda, Sergio Amadori, Maria Teresa Voso, Francesco Lo-Coco, William Arcese, Adriano Venditti
Response to therapy is affected by the genetic heterogeneity of acute myeloid leukemia (AML) and persistence of leukemic cells below the threshold of morphological complete remission (mCR). Such persistence is called minimal (or measurable) residual disease (MRD). Areas covered: MRD assessment allows early identification of patients who are at high risk of relapse and who should timely receive aggressive therapy (e.g. allogeneic stem cell transplantation) and of those with a good quality mCR in whom an aggressive front-line therapy can be spared, avoiding the harm of excessive treatment toxicity...
March 2, 2018: Expert Review of Hematology
Yan-Hua Wang, Yoichi Imai, Masayuki Shiseki, Junji Tanaka, Toshiko Motoji
Multidrug resistance (MDR) is a major obstacle to leukemia treatment. The Frizzled-1 (FZD1) Wnt receptor is involved in MDR in some solid cancers, but has rarely been reported to act in acute myeloid leukemia (AML). We investigated whether the knockdown of FZD1 affects MDR1 expression and P-glycoprotein (P-gp) function in multidrug resistant leukemic cell lines, as well as FZD1 and MDR1/P-gp expression in leukemic cells taken from patients with AML (n = 112). FZD1 knockdown significantly reduced MDR1 expression through the Wnt/β-catenin pathway, disrupted the P-gp efflux function, induced the recovery of sensitivity to chemotherapeutic agents, and hindered cell proliferation in cell lines...
January 31, 2018: Leukemia Research
Danyue Peng, Huifang Wang, Lei Li, Xiao Ma, Ying Chen, Hao Zhou, Yi Luo, Yin Xiao, Lingbo Liu
Leukemia stem cells (LSCs) are responsible for acute myeloid leukemia (AML) chemotherapy resistance and relapse. Here, we discovered that miR-34c-5p, a microRNA central to the senescence regulation network, was significantly down-regulated in AML (non-acute promyelocytic leukemia, non-APL) stem cells compared to that in normal hematopoietic stem cells (HSCs). The lower expression of miR-34c-5p in LSCs was closely correlated to the adverse prognosis and poor responses to therapy of AML patients. Increased miR-34c-5p expression induced LSCs senescence ex vivo, prevented leukemia development and promoted the eradication of LSCs in immune deficient mice...
February 2, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Maja Rothenberg-Thurley, Susanne Amler, Dennis Goerlich, Thomas Köhnke, Nikola P Konstandin, Stephanie Schneider, Maria C Sauerland, Tobias Herold, Max Hubmann, Bianka Ksienzyk, Evelyn Zellmeier, Stefan K Bohlander, Marion Subklewe, Andreas Faldum, Wolfgang Hiddemann, Jan Braess, Karsten Spiekermann, Klaus H Metzeler
Some patients with acute myeloid leukemia (AML) who are in complete remission after induction chemotherapy harbor persisting pre-leukemic clones, carrying a subset of leukemia-associated somatic mutations. There is conflicting evidence on the prognostic relevance of these clones for AML relapse. Here, we characterized paired pre-treatment and remission samples from 126 AML patients for mutations in 68 leukemia-associated genes. Fifty patients (40%) retained ≥1 mutation during remission at a VAF of ≥2%. Mutation persistence was most frequent in DNMT3A (65% of patients with mutations at diagnosis), SRSF2 (64%), TET2 (55%), and ASXL1 (46%), and significantly associated with older age (p < 0...
February 23, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Matteo Zampini, Claudia Tregnago, Valeria Bisio, Luca Simula, Giulia Borella, Elena Manara, Carlo Zanon, Francesca Zonta, Valentina Serafin, Benedetta Accordi, Silvia Campello, Barbara Buldini, Andrea Pession, Franco Locatelli, Giuseppe Basso, Martina Pigazzi
The somatic translocation t(8;21)(q22;q22)/RUNX1-RUNX1T1 is one of the most frequent rearrangements found in children with standard-risk acute myeloid leukemia (AML). Despite the favorable prognostic role of this aberration, we recently observed a higher than expected frequency of relapse. Here, we employed an integrated high-throughput approach aimed at identifying new biological features predicting relapse among 34 t(8;21)-rearranged patients. We found that the DNA methylation status of patients who suffered from relapse was peculiarly different from that of children maintaining complete remission...
February 2, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Stefan O Ciurea, Myriam Labopin, Gerard Socie, Liisa Volin, Jakob Passweg, Patrice Chevallier, Dietrich Beelen, Noel Milpied, Didier Blaise, Jan J Cornelissen, Nathalie Fegueux, Emmanuelle Polge, Piyanuch Kongtim, Gabriela Rondon, Jordi Esteve, Mohamad Mohty, Bipin N Savani, Richard E Champlin, Arnon Nagler
BACKGROUND: Despite recent advances in allogeneic hematopoietic stem cell transplantation (AHSCT), the outcome of patients who have acute myeloid leukemia (AML) with a complex karyotype (CK) remains poor. The objective of this study was to identify prognostic factors associated with post-transplantation survival in a large cohort of patients with CK AML. METHODS: In total, data on 1342 consecutively patients who underwent transplantation for CK (≥3 chromosomal abnormalities) AML were provided by the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation and from the University of Texas MD Anderson Cancer Center database were included in the analysis...
February 22, 2018: Cancer
Tibor J Kovacsovics, Alice Mims, Mohamed E Salama, Jeremy Pantin, Narayanam Rao, Ken M Kosak, Peter Ahorukomeye, Martha J Glenn, Michael W N Deininger, Kenneth M Boucher, Linda M Bavisotto, Gerardo Gutierrez-Sanchez, Thomas P Kennedy, Stephen G Marcus, Paul J Shami
Relapses in acute myelogenous leukemia (AML) are a result of quiescent leukemic stem cells (LSCs) in marrow stromal niches, where they resist chemotherapy. LSCs employ CXCL12/CXCR4 to home toward protective marrow niches. Heparin disrupts CXCL12-mediated sequestration of cells in the marrow. CX-01 is a low-anticoagulant heparin derivative. In this pilot study, we combined CX-01 with chemotherapy for the treatment of AML. Induction consisted of cytarabine and idarubicin (7 + 3) with CX-01. Twelve patients were enrolled (median age, 56 years; 3 women)...
February 27, 2018: Blood Advances
Hamid Sayar, Yan Liu, Rui Gao, Mohammad Abu Zaid, Larry D Cripe, Jill Weisenbach, Katie J Sargent, Mehdi Nassiri, Lang Li, Heiko Konig, Attaya Suvannasankha, Feng Pan, Rajasubramaniam Shanmugam, Chirayu Goswami, Reuben Kapur, Mingjiang Xu, H Scott Boswell
Co-occurrence of Flt3ITD and TET2 mutations provoke an animal model of AML by epigenetic repression of Wnt pathway antagonists, including RUNX3, and by hyperexpression of ID1, encoding Wnt agonist. These affect HOXA over-expression and treatment resistance. A comparable epigenetic phenotype was identified among adult AML patients needing novel intervention. We chose combinations of targeted agents acting on distinct effectors, at the levels of both signal transduction and chromatin remodeling, in relapsed/refractory AML's, including Flt3ITD+ve, described with a signature of repressed tumor suppressor genes, involving Wnt antagonist RUNX3 , occurring along with ID1 and HOXA over-expressions...
January 19, 2018: Oncotarget
Xuejie Jiang, Po Yee Mak, Hong Mu, Duncan Mak, Steven Kornblau, Qi Zhang, Peter Ruvolo, Jared K Burks, Weiguo Zhang, Teresa McQueen, Rongqing Pan, Hongsheng Zhou, Marina Konopleva, Jorge E Cortes, Qifa Liu, Michael Andreeff, Bing Z Carter, Wenjing Tao
PURPOSE: Wnt/β-catenin signaling is required for leukemic stem cell function. FLT3 mutations are frequently observed in acute myeloid leukemia (AML). Anomalous FLT3 signaling increases β-catenin nuclear localization and transcriptional activity. FLT3 tyrosine kinase inhibitors (TKIs) are used clinically to treat FLT3-mutated AML patients, but with limited efficacy. We investigated the anti-leukemia activity of combined Wnt/β-catenin and FLT3 inhibition in FLT3-mutant AML. EXPERIMENTAL DESIGN: Wnt/β-catenin signaling was inhibited by the b-catenin/CBP antagonist C-82/PRI-724 or siRNAs, and FLT3 signaling by sorafenib or quizartinib...
February 20, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
M Begum, A Islam, A A Rahman, M Akter, S T Alam, R Tasmeen
Acute leukemias are the most common child hood malignancy, of which acute myeloid leukemia (AML) are 15 to 20%. Abandonment is one of the most important causes of treatment failure in AML in developing countries. Lost to follow-up is also a big problem in low income countries. Many patients stop therapy soon after diagnosis due to cost, distance and ignorance. To determine the abandonment, outcome and treatment related mortality (TRM) and morbidity among children with AML. This prospective observational study was conducted in the Department of Pediatric hematology and Oncology, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka from February 2013 to January 2014...
January 2018: Mymensingh Medical Journal: MMJ
Raynier Devillier, Faezeh Legrand, Jérôme Rey, Luca Castagna, Sabine Fürst, Angela Granata, Aude Charbonnier, Samia Harbi, Evelyne d'Incan, Thomas Pagliardini, Catherine Faucher, Claude Lemarie, Colombe Saillard, Boris Calmels, Bilal Mohty, Valerio Maisano, Pierre-Jean Weiller, Christian Chabannon, Norbert Vey, Didier Blaise
Haploidentical related donor (HRD) allogeneic hematopoietic stem cell transplantation (Allo-HSCT) was developed as a valid option for the treatment of acute myeloid leukemia (AML) in the absence of a matched donor. However, many investigators are reluctant to consider the use of this alternative in elderly patients, anticipating high morbidity. Here, we report a single-center comparison of HRD vs. matched sibling donor (MSD) and unrelated donor (UD) Allo-HSCT for patients with AML aged ≥60 years. Ninety-four patients (MSD: n = 31; UD: n = 30; HRD: n = 33) were analyzed...
February 12, 2018: Biology of Blood and Marrow Transplantation
Andreas T Björklund, Mattias Carlsten, Ebba Sohlberg, Lisa L Liu, Trevor Clancy, Mohsen Karimi, Sarah Cooley, Jeffrey S Miller, Monika Klimkowska, Marie Schaffer, Emma Watz, Kristina I Wikstrom, Pontus Blomberg, Bjorn E Wahlin, Marzia Palma, Lotta Hansson, Per Ljungman, Eva Hellström-Lindberg, Hans-Gustaf Ljunggren, Karl-Johan Malmberg
PURPOSE: To evaluate the safety, efficacy and immunobiological correlates of allogeneic NK cell-based therapy in primary chemotherapy-refractory or relapsed high-risk myelodysplastic syndrome (MDS), secondary AML (MDS/AML), and de novo AML patients. EXPERIMENTAL DESIGN: Sixteen patients received fludarabine/cyclophosphamide conditioning combined with total lymphoid irradiation followed by adoptive immunotherapy with IL-2-activated haploidentical NK cells. RESULTS: NK cell infusions were well tolerated with only transient adverse events observed in the 16 patients...
February 14, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Hee-Don Chae, Nick Cox, Gary V Dahl, Norman J Lacayo, Kara L Davis, Samanta Capolicchio, Mark Smith, Kathleen M Sakamoto
CREB (cAMP Response Element Binding protein) is a transcription factor that is overexpressed in primary acute myeloid leukemia (AML) cells and associated with a decreased event-free survival and increased risk of relapse. We recently reported a small molecule inhibitor of CREB, XX-650-23, which inhibits CREB activity in AML cells. Structure-activity relationship analysis for chemical compounds with structures similar to XX-650-23 led to the identification of the anthelminthic drug niclosamide as a potent anti-leukemic agent that suppresses cell viability of AML cell lines and primary AML cells without a significant decrease in colony forming activity of normal bone marrow cells...
January 12, 2018: Oncotarget
Yingchan Hao, Yanhong Cheng, Quan Wu, Aimei Zhang, Xiaoxiao Jiang, Xiucai Xu
High expression of the Wilms' tumor gene (WT1) in acute myeloid leukemia (AML) has been considered as a sensitive marker of minimal residual disease (MRD). The present study investigated the significance of quantitative analysis of WT1 mRNA, combined with multiparameter flow cytometry (MFC) regarding its efficacy and prognostic as well as relapse prediction value for leukemia patients with hematopoietic stem cell transplantation. Reverse-transcription quantitative polymerase chain reaction analysis demonstrated that the expression of WT1 in the initial and relapse group was significant higher than that in the complete remission (CR) group (P<0...
February 2018: Experimental and Therapeutic Medicine
Nimitha R Mathew, Francis Baumgartner, Lukas Braun, David O'Sullivan, Simone Thomas, Miguel Waterhouse, Tony A Müller, Kathrin Hanke, Sanaz Taromi, Petya Apostolova, Anna L Illert, Wolfgang Melchinger, Sandra Duquesne, Annette Schmitt-Graeff, Lena Osswald, Kai-Li Yan, Arnim Weber, Sonia Tugues, Sabine Spath, Dietmar Pfeifer, Marie Follo, Rainer Claus, Michael Lübbert, Christoph Rummelt, Hartmut Bertz, Ralph Wäsch, Johanna Haag, Andrea Schmidts, Michael Schultheiss, Dominik Bettinger, Robert Thimme, Evelyn Ullrich, Yakup Tanriver, Giang Lam Vuong, Renate Arnold, Philipp Hemmati, Dominik Wolf, Markus Ditschkowski, Cordula Jilg, Konrad Wilhelm, Christian Leiber, Sabine Gerull, Jörg Halter, Claudia Lengerke, Thomas Pabst, Thomas Schroeder, Guido Kobbe, Wolf Rösler, Soroush Doostkam, Stephan Meckel, Kathleen Stabla, Stephan K Metzelder, Sebastian Halbach, Tilman Brummer, Zehan Hu, Joern Dengjel, Björn Hackanson, Christoph Schmid, Udo Holtick, Christof Scheid, Alexandros Spyridonidis, Friedrich Stölzel, Rainer Ordemann, Lutz P Müller, Flore Sicre-de-Fontbrune, Gabriele Ihorst, Jürgen Kuball, Jan E Ehlert, Daniel Feger, Eva-Maria Wagner, Jean-Yves Cahn, Jacqueline Schnell, Florian Kuchenbauer, Donald Bunjes, Ronjon Chakraverty, Simon Richardson, Saar Gill, Nicolaus Kröger, Francis Ayuk, Luca Vago, Fabio Ciceri, Antonia M Müller, Takeshi Kondo, Takanori Teshima, Susan Klaeger, Bernhard Kuster, Dennis Dong Hwan Kim, Daniel Weisdorf, Walter van der Velden, Daniela Dörfel, Wolfgang Bethge, Inken Hilgendorf, Andreas Hochhaus, Geoffroy Andrieux, Melanie Börries, Hauke Busch, John Magenau, Pavan Reddy, Myriam Labopin, Joseph H Antin, Andrea S Henden, Geoffrey R Hill, Glen A Kennedy, Merav Bar, Anita Sarma, Donal McLornan, Ghulam Mufti, Betul Oran, Katayoun Rezvani, Omid Sha, Robert S Negrin, Arnon Nagler, Marco Prinz, Andreas Burchert, Andreas Neubauer, Dietrich Beelen, Andreas Mackensen, Nikolas von Bubnoff, Wolfgang Herr, Burkhard Becher, Gerard Socié, Michael A Caligiuri, Eliana Ruggiero, Chiara Bonini, Georg Häcker, Justus Duyster, Jürgen Finke, Erika Pearce, Bruce R Blazar, Robert Zeiser
Individuals with acute myeloid leukemia (AML) harboring an internal tandem duplication (ITD) in the gene encoding Fms-related tyrosine kinase 3 (FLT3) who relapse after allogeneic hematopoietic cell transplantation (allo-HCT) have a 1-year survival rate below 20%. We observed that sorafenib, a multitargeted tyrosine kinase inhibitor, increased IL-15 production by FLT3-ITD+ leukemia cells. This synergized with the allogeneic CD8+ T cell response, leading to long-term survival in six mouse models of FLT3-ITD+ AML...
February 12, 2018: Nature Medicine
Jan Jakub Lica, Grzegorz Jan Grabe, Mateusz Heldt, Majus Misiak, Patrycja Bloch, Marcin Serocki, Marta Switalska, Joanna Wietrzyk, Maciej Baginski, Andrzej Hellmann, Edward Borowski, Andrzej Skladanowski
Proliferation and expansion of leukemia is driven by Leukemic Stem Cells (LSCs). Multidrug resistance (MDR) of LSCs is one of the main reasons of failure and relapses in Acute Myeloid Leukemia (AML) treatment. Here we show that maintaining HL-60 at low cell culture density or applying a 240-day treatment with anthrapyridazone (BS-121) increased the percentage of primitive cells which include LSCs determining the overall stage profile. This change manifested in: morphology, expression of both cell surface markers and redox-state proteins as well as mitochondrial potential...
February 12, 2018: Stem Cells and Development
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