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secondary acute myeloid leukemia causes

Guillermo Garcia-Manero, Yasmin Abaza, Koichi Takahashi, Bruno C Medeiros, Martha Arellano, Samer K Khaled, Mrinal Patnaik, Olatoyosi Odenike, Hamid Sayar, Mohan Tummala, Prapti Patel, Lori Maness-Harris, Robert Stuart, Elie Traer, Kasra Karamlou, Abdulraheem Yacoub, Richard Ghalie, Ruben Giorgino, Ehab Atallah
Pracinostat, a potent oral pan-histone deacetylase inhibitor with modest single-agent activity in acute myeloid leukemia (AML), has shown synergistic antitumor activity when combined with azacitidine. This single-group, multicenter phase 2 study assessed the safety and efficacy of pracinostat combined with azacitidine in patients who were at least 65 years old with newly diagnosed AML and who were ineligible for standard induction chemotherapy. Patients received pracinostat 60 mg/d, 3 d/wk, for 3 consecutive weeks, plus azacitidine 75 mg/m2 daily for 7 days in a 28-day cycle...
February 26, 2019: Blood Advances
Jonas Samuel Jutzi, Titiksha Basu, Maximilian Pellmann, Sandra Kaiser, Doris Steinemann, Mathijs A Sanders, Adil S A Hinai, Annelieke Zeilemaker, Sarolta Bojtine Kovacs, Christoph Koellerer, Jenny Ostendorp, Konrad Aumann, Wei Wang, Emmanuel Raffoux, Bruno Cassinat, Lars Bullinger, Brigitte Schlegelberger, Peter J M Valk, Heike Luise Pahl
In acute myeloid leukemia (AML), acquired genetic aberrations carry prognostic implications and guide therapeutic decisions. Clinical algorithms have been improved by the incorporation of novel aberrations. Here, we report the presence and functional characterization of mutations in the transcription factor NFE2 in AML patients and in a patient with myelosarcoma. We previously described NFE2 mutations in patients with myeloproliferative neoplasms and demonstrated that expression of mutant NFE2 in mice causes a myeloproliferative phenotype...
February 12, 2019: Blood
Tomasz Wojdyla, Hrishikesh Mehta, Taly Glaubach, Roberto Bertolusso, Marta Iwanaszko, Rosemary Braun, Seth J Corey, Marek Kimmel
Cancer development is driven by series of events involving mutations, which may become fixed in a tumor via genetic drift and selection. This process usually includes a limited number of driver (advantageous) mutations and a greater number of passenger (neutral or mildly deleterious) mutations. We focus on a real-world leukemia model evolving on the background of a germline mutation. Severe congenital neutropenia (SCN) evolves to secondary myelodysplastic syndrome (sMDS) and/or secondary acute myeloid leukemia (sAML) in 30-40%...
January 2019: PLoS Computational Biology
Johannes Schetelig, Liesbeth C de Wreede, Michel van Gelder, Linda Koster, Jürgen Finke, Dietger Niederwieser, Dietrich Beelen, G J Mufti, Uwe Platzbecker, Arnold Ganser, Silke Heidenreich, Johan Maertens, Gerard Socié, Arne Brecht, Matthias Stelljes, Guido Kobbe, Liisa Volin, Arnon Nagler, Antonin Vitek, Thomas Luft, Per Ljungman, Ibrahim Yakoub-Agha, Marie Robin, Nicolaus Kröger
The causes and rates of late patient-mortality following alloHCT for myelodysplastic syndromes or secondary acute myeloid leukemia were studied, to assess the contribution of relapse-related, treatment-related, and population factors. Data from EBMT on 6434 adults, who received a first alloHCT from January 2000 to December 2012, were retrospectively studied using combined land-marking, relative-survival methods and multi-state modeling techniques. Median age at alloHCT increased from 49 to 58 years, and the number of patients aged ≥65 years at alloHCT increased from 5 to 17%...
December 20, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Olga K Weinberg, Robert P Hasserjian
Myelodysplastic syndromes (MDS) are heterogeneous hematopoietic neoplasms that share key clinical and biologic features, including peripheral blood cytopenias, morphologic dysplasia, ineffective and clonal hematopoiesis, and a variable risk of transformation to acute myeloid leukemia. Diagnostic evaluation of MDS relies on morphologic assessment of the peripheral blood and bone marrow, conventional cytogenetics, and exclusion of secondary causes of dysplasia. The diagnosis of MDS has important clinical consequences, but it can be challenging and requires distinction from mimics...
January 2019: Seminars in Hematology
Zi-Jun Xu, Chun-Yan Tang, Jing-Dong Zhou, Ji-Chun Ma, Xiang-Mei Wen, Zhao-Qun Deng, Jia-Yan Leng, Zhi-Yuan Qiu, Jun Qian, Jiang Lin
OBJECTIVE: SOX7 downregulation caused by its promoter methylation was associated with poor survival in several types of human solid tumors. However, the pattern of SOX7 methylation and its clinical significance are less studied in hematological malignancies. Herein, we evaluated the methylation pattern of SOX7 in myelodysplastic syndrome (MDS) and determined its clinical implication in patients with MDS. METHODS: SOX7 methylation was determined by real-time quantitative methylation-specific PCR (RQ-MSP) in 99 MDS patients...
December 6, 2018: Pathology, Research and Practice
Dennis Liang Fei, Tao Zhen, Benjamin Durham, John Ferrarone, Tuo Zhang, Lisa Garrett, Akihide Yoshimi, Omar Abdel-Wahab, Robert K Bradley, Paul Liu, Harold Varmus
Mutations affecting the spliceosomal protein U2AF1 are commonly found in myelodysplastic syndromes (MDS) and secondary acute myeloid leukemia (sAML). We have generated mice that carry Cre-dependent knock-in alleles of U2af1 (S34F), the murine version of the most common mutant allele of U2AF1 encountered in human cancers. Cre-mediated recombination in murine hematopoietic lineages caused changes in RNA splicing, as well as multilineage cytopenia, macrocytic anemia, decreased hematopoietic stem and progenitor cells, low-grade dysplasias, and impaired transplantability, but without lifespan shortening or leukemia development...
October 30, 2018: Proceedings of the National Academy of Sciences of the United States of America
Anna L Godfrey, Peter J Campbell, Cathy MacLean, Georgina Buck, Julia Cook, Julie Temple, Bridget S Wilkins, Keith Wheatley, Jyoti Nangalia, Jacob Grinfeld, Mary Frances McMullin, Cecily Forsyth, Jean-Jacques Kiladjian, Anthony R Green, Claire N Harrison
Purpose Cytoreductive therapy is beneficial in patients with essential thrombocythemia (ET) at high risk of thrombosis. However, its value in those lacking high-risk features remains unknown. This open-label, randomized trial compared hydroxycarbamide plus aspirin with aspirin alone in patients with ET age 40 to 59 years and without high-risk factors or extreme thrombocytosis. Patients and Methods Patients were age 40 to 59 years and lacked a history of ischemia, thrombosis, embolism, hemorrhage, extreme thrombocytosis (platelet count ≥ 1,500 × 109 /L), hypertension, or diabetes requiring therapy...
August 28, 2018: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
G H Lyman, L Yau, R Nakov, A Krendyukov
Background: The use of supportive granulocyte colony-stimulating factor (G-CSF) to reduce the risk of neutropenic complications in high-risk cancer patients is consistently recommended by several clinical practice guidelines. However, in a previous meta-analysis, G-CSF prophylaxis was associated with an increased risk of secondary malignancies while reducing long-term mortality. We present here an updated systematic review and meta-analysis. Materials and methods: A systematic literature search was carried out to identify randomized controlled trials of cancer patients receiving conventional-dose chemotherapy, assigned to primary G-CSF support or a control group without initial G-CSF, with at least 2 years of follow-up...
September 1, 2018: Annals of Oncology: Official Journal of the European Society for Medical Oncology
Eva J Schaefer, R Coleman Lindsley
Clonal hematopoiesis as a hallmark of myelodysplastic syndrome (MDS) is mediated by the selective advantage of clonal hematopoietic stem cells in a context-specific manner. Although primary MDS emerges without known predisposing cause and is associated with advanced age, secondary MDS may develop in younger patients with bone marrow failure syndromes or after exposure to chemotherapy, respectively. This article discusses recent advances in the understanding of context-dependent clonal hematopoiesis in MDS with focus on clonal evolution in inherited and acquired bone marrow failure syndromes...
August 2018: Hematology/oncology Clinics of North America
Amir T Fathi, Harry P Erba, Jeffrey E Lancet, Eytan M Stein, Farhad Ravandi, Stefan Faderl, Roland B Walter, Anjali S Advani, Daniel J DeAngelo, Tibor J Kovacsovics, Anand Jillella, Dale Bixby, Moshe Y Levy, Megan M O'Meara, Phoenix A Ho, Jenna Voellinger, Anthony S Stein
Treatment of acute myeloid leukemia (AML) among the elderly is challenging because of intolerance of intensive therapy and therapy-resistant biology. Hypomethylating agents (HMAs) are commonly used, with suboptimal outcomes. Vadastuximab talirine is a CD33-directed antibody conjugated to pyrrolobenzodiazepine (PBD) dimers. Preclinically, HMAs followed by vadastuximab talirine produced upregulated CD33 expression, increased DNA incorporation by PBD, and enhanced cytotoxicity. A combination cohort in a phase 1 study (NCT01902329) assessed safety, tolerability, and activity of vadastuximab talirine with HMAs...
September 13, 2018: Blood
Anne Bouvier, Bénédicte Ribourtout, Sylvie François, Corentin Orvain, Damien Luque Paz, Annaëlle Beucher, Alexandre Guérard, Philippe Guardiola, Valérie Ugo, Odile Blanchet, Franck Geneviève, Aline Schmidt, Mathilde Hunault-Berger
Donor cell leukemia (DCL) is an infrequent complication after allogeneic hematopoietic stem cell transplantation (HSCT). Its true incidence is difficult to assess, although improvements in chimerism studies contributed to a better diagnosis of DCL. We report two rare cases of donor cell-derived acute promyelocytic leukemia (APL). To our knowledge, only two cases have been described in the literature. Here, we report one male and one female patients with acute myeloid leukemia (AML), who developed an APL in donor cells after HSCT...
October 2018: European Journal of Haematology
Thomas Briot, Emilie Roger, Sylvain Thépot, Frederic Lagarce
Acute myeloid leukemia (AML) is the most common cause of leukemia-related mortality. The combination of cytarabine and anthracycline has been the gold standard of treatment over the past 40 years, but the distribution of the drugs in the body leads to severe adverse effects. Poor prognosis of older patients with AML is the consequence not only of comorbidities, but also of chemoresistance resulting from frequent secondary AML. Numerous strategies using nanotechnologies are in development to improve drug targeting, pharmacokinetics, administration route, chemoresistance, and adverse effects generally observed...
December 2018: Drug Discovery Today
Úrsula Martínez, Thomas H Brandon, Steven K Sutton, Vani N Simmons
OBJECTIVE: Smoking after a diagnosis of cancer can negatively impact treatment outcomes and quality of life. It is important that patients quit smoking and remain abstinent regardless of cancer type. Some cancer types (eg, lung) have stronger links to smoking as a cause than do others (eg, colorectal). The aims of this study were to (1) assess associations between smoking-relatedness of the cancer type with beliefs and attitudes concerning smoking abstinence (eg, confidence, self-efficacy), and (2) assess these variables as predictors of future abstinence...
September 2018: Psycho-oncology
Marta Cabezón, Joan Bargay, Blanca Xicoy, Olga García, Josep Borrás, Mar Tormo, Sílvia Marcé, Carme Pedro, David Valcárcel, Maria-José Jiménez, Ramón Guàrdia, Laura Palomo, Salut Brunet, Ferran Vall-Llovera, Antoni Garcia, Evarist Feliu, Lurdes Zamora
Myelodysplastic syndromes (MDS) are stem cell disorders caused by various gene abnormalities. We performed targeted deep sequencing in 39 patients with high-risk MDS and secondary acute myeloid leukemia (sAML) at diagnosis and follow-up (response and/or relapse), with the aim to define their mutational status, to establish if specific mutations are biomarkers of response to 5-azacytidine (AZA) and/or may have impact on survival. Overall, 95% of patients harbored at least one mutation. TP53, DNMT3A and SRSF2 were the most frequently altered genes...
April 10, 2018: Oncotarget
Taro Noguchi, Miki Nagao, Masaki Yamamoto, Yasufumi Matsumura, Toshiyuki Kitano, Akifumi Takaori-Kondo, Satoshi Ichiyama
BACKGROUND: Staphylococcus epidermidis can cause nosocomial meningitis in the presence of prosthetic devices. We describe a case of Staphylococcus epidermidis meningitis in a patient with neutropenia who had no intracranial foreign body, and we review the literature on meningitis that is caused by coagulase-negative Staphylococcus spp. without a neurosurgical device. CASE PRESENTATION: A 47-year-old Japanese man with acute myeloid leukemia receiving chemotherapy through a totally implantable central venous catheter developed fever and headache...
April 25, 2018: Journal of Medical Case Reports
Andreas Hanssønn Habberstad, Hoa Thi Tuyet Tran, Ulla Randen, Signe Spetalen, Ingunn Dybedal, Geir E Tjønnfjord, Anders Erik Astrup Dahm
BACKGROUND: Polycythemia vera is a myeloproliferative disease that sometimes evolves to myelofibrosis, causing splenomegaly and neutropenia. In this case report, we describe a patient with polycythemia vera and unexplained neutropenia who later turned out to also have hairy cell leukemia. CASE PRESENTATION: A middle-aged Caucasian man with polycythemia vera presented to our hospital with chronic mouth ulcers. Later he developed leukopenia and pancytopenia. Bone marrow biopsies showed fibrosis...
April 24, 2018: Journal of Medical Case Reports
Asangi R Kumarapeli, Murat Gokden
Central nervous system (CNS) hematologic malignancies, whether primary or secondary, are uncommon and their clinical presentations vary. Intravascular lymphoma (IVL) is a very rare, aggressive systemic malignancy that is often difficult to diagnose and susceptible to early CNS involvement. Blast crisis in myeloid leukemias can cause widespread neoplastic emboli. Here, we report two adult patients (72 years and 22 years of age) who presented with altered mental status followed by rapid decline in their conditions leading to death...
March 25, 2018: Diagnostic Cytopathology
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...
May 15, 2018: Cancer
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 Shah, 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...
March 2018: Nature Medicine
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