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Azacitidine

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https://www.readbyqxmd.com/read/28546581/a-phase-1b-2b-multicenter-study-of-oral-panobinostat-plus-azacitidine-in-adults-with-mds-cmml-or-aml-with-%C3%A2-30-blasts
#1
G Garcia-Manero, M A Sekeres, M Egyed, M Breccia, C Graux, J D Cavenagh, H Salman, A Illes, P Fenaux, D J DeAngelo, R Stauder, K Yee, N Zhu, J-H Lee, D Valcarcel, A MacWhannell, Z Borbenyi, L Gazi, S Acharyya, S Ide, M Marker, O G Ottmann
Treatment with azacitidine (AZA), a demethylating agent, prolonged overall survival (OS) vs conventional care in patients with higher-risk myelodysplastic syndromes (MDS). As median survival with monotherapy is <2 years, novel agents are needed to improve outcomes. This phase 1b/2b trial (n=113) was designed to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of panobinostat (PAN) + AZA (phase 1b) and evaluate early efficacy and safety of PAN+AZA vs AZA monotherapy (phase 2b) in patients with higher-risk MDS, chronic myelomonocytic leukemia, or oligoblastic acute myeloid leukemia with <30% blasts...
May 26, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28535394/red-blood-cell-alloimmunization-in-184-patients-with-myeloid-neoplasms-treated-with-azacitidine-a-retrospective-single-center-experience
#2
M Leisch, L Weiss, N Lindlbauer, C Jungbauer, A Egle, E Rohde, R Greil, C Grabmer, L Pleyer
Alloimmunization to Red Blood Cell (RBC) antigens frequently occurs in patients with myeloid neoplasms (AML, MDS and CMML) and potentially poses the patient at risk for delayed hemolytic transfusion reactions and limited supply of compatible RBC-units. However, there is comparatively little data on transfusion associated characteristics in this patient cohort. We therefore retrospectively analyzed transfusion requirements and clinical outcomes of 184 patients with myloid neoplasms treated with azacitidine at the Paracelsus Medical University Salzburg, which were included in the Austrian Registry of Hypomethylating Agents...
May 9, 2017: Leukemia Research
https://www.readbyqxmd.com/read/28514758/bcl2l10-positive-cells-in-bone-marrow-are-an-independent-prognostic-factor-of-azacitidine-outcome-in-myelodysplastic-syndrome-and-acute-myeloid-leukemia
#3
Valérie Vidal, Guillaume Robert, Laure Goursaud, Laetitia Durand, Clemence Ginet, Jean Michel Karsenti, Frederic Luciano, Lauris Gastaud, Georges Garnier, Thorsten Braun, Pierre Hirsch, Emmanuel Raffoux, Anne Marie Nloga, Rose Ann Padua, Hervé Dombret, Pierre Rohrlich, Lionel Ades, Christine Chomienne, Patrick Auberger, Pierre Fenaux, Thomas Cluzeau
Azacitidine (AZA), the reference treatment for most higher-risk myelodysplastic (MDS) patients can also improve overall survival (OS) in elderly acute myeloid leukemia (AML) patients ineligible for intensive chemotherapy, but reliable biological markers predicting response and OS in patients treated with AZA are lacking. In a preliminary study, we found that an increase of the percentage of BCL2L10, an anti-apoptotic member of the bcl-2 family, was correlated with AZA resistance. In this study, we assessed prospectively by flow cytometry the prognostic value of BCL2L10 positive bone marrow mononuclear cells in 70 patients (42 MDS and 28 AML), prior to AZA treatment...
April 27, 2017: Oncotarget
https://www.readbyqxmd.com/read/28505595/epigenetic-drug-combination-induces-remission-in-mouse-xenograft-models-of-pediatric-acute-myeloid-leukemia
#4
Anilkumar Gopalakrishnapillai, E Anders Kolb, Suzanne M McCahan, Sonali P Barwe
Aberrations in epigenetic modifications contribute to leukemogenesis in childhood acute myeloid leukemia (AML). We combined DNA hypomethylating agent azacitidine with histone deacetylase inhibitor panobinostat in preclinical models of childhood AML. Synergistic cytotoxic effect upon treatment with azacitidine and panobinostat with combination indices <1.0 was observed. Azacitidine and panobinostat increased median survival by 26 and 6days respectively in MV4;11 xenografted mice. Mice treated with both drugs showed a drastic reduction in leukemic burden leading to complete remission sustained for the duration of the experimental period lasting more than 519days...
May 5, 2017: Leukemia Research
https://www.readbyqxmd.com/read/28502936/successful-treatment-of-beh%C3%A3-et-s-disease-associated-with-acute-myeloid-leukemia-with-myelodysplasia-related-changes-using-azacitidine-and-tacrolimus-before-allogeneic-hematopoietic-stem-cell-transplantation
#5
Yukinori Nakamura, Masafumi Matsuguma, Yoshihiro Tokunaga, Kaoru Yamamoto, Mayumi Tanaka, Yoshinori Tanaka, Toshiaki Yujiri, Yukio Tanizawa
The coexistence of acute myeloid leukemia (AML) with Behçet's disease (BD) is rare. The optimum treatment for AML-associated BD has not been established. We herein report a patient with BD who developed AML with myelodysplasia-related changes. Induction chemotherapy caused complete remission of the AML but worsened the BD. Thereafter, AML was treated with azacitidine. The BD was steroid-dependent. Tacrolimus was added, which improved the BD. The patient underwent allogeneic hematopoietic stem cell transplantation (HSCT) and remains in complete remission for both diseases...
2017: Internal Medicine
https://www.readbyqxmd.com/read/28494506/minimal-residual-disease-eradication-with-epigenetic-therapy-in-core-binding-factor-acute-myeloid-leukemia
#6
Brittany Knick Ragon, Naval Daver, Guillermo Garcia-Manero, Farhad Ravandi, Jorge Cortes, Tapan Kadia, Betul Oran, Maro Ohanian, Alessandra Ferrajoli, Naveen Pemmaraju, Hagop M Kantarjian, Gautam Borthakur
Recurrent translocations, t(8;21) or inv(16), in core binding factor acute myeloid leukemia (CBF-AML) are amenable to monitoring for minimal residual disease (MRD) with reverse transcriptase polymerase chain reaction (RTPCR). Despite a favorable prognosis, disease relapse remains the single cause of treatment failure in CBF-AML. Fusion products of these translocations recruit epigenetic silencing complexes resulting in hematopoietic maturation arrest. We hypothesized that maintenance therapy with hypomethylating agents (HMA), including decitabine (DAC) and azacitidine (AZA) after induction/consolidation, can be used for MRD elimination to ultimately prolong relapse free survival...
May 11, 2017: American Journal of Hematology
https://www.readbyqxmd.com/read/28491035/proteomic-analysis-reveals-autophagy-as-pro-survival-pathway-elicited-by-long-term-exposure-with-5-azacitidine-in-high-risk-myelodysplasia
#7
Alessandra Romano, Cesarina Giallongo, Piera La Cava, Nunziatina L Parrinello, Antonella Chiechi, Calogero Vetro, Daniele Tibullo, Francesco Di Raimondo, Lance A Liotta, Virginia Espina, Giuseppe A Palumbo
Azacytidine (5-AZA) is the standard first-choice treatment for high-risk myelodysplasia (MDS) patients. However, the clinical outcome for those patients who interrupt treatment or whose disease failed to respond is very poor. In order to identify the cellular pathways that are modified by long-term exposure to 5-AZA, we evaluated key proteins associated with the autophagy pathway by reverse-phase microarray (RPPA). Comparing bone marrow mononucleated cells (BMMCs) obtained from 20 newly-diagnosed patients and after four 5-AZA cycles we found an increased autophagy signaling...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/28486212/anti-oxidative-and-anti-inflammatory-benefits-of-the-ribonucleoside-analogue-5-azacitidine-in-mice-with-acetaminophen-induced-toxic-hepatitis
#8
Changming Yang, Jun Yi, Xianqiong Gong, Pu Ge, Jie Dai, Ling Lin, Yu Xing, Li Zhang
Toxic hepatitis induced by overdose of acetaminophen (APAP) is one of the major life-threatening problems, oxidative stress and inflammatory injury are the essential underlying mechanisms. 5-Azacytidine (5-AZA) is a ribonucleoside analogue which has been approved for the treatment of patients with acute myeloid leukemia and myelodyplastic syndrome, but recent studies also found that 5-AZA might have anti-oxidative and anti-inflammatory benefits in non-tumor disorders. In the present study, the potential effects of 5-AZA on APAP-induced toxic hepatitis were investigated in a mouse model in vivo...
May 6, 2017: International Immunopharmacology
https://www.readbyqxmd.com/read/28486043/randomized-phase-ii-study-of-azacitidine-alone-or-in-combination-with-lenalidomide-or-with-vorinostat-in-higher-risk-myelodysplastic-syndromes-and-chronic-myelomonocytic-leukemia-north-american-intergroup-study-swog-s1117
#9
Mikkael A Sekeres, Megan Othus, Alan F List, Olatoyosi Odenike, Richard M Stone, Steven D Gore, Mark R Litzow, Rena Buckstein, Min Fang, Diane Roulston, Clara D Bloomfield, Anna Moseley, Aziz Nazha, Yanming Zhang, Mario R Velasco, Rakesh Gaur, Ehab Atallah, Eyal C Attar, Elina K Cook, Alyssa H Cull, Michael J Rauh, Frederick R Appelbaum, Harry P Erba
Purpose Azacitidine is standard, first-line therapy in higher-risk myelodysplastic syndromes (MDS). Whether azacitidine-based combinations with lenalidomide or vorinostat produce superior overall response rates (ORRs) to azacitidine is not known. Patients and Methods North American Intergroup Study S1117 is a phase II/III trial that randomly assigned patients with higher-risk MDS and chronic myelomonocytic leukemia (CMML) 1:1:1 to azacitidine (75 mg/m(2)/day on days 1 to 7 of a 28-day cycle); azacitidine plus lenalidomide (10 mg/day on days 1 to 21); or azacitidine plus vorinostat (300 mg twice daily on days 3 to 9)...
May 9, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/28484169/current-diagnosis-and-treatment-for-myelodysplastc-syndromes
#10
Tomoko Hata
Genetic analysis of myelodysplastic syndrome (MDS) using next-generation sequencing yields medcially important information, showing gene mutations in 90% of MDS cases. The World Health Organization (WHO) classification was revised in 2016 to incorporate SF3B1 gene mutations, frequently seen in MDS with ringed sideroblasts, into the diagnostic criteria. Unlike the poor prognosis seen in cases with ASXL1, EZH2, RUNX1 and in particular, TP53 MDS-related mutations, SF3B1 gene mutations show a favorable prognosis...
2017: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
https://www.readbyqxmd.com/read/28474744/outcome-of-elderly-patients-after-failure-to-hypomethylating-agents-given-as-frontline-therapy-for-acute-myeloid-leukemia-aml-single-institution-experience
#11
Rama Nanah, Kristen McCullough, William Hogan, Kebede Begna, Mrinal Patnaik, Michelle Elliott, Mark Litzow, Aref Al-Kali
Outcomes of acute myeloid leukemia (AML) in elderly patients unfit for intensive chemotherapy is challenging. Hypomethylating agents (HMAs) can be effective in these patients but responses are usually short-lived. The majority of patients will either have stable disease or progress through therapy. We hereby describe the outcome of these patients at our institution after they fail HMAs. The data on 56 AML patients at Mayo Clinic, Rochester were reviewed. Patients were considered for our study if they received HMA as frontline therapy for their AML...
May 5, 2017: American Journal of Hematology
https://www.readbyqxmd.com/read/28474144/a-retrospective-study-evaluating-the-impact-of-infectious-complications-during-azacitidine-treatment
#12
Anna Schuck, Marie-Christine Goette, Judith Neukirchen, Andrea Kuendgen, Norbert Gattermann, Thomas Schroeder, Guido Kobbe, Ulrich Germing, Rainer Haas
Azacitidine has become an available therapy for high-risk myelodysplastic syndromes. Infectious complications (IC) may impede the success of therapy. Since most patients are managed in an outpatient setting, often with low level of clinical and microbiological documentation, the impact of IC remains unclear. We retrospectively evaluated the clinical course of 77 patients with MDS treated with azacitidine between 2004 and 2015 (median age 69 years). Clinical workup included severity and type of IC, days in the hospital and with antimicrobial therapy, response to azacitidine, and overall survival (OS)...
May 4, 2017: Annals of Hematology
https://www.readbyqxmd.com/read/28427179/comprehensive-mapping-of-the-effects-of-azacitidine-on-dna-methylation-repressive-permissive-histone-marks-and-gene-expression-in-primary-cells-from-patients-with-mds-and-mds-related-disease
#13
Magnus Tobiasson, Hani Abdulkadir, Andreas Lennartsson, Shintaro Katayama, Francesco Marabita, Ayla De Paepe, Mohsen Karimi, Kaarel Krjutskov, Elisabet Einarsdottir, Michael Grövdal, Monika Jansson, Asmaa Ben Azenkoud, Lina Corddedu, Sören Lehmann, Karl Ekwall, Juha Kere, Eva Hellström-Lindberg, Johanna Ungerstedt
Azacitidine (Aza) is first-line treatment for patients with high-risk myelodysplastic syndromes (MDS), although its precise mechanism of action is unknown. We performed the first study to globally evaluate the epigenetic effects of Aza on MDS bone marrow progenitor cells assessing gene expression (RNA seq), DNA methylation (Illumina 450k) and the histone modifications H3K18ac and H3K9me3 (ChIP seq). Aza induced a general increase in gene expression with 924 significantly upregulated genes but this increase showed no correlation with changes in DNA methylation or H3K18ac, and only a weak association with changes in H3K9me3...
April 25, 2017: Oncotarget
https://www.readbyqxmd.com/read/28419408/iron-chelating-therapy-with-deferasirox-in-transfusion-dependent-higher-risk-myelodysplastic-syndromes-a-retrospective-multicentre-study
#14
Pellegrino Musto, Luca Maurillo, Vittorio Simeon, Antonella Poloni, Carlo Finelli, Enrico Balleari, Alessandra Ricco, Flavia Rivellini, Agostino Cortelezzi, Giuseppe Tarantini, Oreste Villani, Giovanna Mansueto, Maria R Milella, Daniele Scapicchio, Gioacchino Marziano, Massimo Breccia, Pasquale Niscola, Alessandro Sanna, Cristina Clissa, Maria T Voso, Susanna Fenu, Adriano Venditti, Valeria Santini, Emanuele Angelucci, Alessandro Levis
Iron chelation is controversial in higher risk myelodysplastic syndromes (HR-MDS), outside the allogeneic transplant setting. We conducted a retrospective, multicentre study in 51 patients with transfusion-dependent, intermediate-to-very high risk MDS, according to the revised international prognostic scoring system, treated with the oral iron chelating agent deferasirox (DFX). Thirty-six patients (71%) received azacitidine concomitantly. DFX was given at a median dose of 1000 mg/day (range 375-2500 mg) for a median of 11 months (range 0·4-75)...
June 2017: British Journal of Haematology
https://www.readbyqxmd.com/read/28416490/preclinical-characterization-of-bet-family-bromodomain-inhibitor-abbv-075-suggests-combination-therapeutic-strategies
#15
Mai H Bui, Xiaoyu Lin, Daniel H Albert, Leiming Li, Lloyd T Lam, Emily J Faivre, Scott Warder, Xiaoli Huang, Denise Wilcox, Cherrie K Donawho, George S Sheppard, Le Wang, Steve Fidanze, John K Pratt, Dachun Liu, Lisa Hasvold, Tamar Uziel, Xin Lu, Fred Kohlhapp, Guowei Fang, Steven W Elmore, Saul H Rosenberg, Keith F McDaniel, Warren M Kati, Yu Shen
ABBV-075 is a potent and selective BET family bromodomain inhibitor that recently entered Phase I clinical trials. Comprehensive preclinical characterization of ABBV-075 demonstrated broad activity across cell lines and tumor models representing a variety of hematological malignancies and solid tumor indications. In most cancer cell lines derived from solid tumors, ABBV-075 triggers prominent G1 cell cycle arrest without extensive apoptosis. In this study, we show that ABBV-075 efficiently triggers apoptosis in acute myeloid leukemia (AML), non-Hodgkin's lymphoma (NHL) and multiple myeloma (MM) cells...
April 17, 2017: Cancer Research
https://www.readbyqxmd.com/read/28415946/azacitidine-induced-acute-lung-injury-in-a-patient-with-therapy-related-myelodysplastic-syndrome
#16
Shinichi Makita, Wataru Munakata, Daisuke Watabe, Akiko Miyagi Maeshima, Hirokazu Taniguchi, Kosuke Toyoda, Nobuhiko Yamauchi, Suguru Fukuhara, Dai Maruyama, Yukio Kobayashi, Kensei Tobinai
Azacitidine is a first-in-class demethylating agent, and it is widely used globally as a first-line treatment for higher-risk myelodysplastic syndrome (MDS). Here, we report the case of a patient with MDS who suffered from a rare adverse event, an acute lung injury (ALI), which was suspected to have been caused by azacitidine and was successfully treated with corticosteroids. As it is a rare, but critical, adverse event, clinicians should consider ALI as one of the differential diagnoses in cases where 1) pneumonia and fever of unknown etiology arise in MDS patients treated with azacitidine, 2) antimicrobial agents are not effective, and 3) microbiological tests produce negative results...
April 2017: Journal of International Medical Research
https://www.readbyqxmd.com/read/28415666/azacitidine-or-intensive-chemotherapy-for-older-patients-with-secondary-or-therapy-related-acute-myeloid-leukemia
#17
Pierre-Yves Dumas, Sarah Bertoli, Emilie Bérard, Clémence Médiavilla, Edwige Yon, Suzanne Tavitian, Thibaut Leguay, Françoise Huguet, Edouard Forcade, Noël Milpied, Audrey Sarry, Mathieu Sauvezie, Pierre Bories, Arnaud Pigneux, Christian Récher
The treatment of older patients with acute myeloid leukemia that is secondary to previous myelodysplastic syndrome, myeloproliferative neoplasm, or prior cytotoxic exposure remains unsatisfactory. We compared 92 and 107 patients treated, respectively, with intensive chemotherapy or azacitidine within two centres. Diagnoses were 37.5% post-myelodysplastic syndrome, 17.4% post-myeloproliferative neoplasia, and 45.1% therapy-related acute myeloid leukemia. Patients treated by chemotherapy had less adverse cytogenetics, higher white blood-cell counts, and were younger: the latter two being independent factors entered into the multivariate analyses...
March 7, 2017: Oncotarget
https://www.readbyqxmd.com/read/28407579/plga-peg-nano-delivery-system-for-epigenetic-therapy
#18
Asia Naz, Yi Cui, Christopher J Collins, David H Thompson, Joseph Irudayaraj
Efficient delivery of cytidine analogues such as Azacitidine (AZA) into solid tumors constitutes a primary challenge in epigenetic therapies. We developed a di-block nano-vector based on poly(lactic-co-glycolic acid) (PLGA) and poly(ethylene glycol) (PEG) for stabilization of the conjugated AZA under physiological conditions. With equimolar drug content, our nano-conjugate could elicit a better anti-proliferative effect over free drug in breast cancer both in vitro and in vivo, through reactivation of p21 and BRCA1 to restrict cell proliferation...
June 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28404876/increasing-timp3-expression-by-hypomethylating-agents-diminishes-soluble-mica-micb-and-ulbp2-shedding-in-acute-myeloid-leukemia-facilitating-nk-cell-mediated-immune-recognition
#19
Aroa Baragaño Raneros, Alfredo Minguela Puras, Ramon M Rodriguez, Enrique Colado, Teresa Bernal, Eduardo Anguita, Adela Vasco Mogorron, Alberto Chaparro Gil, Jose Ramon Vidal-Castiñeira, Leonardo Márquez-Kisinousky, Paula Díaz Bulnes, Amelia Martinez Marin, Maria Carmen García Garay, Beatriz Suarez-Alvarez, Carlos Lopez-Larrea
Acute myeloid leukemia (AML) is a disease with great morphological and genetic heterogeneity, which complicates its prognosis and treatment. The hypomethylating agents azacitidine (Vidaza®, AZA) and decitabine (Dacogen®, DAC) have been approved for the treatment of AML patients, but their mechanisms of action are poorly understood. Natural killer (NK) cells play an important role in the recognition of AML blasts through the interaction of the activating NKG2D receptor with its ligands (NKG2DL: MICA/B and ULBPs1-3)...
May 9, 2017: Oncotarget
https://www.readbyqxmd.com/read/28401097/enhanced-differentiation-of-mesenchymal-stromal-cells-by-three-dimensional-culture-and-azacitidine
#20
Yoo-Jin Bae, Yong-Rim Kwon, Hye Joung Kim, Seok Lee, Yoo-Jin Kim
BACKGROUND: Mesenchymal stromal cells (MSCs) are useful for cell therapy because of their potential for multilineage differentiation. However, MSCs that are expanded in traditional two-dimensional (2D) culture systems eventually lose their differentiation abilities. Therefore, we investigated whether azacitidine (AZA) supplementation and three-dimensional culture (3D) could improve the differentiation properties of MSCs. METHODS: 2D- or 3D-cultured MSCs which were prepared according to the conventional or hanging-drop culture method respectively, were treated with or without AZA (1 µM for 72 h), and their osteogenic and adipogenic differentiation potential were determined and compared...
March 2017: Blood Research
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