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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
#1
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...
February 28, 2017: Oncotarget
https://www.readbyqxmd.com/read/28419408/iron-chelating-therapy-with-deferasirox-in-transfusion-dependent-higher-risk-myelodysplastic-syndromes-a-retrospective-multicentre-study
#2
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)...
April 17, 2017: British Journal of Haematology
https://www.readbyqxmd.com/read/28416490/preclinical-characterization-of-bet-family-bromodomain-inhibitor-abbv-075-suggests-combination-therapeutic-strategies
#3
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
#4
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
#5
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
#6
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...
April 10, 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
#7
Aroa Baragaño Raneros, Alfredo Minguela Puras, Ramon M Rodriguez, Enrique Colado, Teresa Bernal, Eduardo Anguita, Adela Vasco Mogorron, Alberto Chaparro Gil, Vidal-Castiñeira Jr, 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)...
March 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/28401097/enhanced-differentiation-of-mesenchymal-stromal-cells-by-three-dimensional-culture-and-azacitidine
#8
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
https://www.readbyqxmd.com/read/28370097/natural-history-of-chronic-myelomonocytic-leukemia-treated-with-hypomethylating-agents
#9
Ana Alfonso, Guillermo Montalban-Bravo, Koichi Takahashi, Elias J Jabbour, Tapan Kadia, Farhad Ravandi, Jorge Cortes, Zeev Estrov, Gautam Borthakur, Naveen Pemmaraju, Marina Konopleva, Carlos Bueso-Ramos, Sherry Pierce, Hagop Kantarjian, Guillermo Garcia-Manero
Hypomethylating agents (HMA) are the most commonly used therapeutic intervention in chronic myelomonocytic leukemia (CMML). Due to the lack of CMML-specific clinical trials, the impact of these agents in the natural history of CMML is not fully understood. We present the largest retrospective series of CMML (n=151) treated with HMA. Mean age at diagnosis was 69 years (range 50-88). According to the CMML-specific prognostic scoring system (CPSS): 17 (15%) were low-risk, 45 (39%) intermediate-1 risk, 42 (36%) intermediate-2, and 12 (10%) high-risk...
March 28, 2017: American Journal of Hematology
https://www.readbyqxmd.com/read/28368509/in-higher-risk-myelodysplastic-syndromes-and-low-blast-count-acute-myeloid-leukemia-results-of-the-bmt-aza-prospective-study
#10
M T Voso, G Leone, A Piciocchi, L Fianchi, S Santarone, A Candoni, M Criscuolo, A Masciulli, E Cerqui, A Molteni, C Finelli, M Parma, A Poloni, A M Carella, F Spina, A Cortelezzi, F Salvi, E P Alessandrino, A Rambaldi, S Sica
Background: Allogeneic stem cell transplantation (HSCT) is the only curative treatment in myelodysplastic syndromes (MDS). Azacitidine (AZA) is increasingly used prior to HSCT, however in Europe it is only approved for patients who are not eligible for HSCT. Patients and Methods: We conducted a phase II multicenter study to prospectively evaluate the feasibility of HSCT after treatment with AZA in 70 patients with a myelodysplastic syndrome (MDS), 19 with acute myeloid leukemia (AML), and 8 with chronic myelomonocytic leukemia (CMML)...
March 29, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/28359286/the-double-edged-sword-of-re-expression-of-genes-by-hypomethylating-agents-from-viral-mimicry-to-exploitation-as-priming-agents-for-targeted-immune-checkpoint-modulation
#11
REVIEW
Florian Wolff, Michael Leisch, Richard Greil, Angela Risch, Lisa Pleyer
Hypomethylating agents (HMAs) have been widely used over the last decade, approved for use in myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML) and acute myeloid leukemia (AML). The proposed central mechanism of action of HMAs, is the reversal of aberrant methylation in tumor cells, thus reactivating CpG-island promoters and leading to (re)expression of tumor suppressor genes. Recent investigations into the mode of action of azacitidine (AZA) and decitabine (DAC) have revealed new molecular mechanisms that impinge on tumor immunity via induction of an interferon response, through activation of endogenous retroviral elements (ERVs) that are normally epigenetically silenced...
March 31, 2017: Cell Communication and Signaling: CCS
https://www.readbyqxmd.com/read/28330901/azacitidine-mitigates-graft-versus-host-disease-via-differential-effects-on-the-proliferation-of-t-effectors-and-natural-regulatory-t-cells-in-vivo
#12
Matthew L Cooper, Jaebok Choi, Darja Karpova, Kiran Vij, Julie Ritchey, Mark A Schroeder, John F DiPersio
Azacitidine (AzaC) mitigates graft-versus-host disease (GvHD) in both murine preclinical transplant models and in human clinical trials while maintaining a robust graft-versus-leukemia effect. Previous studies have failed to investigate the role of natural regulatory T cells (nTregs) on the mitigation of GvHD by AzaC, instead focusing on the generation of suppressive Tregs (CD4(+)CD25(+)FOXP3(+)) through the in vivo conversion of alloreactive donor T effectors (Teffs; CD4(+)CD25(-)FOXP3(-)) and the direct antiproliferative effects of AzaC on allogeneic T cells...
March 22, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28321924/infectious-complications-in-patients-with-myelodysplastic-syndromes-a-review-of-the-literature-with-emphasis-on-patients-treated-with-5-azacitidine
#13
REVIEW
Markus Radsak, Uwe Platzbecker, Cornelia S Schmidt, Wolf-Karsten Hofmann, Florian Nolte
Myelodysplastic Syndromes are oligo-clonal stem cell disorders that are associated with cytopenias in the peripheral blood. Major causes for morbidity and mortality in myelodysplastic syndromes (MDS) patients are infections mostly due to bacteria or fungi. Beside leucopenia per se in affected patients, function of white blood cells particularly that of neutrophils seems to be impaired. Here we summarize the available data on infections in MDS patients in general and particularly those treated with 5-azacitidine...
March 21, 2017: European Journal of Haematology
https://www.readbyqxmd.com/read/28321091/azacitidine-therapy-for-low-risk-myelodysplastic-syndrome-developing-after-solid-organ-transplantation
#14
Hiroaki Inoue, Yasuyoshi Morita, Shinya Rai, Hiroaki Kakutani, Yasuyo Ohyama, Yasuhiro Taniguchi, Hirokazu Tanaka, Takahiro Shimada, Yoichi Tatsumi, Takashi Ashida, Itaru Matsumura
Immunosuppressive therapy after solid organ transplantation is known to be a risk factor for the development of myelodysplastic syndromes (MDS). Herein, we report 2 patients, both of whom developed low-risk MDS after solid organ transplantation and were successfully treated with azacitidine (AZA). The 1st case was a 74-year-old man who had received liver transplantation. The initial immunosuppressive therapy consisted of cyclosporine and prednisolone. Nine years after transplantation, he was diagnosed as having MDS (RCMD)...
2017: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
https://www.readbyqxmd.com/read/28321087/myelodysplastic-syndrome-diagnosed-on-the-occasion-of-fournier-s-gangrene
#15
Masaaki Adachi, Kimiyoshi Mitsuhashi, Hiroyuki Matsuda, Junko Watanabe, Katsuya Nakanishi
Fournier's gangrene (FG) is a fulminant infective necrotizing fasciitis, which includes the genital, perineal, and perianal regions. A 77-year-old man had previously been diagnosed as having diabetes mellitus (DM) and was treated with pioglitazone (15 mg) and miglitol (150 mg). He developed sudden perineal discomfort, fever with painful penile, and scrotal edema, subsequently leading to urinary retention. According to physical examination and CT scan results for the swollen penis and scrotum, he was diagnosed with FG...
2017: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
https://www.readbyqxmd.com/read/28278704/incidence-etiology-and-timing-of-infections-following-azacitidine-therapy-for-myelodysplastic-syndromes
#16
Jason A Trubiano, Michael Dickinson, Karin A Thursky, Timothy Spelman, John F Seymour, Monica A Slavin, Leon J Worth
We examine the infective complications occurring during azacitidine (AZA) therapy in patients with myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). A retrospective review of patients receiving ≥1 cycle of AZA for MDS or AML was performed. Patient demographics, infection prophylaxis/episodes and outcomes were evaluated. Sixty eight patients received 884 AZA cycles. Bacterial infections occurred in 25% of cycle-1 and 27% of cycle-2 AZA therapy. Febrile neutropenia complicated 5.3% of AZA cycles, bacteremia 2% and invasive Aspergillosis 0...
February 28, 2017: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/28217822/how-to-diagnose-early-5-azacytidine-induced-pneumonitis-a-case-report
#17
Srimanta Chandra Misra, Laurence Gabriel, Eric Nacoulma, Gérard Dine, Valentina Guarino
Interstitial pneumonitis is a classical complication of many drugs. Pulmonary toxicity due to 5-azacytidine, a deoxyribonucleic acid methyltransferase inhibitor and cytotoxic drug, has rarely been reported. We report a 67-year-old female myelodysplastic syndrome patient treated with 5-azacytidine at the conventional dosage of 75 mg/m(2) for 7 days. One week after starting she developed moderate fever along with dry cough and subsequently her temperature rose to 39.5 °C. She was placed under broad-spectrum antibiotics based on the protocol for febrile neutropenia, including ciprofloxacin 750 mg twice daily, ceftazidime 1 g three times daily (tid), and sulfamethoxazole/trimethoprim 400 mg/80 mg tid...
December 2017: Drug Safety—Case Reports
https://www.readbyqxmd.com/read/28212292/azacitidine-for-front-line-therapy-of-patients-with-aml-reproducible-efficacy-established-by-direct-comparison-of-international-phase-3-trial-data-with-registry-data-from-the-austrian-azacitidine-registry-of-the-agmt-study-group
#18
Lisa Pleyer, Hartmut Döhner, Hervé Dombret, John F Seymour, Andre C Schuh, C L Beach, Arlene S Swern, Sonja Burgstaller, Reinhard Stauder, Michael Girschikofsky, Heinz Sill, Konstantin Schlick, Josef Thaler, Britta Halter, Sigrid Machherndl Spandl, Armin Zebisch, Angelika Pichler, Michael Pfeilstöcker, Eva M Autzinger, Alois Lang, Klaus Geissler, Daniela Voskova, Wolfgang R Sperr, Sabine Hojas, Inga M Rogulj, Johannes Andel, Richard Greil
We recently published a clinically-meaningful improvement in median overall survival (OS) for patients with acute myeloid leukaemia (AML), >30% bone marrow (BM) blasts and white blood cell (WBC) count ≤15 G/L, treated with front-line azacitidine versus conventional care regimens within a phase 3 clinical trial (AZA-AML-001; NCT01074047; registered: February 2010). As results obtained in clinical trials are facing increased pressure to be confirmed by real-world data, we aimed to test whether data obtained in the AZA-AML-001 trial accurately represent observations made in routine clinical practice by analysing additional AML patients treated with azacitidine front-line within the Austrian Azacitidine Registry (AAR; NCT01595295; registered: May 2012) and directly comparing patient-level data of both cohorts...
February 15, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28209655/mutational-analysis-in-serial-marrow-samples-during-azacitidine-treatment-in-patients-with-post-transplant-relapse-of-acute-myeloid-leukemia-or-myelodysplastic-syndromes
#19
Janghee Woo, Nicholas P Howard, Barry E Storer, Min Fang, Cecilia C Yeung, Bart L Scott, H Joachim Deeg
No abstract text is available yet for this article.
February 16, 2017: Haematologica
https://www.readbyqxmd.com/read/28203345/sweet-s-syndrome-associated-with-clonal-hematopoiesis-of-indeterminate-potential-responsive-to-5-azacitidine
#20
REVIEW
George Yaghmour, Eric Wiedower, Bassam Yaghmour, Sara Nunnery, Eric Duncavage, Mike G Martin
Sweet's syndrome (SS) is a rare condition characterized by the abrupt appearance of painful skin lesions due to neutrophilic dermal infiltration. Hematologic neoplasms, particularly acute myeloid leukemia (AML) and myelodysplastic syndromes (MDSs), have been commonly reported in association with SS. Clonal hematopoiesis of indeterminate potential (CHIP) is an emerging entity that is a precursor state to myeloid neoplasms. CHIP has not been previously associated with SS. We report the case of a 71-year-old man who presented with recurrent, painful edematous and erythematous papules and nodules for 18 months despite treatment with corticosteroids...
February 2017: Therapeutic Advances in Hematology
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