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Irina A Tikhonova, Martin W Hoyle, Tristan M Snowsill, Chris Cooper, Joanna L Varley-Campbell, Claudius E Rudin, Ruben E Mujica Mota
The National Institute for Health and Care Excellence (NICE) invited the manufacturer of azacitidine (Celgene) to submit evidence for the clinical and cost effectiveness of this drug for the treatment of acute myeloid leukaemia with more than 30 % bone marrow blasts in adults who are not eligible for haematopoietic stem cell transplantation, as part of the NICE's Single Technology Appraisal process. The Peninsula Technology Assessment Group was commissioned to act as the Evidence Review Group (ERG). The ERG produced a critical review of the evidence contained within the company's submission to NICE...
October 17, 2016: PharmacoEconomics
Nikolai A Podoltsev, Maximilian Stahl, Amer M Zeidan, Steven D Gore
More than half of the patients with acute myeloid leukaemia (AML) are older than 60years. The treatment outcomes in this group remain poor with a median overall survival of <1year. Selecting initial treatment for these patients involves an assessment of 'fitness' for induction chemotherapy. This is done based on patient and disease-related characteristics which help to estimate treatment-related mortality and chance of complete remission with induction chemotherapy. If the risk of treatment-related mortality is high and/or the likelihood of a patient achieving a complete remission is low, lower-intensity treatment (low-dose cytarabine, decitabine and azacitidine) should be discussed...
October 8, 2016: Blood Reviews
John F Seymour, Hartmut Döhner, Mark D Minden, Richard Stone, Dominique Gambini, Donna Dougherty, C L Beach, Jerry Weaver, Hervé Dombret
Relative risks of treatment-emergent adverse events (TEAEs) and related hospitalization is most accurate when accounting for treatment exposure. AZA-AML-001 showed azacitidine (AZA) prolonged overall survival versus conventional care regimens (CCR) in older patients (≥65 years) with acute myeloid leukemia (AML) by 3.9 months. Preselection of CCR before study randomization allows evaluation of AZA safety in patient subgroups with similar clinical features. Within preselection groups, AZA exposure was greater than each CCR...
October 14, 2016: Leukemia & Lymphoma
Beejal R Ganti, Bernard L Marini, Jerod Nagel, Dale Bixby, Anthony J Perissinotti
PURPOSE: This study evaluated the impact of antibacterial prophylaxis with levofloxacin in relapsed/refractory acute myeloid leukemia (AML) patients. METHODS: This was a retrospective, single-center, cohort study. Adult patients with relapsed/refractory AML admitted for reinduction chemotherapy between November 1, 2006 and June 15, 2015 were screened for inclusion. A protocol initiating levofloxacin prophylaxis was implemented on December 1, 2013. Patients receiving hypomethylating agents (decitabine/azacitidine) were not administered antibacterial prophylaxis and thus not included in this analysis...
October 14, 2016: Supportive Care in Cancer: Official Journal of the Multinational Association of Supportive Care in Cancer
Martin Wermke, Claudia Schuster, Florian Nolte, Haifa-Kathrin Al-Ali, Philipp Kiewe, Claudia Schönefeldt, Christiane Jakob, Malte von Bonin, Leopold Hentschel, Ina-Maria Klut, Gerhard Ehninger, Martin Bornhäuser, Gustavo Baretton, Ulrich Germing, Regina Herbst, Detelef Haase, Wolf K Hofmann, Uwe Platzbecker
The mammalian-target of rapamycin (also termed mechanistic target of rapamycin, mTOR) pathway integrates various pro-proliferative and anti-apoptotic stimuli and is involved in regulatory T-cell (TREG) development. As these processes contribute to the pathogenesis of myelodysplastic syndromes (MDS), we hypothesized that mTOR modulation with temsirolimus (TEM) might show activity in MDS. This prospective multicentre trial enrolled lower and higher risk MDS patients, provided that they were transfusion-dependent/neutropenic or relapsed/refractory to 5-azacitidine, respectively...
October 7, 2016: British Journal of Haematology
Aleksandra Butrym, Justyna Rybka, Dagmara Baczyńska, Rafał Poręba, Grzegorz Mazur, Kazimierz Kuliczkowski
MicroRNAs (miRs) are small non-coding RNAs that play important roles in cell differentiation and survival. Abnormal expression of miRs has been demonstrated in numerous types of cancer, including acute myeloid leukaemia (AML). The aim of the present study was to evaluate miR-181 expression at diagnosis and following the completion of chemotherapy in AML patients, with regard to clinical response and outcome, particularly in patients treated with azacitidine. miR-181 expression was analysed using reverse transcription-quantitative polymerase chain reaction in 95 bone marrow specimens from newly diagnosed AML patients and in 20 healthy subjects for comparison...
October 2016: Oncology Letters
Xiao Huang, Guiqing Kong, Yan Li, Weiwei Zhu, Haixiao Xu, Xiaohua Zhang, Jiankui Li, Lipeng Wang, Zhongwen Zhang, Yaru Wu, Xiangyong Liu, Xiaozhi Wang
Decitabine (5-aza-2'-deoxycytidine, DAC) and 5-azacitidine (Aza), an inhibitor of DNA methyltransferases, possess a wide range of anti-metabolic and anti-cancer activities. This study examined the effects of DAC and Aza on inflammatory and oxidative injuries, as well as on glycocalyx and MAPK signaling pathways, in a LPS-stimulated ARDS mouse model. Results of ELISA revealed that DAC and Aza significantly inhibited the production of TNF-α and IL-1β and prevented LPS-induced elevation of myeloperoxidase and malondialdehyde levels in serum...
September 26, 2016: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Marios Dimitriou, Petter S Woll, Teresa Mortera-Blanco, Mohsen Karimi, David C Wedge, Helen Doolittle, Iyadh Douagi, Elli Papaemmanuil, Sten Eirik W Jacobsen, Eva Hellström-Lindberg
The stem and progenitor cell compartments in low- and intermediate-risk myelodysplastic syndromes (MDS) have recently been described, and shown to be highly conserved when compared to those in acute myeloid leukemia (AML). Much less is known about the characteristics of the hematopoietic hierarchy of subgroups of MDS with a high risk of transforming to AML. Immunophenotypic analysis of immature stem and progenitor cell compartments from patients with an isolated loss of the entire chromosome 7 (isolated -7), an independent high-risk genetic event in MDS, showed expansion and dominance of the malignant -7 clone in the granulocyte and macrophage progenitors (GMP), and other CD45RA+ progenitor compartments, and a significant reduction of the LIN-CD34+CD38low/-CD90+CD45RA- hematopoietic stem cell (HSC) compartment, highly reminiscent of what is typically seen in AML, and distinct from low-risk MDS...
September 24, 2016: Oncotarget
Michael Leung, Kaitlin Highsmith, Amber Rexwinkle
Myelofibrosis is a BCR-ABL-negative myeloproliferative neoplasm characterized by abnormal hematopoiesis. Alterations to the Janus kinase-signal transducer and activator of transcription pathway result in dysregulation of gene transcription and cell proliferation. Patients with symptomatic myelofibrosis present with a variety of signs and symptoms including, but not limited to myelosuppression, marked splenomegaly, abdominal discomfort, fatigue, and blood transfusion-dependence. Traditional myelosuppressive therapies including hydroxyurea, azacitidine, and cladribine aim to reduce constitutional symptoms and control the burden of disease...
September 26, 2016: Journal of Oncology Pharmacy Practice
Marta Garcia-Recio, Jordi Martinez-Serra, Leyre Bento, Rafael Ramos, Jordi Gines, Jaime Daumal, Antonia Sampol, Antonio Gutierrez
Blastic plasmocytoid dendritic cell neoplasm is characterized by aggressive behavior with a tendency for systemic dissemination and a predilection for skin, lymph nodes, soft tissues, peripheral blood, or bone marrow. It usually occurs in elderly patients with a mean age between 60 and 70 years. Despite initial response to chemotherapy, the disease regularly relapses with a short median overall survival. Better outcomes have been reported with high-dose acute leukemia-like induction chemotherapy followed by consolidation with allogeneic hematopoietic stem cell transplantation...
2016: OncoTargets and Therapy
Eunsohl Lee, Jingcheng Wang, Kenji Yumoto, Younghun Jung, Frank C Cackowski, Ann M Decker, Yan Li, Renny T Franceschi, Kenneth J Pienta, Russell S Taichman
Cancer metastasis is a multistep process associated with the induction of an epithelial-mesenchymal transition (EMT) and cancer stem cells (CSCs). Although significant progress has been made in understanding the molecular mechanisms regulating EMT and the CSC phenotype, little is known of how these processes are regulated by epigenetics. Here we demonstrate that reduced expression of DNA methyltransferase 1 (DNMT1) plays an important role in the induction of EMT and the CSC phenotype by prostate cancer (PCa) cells, with enhanced tumorigenesis and metastasis...
September 2016: Neoplasia: An International Journal for Oncology Research
Amer M Zeidan, Amy J Davidoff, Jessica B Long, Xin Hu, Rong Wang, Xiaomei Ma, Cary P Gross, Gregory A Abel, Scott F Huntington, Nikolai A Podoltsev, Uno Hajime, Thomas Prebet, Steven D Gore
The hypomethylating agents (HMAs) azacitidine and decitabine are both approved for treatment of myelodysplastic syndromes (MDS) in the USA. In Europe, decitabine is not approved due to lack of survival advantage in randomized trials. The two drugs have not been compared in clinical trials. We identified patients diagnosed with MDS between 2004 and 2011 from the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database in the USA who received ≥ 10 doses of either HMA. We estimated survival from HMA initiation with Kaplan-Meier methods and used multivariate Cox proportional hazards models to adjust for covariates...
September 21, 2016: British Journal of Haematology
A K Burnett, N H Russell, R K Hills, J Kell, O J Nielsen, M Dennis, P Cahalin, C Pocock, S Ali, S Burns, S Freeman, D Milligan, R E Clark
The study was designed to compare clofarabine plus daunorubicin versus daunorubicin/ara-C in older patients with acute myeloid leukaemia (AML) or high-risk myelodysplastic syndrome (MDS). Eight hundred and six untreated patients in the UK NCRI AML16 trial with AML/high-risk MDS (median age, 67yrs; range 56-84) and normal serum creatinine were randomised to two courses of induction chemotherapy with either daunorubicin/ara-C (DA) or daunorubicin/clofarabine (DClo). Patients were also included in additional randomisations; +/- one dose of gemtuzumab ozogamicin in course 1; 2v3 courses and +/- azacitidine maintenance...
September 2, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Tomoyasu Yoshihiro, Tsuyoshi Muta, Kenichi Aoki, Syo Shimamoto, Yasuhisa Tamura, Ryosuke Ogawa
We describe two hemodialysis patients with high-risk myelodysplastic syndrome (MDS) treated with azacitidine. A 65-year-old woman (case 1) received azacitidine at 75 mg/m(2) for 7 days, and a 52-year-old man (case 2) with liver cirrhosis received a 70% dose of azacitidine. Both cases developed grade 4 cytopenia, but they achieved transfusion independence after 3 and 2 courses, and the durations of remission were 10 and 11 months, respectively. Case 1 had the complication of febrile neutropenia (FN) twice during the 1(st) and 2(nd) courses, but continued to receive azacitidine treatment thereafter...
August 2016: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
Moshe Mittelman, Kalman Filanovsky, Yishai Ofran, Hanna Rosenbaum, Pia Raanani, Andrei Braester, Neta Goldschmidt, Ilya Kirgner, Yair Herishanu, Chava Perri, Martin Ellis, Howard S Oster
Azacitidine treatment is effective in higher risk MDS (HR-MDS), with less than 50 % response, lasting 2 years. Aza and lenalidomide (Len) have a potential synergistic effect. ViLen-01 phase IIa trial includes 6-month induction (Aza 75 mg/m(2)/day, days 1-5, Len 10 mg/day, days 6-21, every 28 days), 6-month consolidation (Aza 75 mg/m(2)/day, days 1-5, every 28 days), and 12-month maintenance (Len 10 mg/day, days 1-21, every 28 days). Response was evaluated according to IWG criteria. Totally, 25 patients enrolled, with an average of 76...
October 2016: Annals of Hematology
Michael J Overman, Van Morris, Helen Moinova, Ganiraju Manyam, Joe Ensor, Michael S Lee, Cathy Eng, Bryan Kee, David Fogelman, Rachna T Shroff, Thomas LaFramboise, Thibault Mazard, Tian Feng, Stanley Hamilton, Bradley Broom, James Lutterbaugh, Jean-Pierre Issa, Sanford D Markowitz, Scott Kopetz
PURPOSE: Hypermethylation of promoter CpG islands (CIMP) has been strongly implicated in chemotherapy resistance and is implicated in the pathogenesis of a subset of colorectal cancers (CRCs) termed CIMP-high. EXPERIMENTAL DESIGN: This phase I/II study in CRC (phase II portion restricted to CIMP-high CRC), treated fluoropyrimidine/oxaliplatin refractory patients with azacitidine (75 mg/m2/day subcutaneously D1-5) and CAPOX (capecitibine and oxaliplatin) every three weeks...
August 16, 2016: Oncotarget
Nicolas Waespe, Machiel Van Den Akker, Robert J Klaassen, Lani Lieberman, Meredith S Irwin, Salah S Ali, Mohamed Abdelhaleem, Bozana Zlateska, Mira Liebman, Michaela Cada, Tal Schechter, Yigal Dror
Advanced myelodysplastic syndrome harbors a high risk of progression to acute myeloid leukemia and poor prognosis. In children, there is no established treatment to prevent or delay progression to leukemia prior to hematopoietic stem cell transplantation. Azacitidine is a hypomethylating agent, which was shown to slow progression to leukemia in adults with myelodysplastic syndrome. There is little data on the efficacy of azacitidine in children. We reviewed 22 pediatric patients with advanced myelodysplastic syndrome from a single center, diagnosed between January 2000 and December 2015...
August 18, 2016: Haematologica
Mintallah Haider, Najla Al Ali, Eric Padron, Pearlie Epling-Burnette, Jeffrey Lancet, Alan List, Rami Komrokji
BACKGROUND: Immunosuppressive therapy (IST) in low risk myelodysplastic syndrome (MDS) is known to achieve hematologic improvement but remains an underutilized treatment option. We report our experience using antithymocyte globulin (ATG) and cyclosporine A (CSA) to explore clinical predictive response factors. PATIENTS AND METHODS: Patients treated with IST identified in the Moffitt Cancer Center MDS database were analyzed using baseline data, IST details, and response rates...
August 2016: Clinical Lymphoma, Myeloma & Leukemia
Rami S Komrokji
The higher risk myelodysplastic syndrome (MDS) patients, defined by the International Prognostic Scoring System (IPSS) as intermediate-2 or high-risk groups, compromise a third of MDS patients who have an expected survival of less than 1.5 years. Our ability to better define higher risk MDS improved with the proposal of new clinical risk models such as the revised IPSS and by integration of molecular data, including somatic gene mutations. Allogeneic hematopoietic stem-cell transplantation (AHSCT) remains the only curative option...
August 2016: Clinical Lymphoma, Myeloma & Leukemia
Armin Ghobadi, Jaebok Choi, Mark A Fiala, Theresa Fletcher, Jingxia Liu, Linda G Eissenberg, Camille Abboud, Amanda Cashen, Ravi Vij, Mark A Schroeder, Iskra Pusic, Keith Stockerl-Goldstein, Meagan Jacoby, Geoffrey Uy, John DiPersio, Peter Westervelt
Donor lymphocyte infusion (DLI) without prophylactic immunosuppression has been used for relapsed AML after allogeneic stem cell transplant (allo-SCT). However DLI is associated with an increased incidence of acute Graft vs. Host Disease (aGVHD). In mice, administration of azacitidine (AzaC) on days 4, 6, 8, and 10 post DLI increases regulatory T cell (Treg) numbers and prevents GVHD without hindering Graft vs. Leukemia (GVL). Based on these findings, we conducted a phase 1 study of AzaC post DLI for AML relapse post allo-SCT...
October 2016: Leukemia Research
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