ABSTRACT
Azacitidine/venetoclax is an active regimen in patients with newly diagnosed AML. However, primary or secondary resistance to azacitidine/venetoclax is an area of unmet need and overexpression of MCL-1 is suggested to be a potential resistance mechanism. Pevonedistat inhibits MCL-1 through activation of NOXA, and pevonedistat/azacitidine has previously shown activity in AML. To assess the tolerability and efficacy of adding pevonedistat to azacitidine/venetoclax in relapsed/refractory AML, we conducted a phase I multicenter openlabel study in 16 adults with relapsed/refractory AML. Patients were treated with azacitidine, venetoclax along with pevonedistat intravenously on days 1, 3 and 5 of each 28-day cycle at 10, 15 or 20 mg/m2 in successive cohorts in the dose escalation phase. The impact of treatment on protein neddylation as well as expression of pro-apoptotic BCL2 family members was assessed. The recommended phase II dose of pevonedistat was 20 mg/m2. Grade 3 or higher adverse events included neutropenia (31%), thrombocytopenia (13%), febrile neutropenia (19%), anemia (19%), hypertension (19%) and sepsis (19%). The overall response rate was 46.7% for the whole cohort including complete remission (CR) in 5 of 7 (71.4%) patients who were naïve to the hypomethylating agent/venetoclax. No measurable residual disease (MRD) was detected in 80.0% of the patients who achieved CR. The median time to best response was 50 (range: 23 - 77) days. Four patients were bridged to allogeneic stem cell transplantation. The combination of azacitidine, venetoclax and pevonedistat is safe and shows encouraging preliminary activity in patients with relapsed/refractory AML. (NCT04172844).
ABSTRACT
Modelling of environmental impacts from the application of treated organic municipal solid waste (MSW) in agriculture differs widely between different models for environmental assessment of waste systems. In this comparative study five models were examined concerning quantification and impact assessment of environmental effects from land application of treated organic MSW: DST (Decision Support Tool, USA), IWM (Integrated Waste Management, U.K.), THE IFEU PROJECT (Germany), ORWARE (ORganic WAste REsearch, Sweden) and EASEWASTE (Environmental Assessment of Solid Waste Systems and Technologies, Denmark). DST and IWM are life cycle inventory (LCI) models, thus not performing actual impact assessment. The DST model includes only one water emission (biological oxygen demand) from compost leaching in the results and IWM considers only air emissions from avoided production of commercial fertilizers. THE IFEU PROJECT, ORWARE and EASEWASTE are life cycle assessment (LCA) models containing more detailed land application modules. A case study estimating the environmental impacts from land application of 1 ton of composted source sorted organic household waste was performed to compare the results from the different models and investigate the origin of any difference in type or magnitude of the results. The contributions from the LCI models were limited and did not depend on waste composition or local agricultural conditions. The three LCA models use the same overall approach for quantifying the impacts of the system. However, due to slightly different assumptions, quantification methods and environmental impact assessment, the obtained results varied clearly between the models. Furthermore, local conditions (e.g. soil type, farm type, climate and legal regulation) and waste composition strongly influenced the results of the environmental assessment.
