20 research outputs found
On the move: New insights on the ecology and management of native and alien macrophytes
Globally, freshwater ecosystems are under threat. The main threats come from catchment land-use changes, altered water regimes, eutrophication, invasive species, climate change and combinations of these factors. We need scientific research to respond to these challenges by providing solutions to halt the deterioration and improve the condition of our valuable freshwaters. This requires a good understanding of aquatic ecosystems, and the nature and scale of changes occurring. Macrophytes play a fundamental role in aquatic systems. They are sensitive indicators of ecosystem health, as they are affected by run-off from agricultural, industrial or urban areas. On the other hand, alien macrophytes are increasingly invading aquatic systems all over the world. Improving our knowledge on the ecology and management of both native and alien plants is indispensable to address threats to freshwaters in order to protect and restore aquatic habitats. The International Aquatic Plants Group (IAPG) brings together scientists and practitioners based at universities, research and environmental organisations around the world. The main themes of the 15th symposium 2018 in New Zealand were biodiversity and conservation, management, invasive species, and ecosystem response and restoration. This Virtual Special Issue provides a comprehensive review from the symposium, addressing the ecology of native macrophytes, including those of conservation concern, and highly invasive alien macrophytes, and the implications of management interventions. In this editorial paper, we highlight insights and paradigms on the ecology and management of native and alien macrophytes gathered during the meeting
Olutasidenib Alone or With Azacitidine in IDH1-Mutated Acute Myeloid Leukaemia and Myelodysplastic Syndrome: Phase 1 Results of a Phase 1/2 Trial
BACKGROUND: Olutasidenib (FT-2102) is a potent, selective, oral, small-molecule inhibitor of mutant isocitrate dehydrogenase 1 (IDH1). The aims for phase 1 of this phase 1/2 study were to assess the safety, pharmacokinetics, pharmacodynamics, and clinical activity of olutasidenib, as monotherapy or in combination with azacitidine, in patients with acute myeloid leukaemia or myelodysplastic syndrome, harbouring mutant IDH1. METHODS: In this phase 1/2, multicentre, open-label clinical trial, we enrolled patients aged 18 years or older with acute myeloid leukaemia or intermediate, high, or very high risk myelodysplastic syndrome harbouring mutant IDH1 at 18 study sites in the USA, Australia, France, and Spain. Other key eligibility criteria included Eastern Cooperative Oncology Group performance status 0-2 with adequate liver and renal function. The primary outcomes were dose-limiting toxicities and the maximum tolerated dose, maximum evaluated dose, and the recommended phase 2 dose of olutasidenib. Olutasidenib was administered orally in doses of 150 mg once daily, 150 mg twice per day, and 300 mg once daily. Azacitidine (75 mg/m) was administered subcutaneously or intravenously daily for 7 days on, 21 days off. The study was ongoing at the data cutoff (Oct 2, 2019) and is registered with ClinicalTrials.gov, NCT02719574. FINDINGS: Patients were enrolled between Aug 8, 2016, and Nov 14, 2018. 78 patients received olutasidenib as monotherapy (n=32) or in combination with azacitidine (n=46). The median follow-up was 8·3 months (IQR 3·1-13·3) for monotherapy and 10·1 months (4·2-15·3) for combination therapy. 16 (50%) of 32 patients in the monotherapy group and 24 (52%) of 46 patients in the combination therapy group were women. Most patients were White (26 [81%] for monotherapy and 31 [67%] for combination therapy). No dose-limiting toxicities were reported in the dose-escalation cohorts and 150 mg twice per day was declared the recommended phase 2 dose on the basis of safety, pharmacokinetics and pharmacodynamics, and clinical activity. The most common (≥20%) grade 3-4 treatment-emergent adverse events with monotherapy were thrombocytopenia (nine [28%] of 32 patients), febrile neutropenia (seven [22%] of 32), and anaemia (seven [22%] of 32); and with combination therapy were thrombocytopenia (19 [41%] of 46), febrile neutropenia (13 [28%] of 46), neutropenia (13 [28%] of 46), and anaemia (nine [20%] of 46). 11 (34%) of 32 patients in the monotherapy group and nine (20%) of 46 patients in the combination therapy group died (most commonly from disease progression [three (9%) of 32 and four (9%) of 46]). No deaths were considered study-drug related. For patients with relapsed or refractory acute myeloid leukaemia, 41% (95% CI 21-64; nine of 22) receiving monotherapy and 46% (27-67; 12 of 26) receiving combination therapy had an overall response. For treatment-naive patients with acute myeloid leukaemia, 25% (1-81; one of four) receiving monotherapy and 77% (46-95; ten of 13) receiving combination therapy had an overall response. INTERPRETATION: Olutasidenib, with or without azacitidine, was well tolerated and showed meaningful clinical activity in patients with IDH1-mutated acute myeloid leukaemia. The results of this phase 1 study provide rationale for the continued evaluation of olutasidenib in multiple patient populations with myeloid malignancies. FUNDING: Forma Therapeutics
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Olutasidenib (FT-2102), an IDH1m Inhibitor As a Single Agent or in Combination with Azacitidine, Induces Deep Clinical Responses with Mutation Clearance in Patients with Acute Myeloid Leukemia Treated in a Phase 1 Dose Escalation and Expansion Study
Background: Isocitrate dehydrogenase 1 mutations (IDH1m) occur in 7-14% of AML patients (pts) and approximately 3-4% of MDS pts. Olutasidenib is a highly potent, selective small molecule inhibitor of IDH1m with the therapeutic potential to restore normal cellular differentiation. Azacitidine (AZA) has shown synergistic effects with IDHm inhibitors on releasing differentiation block in IDHm leukemia models in vitro. Methods: The Phase 1 study (NCT02719574) assessed the safety, PK/PD, and clinical activity of olutasidenib in patients with IDH1m AML or MDS. Eligibility criteria included: IDH1m AML or MDS [relapsed/refractory (R/R) or treatment naïve (TN) pts not eligible for or refusing standard therapy], adequate liver and renal function. There were no restrictions for concomitant non-anticancer medications. IDH1m variant allele frequency (VAF) and co-mutations were measured at baseline and during treatment. Available safety data are presented for all pts (AML/MDS); efficacy data are presented for AML pts only. Results: As of April 12, 2019, 32 pts had been treated with single agent (SA) olutasidenib and 46 pts with olutasidenib in combination (COMBO) with AZA; median time on treatment was 4.2 mo for SA (range: 10% of pts, including thrombocytopenia (28% vs 33%), febrile neutropenia (22% vs 28%), anemia (22% vs 20%), pneumonia (16% vs 11%), and leukocytosis (13% vs 15%); COMBO-treated pts had more Gr 3/4 neutropenia (6% vs 28%), fatigue (6% vs 15%), and nausea (0% vs 9%). No QTcF prolongation was reported in SA while 3 (7%) pts treated with COMBO reported prolonged QTcF (1 Gr 3). Ten (13%) pts had differentiation syndrome (4 SA; 6 COMBO), which resolved with temporary interruption of olutasidenib and treatment with dexamethasone, hydroxyurea, and/or supportive care. None led to treatment discontinuation. Nineteen (24%) pts died on treatment or within 28 days of the last dose, no deaths were considered treatment-related. For AML pts, clinical responses occurred in 39% SA and 54% COMBO (CR 15% and 23%, respectively; Table 1). CRs were durable (up to >27 mo); disease control (SD >13 mo) was observed in pts without an IWG-defined response. Of the 59 AML pts (23 SA; 36 COMBO) who were transfusion-dependent at baseline, 26 (11 [48%] SA; 15 [42%] COMBO) and 21 (9 [39%] SA; 12 [33%] COMBO) became transfusion-independent (seen in all response categories) during 28 and 56 days on treatment, respectively. For R/R AML pts, median survival was 8.7 mo for SA and 12.1 mo for COMBO; for TN AML pts, median survival was 8.8 mo for SA (n=4) and not reached for COMBO. For R/R and TN AML patients with available pre- and on-treatment samples, IDH1m clearance or significant reduction (VAF <1%) was observed in 10/25 pts (40%) achieving an objective response and in 3/6 pts (50%) with stable disease. Mutation and 2-HG analyses suggest that pts who progressed on olutasidenib had a non-IDH1m-driven mechanism; updated analyses will be presented. Conclusions: SA and COMBO olutasidenib has shown favorable safety and clinical activity in IDH1m R/R AML with a SA ORR of 41% (95% CI: 21, 64) and a COMBO ORR of 46% (27, 67), and durable disease control. Olutasidenib induces deep responses with IDH1 mutation clearance in a subset of treated pts. Phase 2 investigations of SA and COMBO olutasidenib at the RP2D are ongoing in multiple IDH1m AML populations. Additional combinations are also being explored. Disclosures Watts: Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding. Baer:Forma: Research Funding; Kite: Research Funding; Astellas: Research Funding; Incyte: Research Funding; Takeda: Research Funding; Abbvie: Research Funding; Al Therapeutics: Research Funding. Yang:Agios: Consultancy; AstraZeneca: Research Funding. Prebet:pfizer: Honoraria; novartis: Honoraria; pfizer: Honoraria; Boehringer Ingelheim: Research Funding; novartis: Honoraria. Lee:Helsinn: Consultancy; Jazz Pharmaceuticals, Inc: Consultancy; Roche Molecular Systems: Consultancy; AstraZeneca Pharmaceuticals: Consultancy; Karyopharm Therapeutics: Consultancy; Ai Therapeutics: Research Funding. Schiller:Biomed Valley Discoveries: Research Funding; Bristol Myer Squibb: Research Funding; Astellas: Research Funding; Agios: Research Funding, Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Constellation Pharmaceutical: Research Funding; Daiichi Sankyo: Research Funding; Eli Lilly and Company: Research Funding; FujiFilm: Research Funding; Genzyme: Research Funding; Gilead: Research Funding; Incyte: Research Funding; J&J: Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; Karyopharm: Research Funding; Novartis: Research Funding; Onconova: Research Funding; Pfizer Pharmaceuticals: Equity Ownership, Research Funding; Sangamo Therapeutics: Research Funding; Amgen: Other, Research Funding. Dinner:Agios: Consultancy; Pfizer: Consultancy; AstraZeneca: Consultancy. Pigneux:Roche: Honoraria; F. Hoffmann-La Roche Ltd: Honoraria; Pfizer: Honoraria; Abbvie: Honoraria; Jazz: Honoraria; Amgen: Honoraria; Daichi: Honoraria; Astellas: Honoraria; Novartis: Honoraria. Montesinos:Abbvie: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Research support, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Research support, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Other: Research support; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau; Teva: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau. Wang:Stemline: Other: Advisory role, Speakers Bureau; Daiichi: Other: Advisory role; Amgen: Other: Advisory role; Abbvie: Other: Advisory role; Kite: Other: Advisory role; Jazz: Other: Advisory role; Astellas: Other: Advisory role, Speakers Bureau; celyad: Other: Advisory role; Pfizer: Other: Advisory role, Speakers Bureau; Agios: Other: Advisory role. Seiter:Novartis, Incyte, Celgene, Astellas, Sanofi: Speakers Bureau; Novartis, Astellas,: Consultancy; Novartis, Forma, Sun Pharma, Celgene, Jazz, Roche: Research Funding. Wei:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Macrogenics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra Zeneca: Honoraria, Research Funding; Janssen: Honoraria; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: AHW is a former employee of the Walter and Eliza Hall Institute and receives a fraction of its royalty stream related to venetoclax, Research Funding, Speakers Bureau; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. De Botton:Agios: Consultancy, Research Funding; Celgene: Consultancy, Speakers Bureau; Pierre Fabre: Consultancy; Servier: Consultancy; Pfizer: Consultancy; Novartis: Consultancy; Janssen: Consultancy; FORMA: Consultancy, Research Funding; Syros: Consultancy; Bayer: Consultancy; Abbvie: Consultancy; Daiichi: Consultancy; Astellas: Consultancy. Jonas:AbbVie, Accelerated Medical Diagnostics, AROG, Celgene, Daiichi Sankyo, Esanex, Forma, Genentech/Roche, GlycoMimetics, Incyte, LP Therapeutics, Pharmacyclics: Research Funding; AbbVie, Amgen, GlycoMimetics: Other: Travel expenses; AbbVie, Amgen, Celgene, GlycoMimetics, Jazz, Pharmacyclics, Tolero: Consultancy, Membership on an entity's Board of Directors or advisory committees. Ferrell:Astex Pharmaceuticals: Re
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Flavonoid-rich fruit and vegetables improve microvascular reactivity and inflammatory status in men at risk of cardiovascular disease-FLAVURS:a randomized controlled trial
Observed associations between increased fruit and vegetable (F&V) consumption, particularly those F&Vs that are rich in flavonoids, and vascular health improvements require confirmation in adequately powered randomized controlled trials