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Four hydrogen bond-based macrocyclic and tripodal neutral receptors with increasing conformational complementarity with sulfate were used for the first time as ionophores to develop polymeric membrane sulfate-selective electrodes. Optimizing the membrane composition such as ionophores, lipophilic additives, and plasticizers yielded ISEs which showed Nernstian response to sulfate with the best selectivity so far and improved detection limits (a slope of -29.8 mV/dec in the linear range of 1 X 10(-6) -1 x 10(-1 )M with a detection limit of 5 x 10(-7) M), which led to the success of the determination of sulfate in drinking water samples and neomycine tablets. The anion-ionophore complex constants in the membrane phase were determined and correlated with the selectivity sequence of the ISEs. Studies on the influence of pH of the sample solution demonstrated that the developed ISEs can be operated in a wide pH range of 3-8 with fast response and rapid (in 1 min) and long lifetime. The success of these ionophores represents a feasible strategy for overcoming the "Hofmeister series" by employing a combination of complementarity and hydrogen bonds.

Background: In the Phase 3 randomized, placebo-controlled VIALE-A study, venetoclax (Ven) + azacitidine (Aza) improved overall survival (OS) and complete response (CR) rates vs Aza + placebo (Pbo; DiNardo et al. N Engl J Med. 2020. In Press). Neutropenia and related infections are common in acute myeloid leukemia (AML) and exacerbated by Ven combinations. Antimicrobial prophylaxis is used variably in patients (pts) with AML receiving low-intensity therapies. Ven dose modifications are required for concomitant use of commonly used antimicrobials that are strong or moderate cytochrome P450 3A inhibitors (CYP3Ai). A previous report's findings showed that Ven dose reductions with CYP3Ai do not affect Ven exposure (Wei et al. Blood. 2020;135:2137). This analysis evaluated the use of prophylactic anti-infective CYP3Ai and these agents' effects on infections and efficacy outcomes in the VIALE-A study (NCT02993523). Methods: Pts with newly diagnosed AML, aged ≥75 y or 18-75 yand ineligible for induction therapy were enrolled. Pts were randomized 2:1 to receive Ven (daily, orally) + Aza (75 mg/m2 d 1-7, subcutaneously/intravenously) or Pbo + Aza in 28-d cycles. Anti-infective prophylaxis was required for pts with absolute neutrophil count Results: In total, 286 pts were randomized to Ven + Aza and 145 to Pbo + Aza. Within the first 2 cycles of therapy, concomitant anti-infective prophylaxis agents considered moderate CYP3Ai were received by 41/286 pts (14%) in the Ven + Aza arm and 18/145 (12%) in the Pbo + Aza arm. Concomitant anti-infective prophylaxis agents considered strong CYP3Ai were received in the first 2 cycles by 22/286 pts (8%) treated with Ven + Aza and 13/145 pts (9%) treated with Pbo + Aza. The median duration of each prophylactic CYP3Ai agent use was 12.5 d (range, 1-614) in the Ven + Aza arm and 15 d (range, 1-731) in the Pbo + Aza arm. The rates of CR+CR with incomplete marrow recovery (CRi) as a best response during the study were similar with concomitant use of moderate (61%; CR, 24%; CRi, 37%) or strong (64%; CR, 27%; CRi, 36%) CYP3Ai with adjusted-dose Ven vs no use of CYP3Ai (67%; CR, 39%; CRi, 27%; Table 1). The relatively lower CR and higher CRi rates appear to be due to delay in recovery of peripheral blood counts in pts who received strong CYP3Ai during the first 2 cycles (Table 2). The median time to first CR+CRi was 1.2 mo (range, 0.6-9.9), 1.4 mo (range 1.0-5.5), and 1.4 mo (range, 0.9-5.4) in those receiving no, moderate, and strong CYP3Ai agents, respectively, in the Ven + Aza arm. Median OS was not statistically different regardless of use of moderate or strong CYP3Ai in both arms, as noted by overlapping CIs (Table 1). The 24-month estimated OS was 26.2% (95% CI, 8.1-48.9) for pts receiving strong CYP3Ai vs 37.9% (95% CI, 30.2-45.6) for those receiving no CYP3Ai. Rates of any-grade or Grade 3/4 infections within the first 2 cycles varied between those with or without use of moderate CYP3Ai reported as being given as prophylaxis in both treatment arms (Table 1). Rates of invasive fungal infections were 3%, 12%, and 9% with Ven + Aza and 0%, 0%, and 15% with Pbo + Aza in pts receiving no, moderate, and strong CYP3Ai agents, respectively. Rates of discontinuation from infections were similar in both arms regardless of CYP3Ai use. Conclusions:Antimicrobial prophylaxis with moderate or strong CYP3Ai was used in neutropenic pts in the VIALE-A study, with overall similar composite remission rates with Ven dose reductions. The use of CYP3Ai did not increase rates of discontinuation from infections. Analysis of differences in baseline characteristics, rates of infections, and efficacy outcomes for pts who began anti-infective prophylaxis at the initiation of therapy is ongoing. Disclosures Jonas: Amgen: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; GlycoMimetics: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Celgene: Consultancy, Research Funding; Jazz: Consultancy, Research Funding; Takeda: Consultancy; Tolero: Consultancy; Treadwell: Consultancy; Forty Seven: Research Funding; Accelerated Medical Diagnostics: Research Funding; AROG: Research Funding; Daiichi Sankyo: Research Funding; F. Hoffmann-La Roche: Research Funding; Forma: Research Funding; AbbVie: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Genentech/Roche: Research Funding; Sigma Tau: Research Funding; Hanmi: Research Funding; Pfizer: Research Funding; LP Therapeutics: Research Funding; Incyte: Research Funding; Pharmacyclics: Research Funding. Dinardo:Takeda: Honoraria; Notable Labs: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Daiichi Sankyo: Consultancy, Research Funding; Calithera: Research Funding; Celgene: Research Funding; Agios: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; ImmuneOnc: Honoraria. Fracchiolla:AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau. Pristupa:Beigene: Honoraria, Research Funding; State Institution of Health of the Ryazan Regional Clinical Hospital: Current Employment; Pfizer: Honoraria, Research Funding, Speakers Bureau; Janssen: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Takeda: Honoraria, Research Funding, Speakers Bureau; Daiichi Sankyo: Honoraria, Research Funding; Paraxel: Honoraria, Research Funding; Acerta: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding; Geron: Honoraria, Research Funding. Ishizawa:Takeda: Honoraria; Ono: Honoraria; Chugai: Honoraria; Eizai: Honoraria; Novartis: Honoraria, Research Funding; Celgene: Honoraria; SymBio: Research Funding; Bayer: Research Funding; AbbVie: Research Funding. Jin:The First Affiliated Hospital of Zhejiang University: Current Employment. Konopleva:Rafael Pharmaceutical: Research Funding; F. Hoffmann La-Roche: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Eli Lilly: Research Funding; Sanofi: Research Funding; Calithera: Research Funding; Kisoji: Consultancy; AstraZeneca: Research Funding; AbbVie: Consultancy, Research Funding; Amgen: Consultancy; Ascentage: Research Funding; Reata Pharmaceutical Inc.;: Patents & Royalties: patents and royalties with patent US 7,795,305 B2 on CDDO-compounds and combination therapies, licensed to Reata Pharmaceutical; Ablynx: Research Funding; Forty-Seven: Consultancy, Research Funding; Stemline Therapeutics: Consultancy, Research Funding; Cellectis: Research Funding; Agios: Research Funding. Ofran:AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy; Rambam Health Care: Current Employment; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy. Kovacsovics:Pfizer: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Jazz: Honoraria; Astella: Honoraria; Agios: Honoraria. Kantarjian:Daiichi-Sankyo: Honoraria, Research Funding; BMS: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oxford Biomedical: Honoraria; Janssen: Honoraria; Delta Fly: Honoraria; BioAscend: Honoraria; Jazz: Research Funding; Abbvie: Honoraria, Research Funding; Sanofi: Research Funding; Aptitute Health: Honoraria; Adaptive biotechnologies: Honoraria; Pfizer: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Immunogen: Research Funding; Ascentage: Research Funding. Hong:Genentech, Inc.: Current Employment; F. Hoffmann-La Roche: Current equity holder in publicly-traded company. Duan:AbbVie: Current Employment, Other: may hold stock or options. Ainsworth:AbbVie: Current Employment, Current equity holder in publicly-traded company. Potluri:AbbVie: Current Employment, Other: may hold stock or stock options. Werner:AbbVie: Current Employment, Current equity holder in publicly-traded company. Svensson:AbbVie: Current Employment, Current equity holder in publicly-traded company. Pratz:Millennium: Research Funding; Daiichi Sankyo: Research Funding; Agios: Other: Scientific Advisory Board, Research Funding; Jazz Pharmaceutical: Consultancy; Celgene: Other: Scientific Advisory Board; Boston BioMedical: Consultancy; AbbVie: Other: Scientific Advisory Board, Research Funding; Astellas: Other: Scientific Advisory Board, Research Funding.

Introduction The FMS-like tyrosine kinase 3 (FLT3) gene is mutated in ~20% of patients (pts) with AML ≥70 years (Schneider et al, 2012). Both FLT3-ITD and FLT3-TKD mutations (mut) are associated with AML proliferation and potentially targetable with small molecule inhibitors. The presence of a FLT3mut, particularly FLT3-ITD, often correlates with high leukemic burden and risk of relapse despite high response rates (Gale et. al, 2008). There is limited evidence of the effect of currently available therapies on treatment-naïve AML pts unfit for intensive treatment with FLT3mut. We evaluated the efficacy and safety of venetoclax (Ven) and Azacitidine (Aza) combination among treatment-naïve AML pts with co-morbidities and/or age ≥ 75 years, unfit for intensive treatment, and with FLT3mut. Methods Data were pooled from pts enrolled in a phase 3 study (NCT02993523, data cut-off: 04Jan2020) that compared pts treated with Ven+Aza or placebo (Pbo)+Aza, and a prior phase 1b study (NCT02203773, data cut-off: 19Jun2019) where pts were treated with Ven+Aza. Pts on Ven+Aza received Ven 400 mg daily orally (days 1-28) and Aza (75 mg/m2; days 1-7/28-day cycle). Disease assessments were performed per the modified International Working Group response criteria for AML. DNA was isolated from bone marrow aspirates collected from pts prior to the first dose of study drug and analyzed centrally. Pts with positive test results for FLT3; [Leukostrate FLT3 CDx for phase 3 study or MyAML panel (Invivoscribe) for Phase 1b study] were counted as mutation "detected"; pts with a negative test result were counted as mutation "not detected." Pts without a result either due to an inconclusive test or missing specimen were not included in the analyses. Results In this pooled analysis, FLT3mut was detected in 40 pts treated with Ven+Aza and 22 pts treated with Pbo+Aza. At baseline (Ven+Aza/Pbo+Aza), the median age was 75 (range: 49-91)/75 (65-85) years. Cytogenetic risks were: intermediate: 88%/96% and poor: 13%/5%, Eastern Co-operative Oncology Group performance scores were: 0-1: 40%/50% and 2-3: 60%/50%. 78%/86% had de novo AML, while 23%/14% had secondary AML. FLT3-ITD was detected in 28/13 and FLT3-TKD in 13/10 pts, respectively. FLT3-ITD allelic ratios were: Complete response (CR)+CR with partial hematologic recovery (CRh) rates in FLT3mut pts (Ven+Aza/Pbo+Aza) were 65% (95% CI:48%-79%)/18% (5%-40%) (Table) with a median duration of response (mDoR) 18.3 [95% CI: 10.1- not reached (NR)]/15.1 (13.9-NR) mos. Median time to first CR/CRh response was 1.0/3.2 months (mos). 43%/0% achieved CR+CRh by initiation of cycle (C) 2. Median overall survival (mOS) was 13.3 (95% CI: 8.4-23.5)/8.6 (5.9-14.7) mos, respectively. Among pts with FLT3-ITD, CR+CRh rates (Ven+Aza/Pbo+Aza) were 61% (95% CI: 41%-79%)/23% (5%-54%) with mDoR 17.4 (95% CI: 3.7-NR)/14.5 (13.9-15.1) mos. The median time to first CR/CRh response was 1.0/3.5 mos and 39%/0% pts achieved CR+CRh by initiation of C2. The mOS was 11.5 (95% CI: 6.4-23.5)/8.5 (6.1-20.3) mos, respectively. CR+CRh rates in pts with FLT3-TKD were 69% (95% CI: 39%-91%)/20% (3%-56%) with mDoR 18.3 (95% CI: 3.0-NR)/NR (15.1-NR) mos. The median time to first CR/CRh response was 1.0/2.7 mos and 46%/0% achieved a response by initiation of C2. The mOS was 19.2 (95% CI:1.8-NR/10.0 (0.2-14.7) mos, respectively. In pts treated with Ven+Aza, CR+CRh rates among pts with FLT3 detected/FLT3 not detected were 65% (95% CI: 48%-79%)/63% (56%-69%) with mDoR 18.3 (95% CI: 10.1-NE)/18.1 (15.3-NR) mos. The mOS was 13.3 (95%CI: 8.4-23.5)/14.1 (10.6-18.7) mos, respectively (Figure). Among pts treated with Ven+Aza, grade 3/4 hematologic adverse events (AEs) in pts with FLT3 detected/FLT3 not detected was 67%/77%, and included anemia (33%/25%), neutropenia (36%/33%), thrombocytopenia (39%/36%), and febrile neutropenia (36%/43%). Grade 3/4 hematologic AEs among pts with FLT3-ITD/FLT3-TKD treated with Ven+Aza was 67%/69%. Conclusion Ven+Aza compared to Aza monotherapy resulted in significantly higher CR+CRh rates among treatment-naïve pts with FLT3mut ineligible for intensive chemotherapy. In this unselected AML population, insufficient pt numbers in various subgroups limit the ability to draw conclusions regarding DoR and mOS for FLT3-ITD and TKD subgroups. There were no unexpected toxicities in the Ven+Aza arm. Future studies with larger sample sizes are warranted. Disclosures Konopleva: Ascentage: Research Funding; Amgen: Consultancy; Genentech: Consultancy, Research Funding; Stemline Therapeutics: Consultancy, Research Funding; Forty-Seven: Consultancy, Research Funding; Rafael Pharmaceutical: Research Funding; Kisoji: Consultancy; Agios: Research Funding; Calithera: Research Funding; F. Hoffmann La-Roche: Consultancy, Research Funding; Reata Pharmaceutical Inc.;: Patents & Royalties: patents and royalties with patent US 7,795,305 B2 on CDDO-compounds and combination therapies, licensed to Reata Pharmaceutical; AstraZeneca: Research Funding; AbbVie: Consultancy, Research Funding; Sanofi: Research Funding; Eli Lilly: Research Funding; Cellectis: Research Funding; Ablynx: Research Funding. Thirman:AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Syndax: Research Funding; TG Therapeutics: Research Funding; Tolero: Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Gilead Sciences: Research Funding. Pratz:Millennium: Research Funding; Celgene: Other: Scientific Advisory Board; AbbVie: Other: Scientific Advisory Board, Research Funding; Astellas: Other: Scientific Advisory Board, Research Funding; Boston BioMedical: Consultancy; Agios: Other: Scientific Advisory Board, Research Funding; Daiichi Sankyo: Research Funding; Jazz Pharmaceutical: Consultancy. Letai:Flash Therapeutics: Membership on an entity's Board of Directors or advisory committees; Dialectic: Membership on an entity's Board of Directors or advisory committees; Chugai: Other: Lecture Fees; Novartis: Research Funding; AbbVie: Consultancy; Zentalis: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy. Pullarkat:AbbVie, Inc.: 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, Speakers Bureau; Dova: Consultancy, Honoraria; Genetech: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Kantarjian:Immunogen: Research Funding; Janssen: Honoraria; Sanofi: Research Funding; BioAscend: Honoraria; Abbvie: Honoraria, Research Funding; Oxford Biomedical: Honoraria; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Aptitute Health: Honoraria; BMS: Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; Delta Fly: Honoraria; Pfizer: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Ascentage: Research Funding; Adaptive biotechnologies: Honoraria; Novartis: Honoraria, Research Funding; Jazz: Research Funding. Dail:Genentech: Current Employment, Current equity holder in publicly-traded company. Duan:AbbVie: Current Employment, Other: may hold stock or options. Chyla:AbbVie: Current Employment, Current equity holder in publicly-traded company. Potluri:AbbVie: Current Employment, Other: may hold stock or stock options. Miller:AbbVie: Current Employment, Current equity holder in publicly-traded company. Dinardo:Takeda: Honoraria; Daiichi Sankyo: Consultancy, Research Funding; Novartis: Consultancy; Notable Labs: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Research Funding; Celgene: Research Funding; Agios: Consultancy, Research Funding; Calithera: Research Funding; ImmuneOnc: Honoraria. Wei:AbbVie: Honoraria, Research Funding, Speakers Bureau; Servier: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Research Funding, Speakers Bureau; AstraZeneca: Honoraria, Research Funding; Pfizer: Honoraria; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Honoraria; Amgen: Honoraria, Research Funding; Walter and Eliza Hall Institute of Medical Research: Patents & Royalties; Genetech: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Background: Patients with acute myeloid leukemia (AML) who are older or ineligible for intensive induction chemotherapy have limited treatment options and poor survival. In the VIALE-A study, venetoclax (Ven) + azacitidine (Aza) improved overall survival and response rates compared with placebo (Pbo) + Aza in older or unfit patients with newly diagnosed AML (DiNardo et al. N Engl J Med. 2020). Although cytopenia is common in AML, Ven+Aza was associated with hematologic adverse events in 83% of patients in the VIALE-A study (vs 69% in the Pbo+Aza arm). Here, the frequency and management of cytopenia are analyzed in patients achieving a best response of complete remission (CR) or CR with partial hematologic recovery (CRh) in the VIALE-A study. Methods: This double-blind, Pbo-controlled, multicenter Phase 3 study (NCT02993523) enrolled patients with newly diagnosed AML who were ineligible for intensive chemotherapy due to age ≥75 years or comorbidities. Patients were randomized 2:1 to receive 75 mg/m2 Aza (Days 1-7 of each 28-day cycle) plus either daily 400 mg Ven (Ven+Aza) or Pbo (Pbo+Aza). Disease response was assessed via bone marrow aspirate and biopsy at the end of Cycle 1 and at least every 3 cycles thereafter. After patients achieved blast clearance (bone marrow blasts Results: In total, 186 of 283 (66%) Ven+Aza-treated patients and 33 of 144 (23%) Pbo+Aza-treated patients achieved a best response of CR or CRh (CR/CRh). Of patients with a best response of CR/CRh in the Ven+Aza arm, 77% achieved blast clearance by the end of Cycle 1, 88% by the end of Cycle 2, 92% by the end of Cycle 3, and 98% by the end of Cycle 4. Of patients with a best response of CR/CRh in the Pbo+Aza arm, 33% achieved blast clearance by the end of Cycle 1, 55% by the end of Cycle 2, 76% by the end of Cycle 3, and 91% by the end of Cycle 4. After achieving blast clearance, 75% and 67% of patients in the Ven+Aza and Pbo+Aza arms, respectively, had a delay of the next cycle, with a median duration per cycle delay post-blast clearance (range) of 9.0 (1-39) and 5.5 (1-21) days. Among CR/CRh patients, more patients receiving Ven+Aza versus Pbo+Aza had post-remission cytopenia (87% vs 45%; Table 2). A similar percentage of CR/CRh patients in both arms (Ven+Aza, 26%; Pbo+Aza, 24%) had in-cycle dose interruptions (ie, days without Ven/Pbo exposure between a cycle's first and last Ven/Pbo dose), with a median duration (range) of 2.0 days (1-20) for Ven+Aza and 1.0 (1-13) for Pbo+Aza. A greater proportion of CR/CRh patients experienced post-remission cycle delays due to cytopenia in the Ven+Aza arm (77%) than in the Pbo+Aza arm (30%). Furthermore, a higher percentage of CR/CRh patients had post-remission cycles with a reduction in Ven/Pbo dosing days and/or cycle delays totaling ≥7 days due to cytopenia in the Ven+Aza arm (75%) than in the Pbo+Aza arm (27%). Among these patients, the median percentage of days without Ven/Pbo administration while in remission (out of the total number of days in remission) was 18% (range, 1-69) in the Ven+Aza arm and 13% (3-44) in the Pbo+Aza arm. Ultimately, 129 CR/CRh patients (69%) in the Ven+Aza arm and 10 (30%) in the Pbo+Aza arm received ≤21-day Ven/Pbo dosing post-remission, with a median time from remission to first ≤21-day cycle (range) of 92.0 days (1-480) for Ven+Aza and 74.0 days (6-405) for Pbo+Aza. Conclusion: In the VIALE-A study of older or unfit patients with newly diagnosed AML, the majority of responding patients in the Ven+Aza arm required dosing modifications to manage cytopenia, of which delays between cycles or within-cycle reductions of Ven dosing days were most common. Post-remission cytopenia and dosing modifications were more frequent with Ven+Aza versus Pbo+Aza treatment. The impact of cytopenia and dosing modifications on patient outcomes with Ven+Aza is currently being analyzed and will be reported at a future date. Disclosures Pratz: AbbVie: Other: Scientific Advisory Board, Research Funding; Boston BioMedical: Consultancy; Astellas: Other: Scientific Advisory Board, Research Funding; Jazz Pharmaceutical: Consultancy; Millennium: Research Funding; Daiichi Sankyo: Research Funding; Agios: Other: Scientific Advisory Board, Research Funding; Celgene: Other: Scientific Advisory Board. DiNardo:MedImmune: Honoraria; Agios: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Jazz: Honoraria; Takeda: Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Syros: Honoraria; Notable Labs: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; ImmuneOnc: Honoraria; Novartis: Consultancy; Calithera: Research Funding. Selleslag:Amgen: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Astellas: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Speakers Bureau; Janssen Cilag: Consultancy, Honoraria, Speakers Bureau; AbbVie: Consultancy, Honoraria, Speakers Bureau; Belgian College: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Speakers Bureau; MSD: Consultancy, Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria; Alexion: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Teva: Consultancy, Honoraria, Speakers Bureau; Sanofi: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Speakers Bureau. Yamamoto:AbbVie: Consultancy, Honoraria, Research Funding; Astra-Zeneca: Consultancy, Research Funding; Zenyaku: Research Funding; Sumitomo Dainippon: Honoraria; Sanofi: Honoraria; Pfizer: Honoraria; Otsuka: Consultancy, Honoraria, Research Funding; Ono: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Nippon Shinyaku: Honoraria, Research Funding; Mundipharma: Consultancy, Honoraria, Research Funding; MSD: Consultancy, Honoraria, Research Funding; Mochida: Honoraria; Meiji Seika Pharma: Consultancy, Honoraria; Kyowa Kirin: Honoraria; Janssen: Honoraria; Gilead Sciences: Research Funding; IQIVA/Incyte: Research Funding; HUYA: Consultancy; IQIVA/HUYA: Honoraria; Daiichi Sankyo: Consultancy; Eisai: Consultancy, Honoraria, Research Funding; Chugai: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Yakult: Research Funding; Stemline Therapeutics: Consultancy; Solasia Pharma: Research Funding; SymBio: Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria; Bayer: Research Funding; Aichi Cancer Center: Current Employment. Konopleva:AbbVie: Consultancy, Research Funding; Cellectis: Research Funding; Agios: Research Funding; Sanofi: Research Funding; Amgen: Consultancy; Reata Pharmaceutical Inc.;: Patents & Royalties: patents and royalties with patent US 7,795,305 B2 on CDDO-compounds and combination therapies, licensed to Reata Pharmaceutical; Ascentage: Research Funding; Eli Lilly: Research Funding; Stemline Therapeutics: Consultancy, Research Funding; Calithera: Research Funding; Forty-Seven: Consultancy, Research Funding; Ablynx: Research Funding; Rafael Pharmaceutical: Research Funding; F. Hoffmann La-Roche: Consultancy, Research Funding; Kisoji: Consultancy; AstraZeneca: Research Funding; Genentech: Consultancy, Research Funding. McDonald:venetoclax advisory board in South Africa (in CLL context): Consultancy; Alberts Cellular Therapy: Current Employment. Babu:Genentech, Inc./ F. Hoffmann-La Roche: Research Funding; Novartis: Research Funding; Janssen Oncology: Research Funding; Syndax: Research Funding; Nektar: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Alexion Pharmaceuticals: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding, Speakers Bureau; Lilly: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Bayer: Honoraria; AstraZeneca: Consultancy, Honoraria; AstraZeneca/MedImmune: Research Funding; Argenx: Consultancy, Research Funding; Boehringer Ingelheim: Consultancy; Merck: Research Funding; AbbVie: Research Funding; TG Therapeutics: Research Funding; Amgen: Research Funding; Lutheran Hospital: Other; Fort Wayne Medical Oncology & Hematology: Current Employment, Current equity holder in publicly-traded company; Sanofi: Research Funding. Stevens:Amgen, MorphoSys: Consultancy. Kantarjian:BioAscend: Honoraria; Delta Fly: Honoraria; Abbvie: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Ascentage: Research Funding; Janssen: Honoraria; Adaptive biotechnologies: Honoraria; Aptitute Health: Honoraria; Oxford Biomedical: Honoraria; Daiichi-Sankyo: Honoraria, Research Funding; BMS: Research Funding; Jazz: Research Funding; Immunogen: Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Sanofi: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees. Traina:University of São Paulo at Ribeirão Preto Medical School: Current Employment; AbbVie: Other: Principal Investigator for Protocol Number M15-656 . Venditti:Jazz: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); AbbVie: Consultancy, Honoraria, Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company); Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company); Amgen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Pfizer: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; Novartis: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Mayer:AbbVie: Research Funding; Principia Biopharma: Research Funding. Montez:F. Hoffmann-La Roche: Current equity holder in publicly-traded company; Genentech, Inc.: Current Employment. Ramsingh:Roche: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Genentech: Current Employment, Current equity holder in publicly-traded company. Jin:Genentech: Current Employment. Ainsworth:AbbVie: Current Employment, Current equity holder in publicly-traded company. Duan:AbbVie: Current Employment, Other: may hold stock or options. Svensson:AbbVie: Current Employment, Current equity holder in publicly-traded company. Werner:AbbVie: Current Employment, Current equity holder in publicly-traded company. Potluri:AbbVie: Current Employment, Other: may hold stock or stock options. Jonas:AbbVie: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Amgen: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; GlycoMimetics: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Celgene: Consultancy, Research Funding; Jazz: Consultancy, Research Funding; Takeda: Consultancy; Tolero: Consultancy; Treadwell: Consultancy; Forty Seven: Research Funding; Accelerated Medical Diagnostics: Research Funding; AROG: Research Funding; Daiichi Sankyo: Research Funding; F. Hoffmann-La Roche: Research Funding; Forma: Research Funding; Genentech/Roche: Research Funding; Hanmi: Research Funding; Incyte: Research Funding; LP Therapeutics: Research Funding; Pfizer: Research Funding; Pharmacyclics: Research Funding; Sigma Tau: Research Funding.

Mouse T cells express the ecto-ADP-ribosyltransferase ARTC2.2, which can transfer the ADP-ribose group of extracellular nicotinamide adenine dinucleotide (NAD+) to arginine residues of various cell surface proteins thereby influencing their function. Several targets of ARTC2.2, such as P2X7, CD8a and CD25 have been identified, however a comprehensive mouse T cell surface ADP-ribosylome analysis is currently missing. Using the Af1521 macrodomain-based enrichment of ADP-ribosylated peptides and mass spectrometry, we identified 93 ADP-ribsoylated peptides corresponding to 67 distinct T cell proteins, including known targets such as CD8a and CD25 but also previously unknown targets such as CD73. We evaluated the impact of ADP-ribosylation on the capability of CD73 to generate adenosine from adenosine monophosphate. Our results show that extracellular NAD+reduces the enzymatic activity of CD73 HEK cells co-transfected with CD73/ARTC2.2. Importantly, NAD+significantly reduced CD73 activity on WT CD8 T cells compared to ARTC2ko CD8 T cells or WT CD8 T cells treated with an ARTC2.2-blocking nanobody. Our study provides a comprehensive list of T cell membrane proteins that serve as targets for ADP-ribosylation by ARTC2.2 and whose function may be therefore affected by ADP-ribosylation.

Four Lewis acidic organo-antimony(V) compounds with strong binding affinity to fluoride were used for the first time as ionophores to fabricate polymeric membrane fluoride-selective electrodes. Improved detection limits and significant anti-Hofmeister selectivity could be achieved by optimizing ionophores, lipophilic additives, and plasticizers. Membrane electrodes fabricated with tetrakis-(pentafluorophenyl)stibonium (ionophore 2) performed best in detection limit, sensitivity, and selectivity. Optimal performance was obtained by fluoride with a slope of -59.5 mV/decade in the linear range of 1 × 10-5 to 4 × 10-2 M and a detection limit of 5 × 10-6 M. Studies on the influence of sample solution pH demonstrate that the best pH for fluoride determination is pH 3.0. All of the electrodes studied respond rapidly (in 1 min) in different concentrations of fluoride solutions. The anion-ionophore complex constants in the membrane phase determined using the segmented sandwich membrane method correlate well with the solution-phase binding data and determined selectivity sequence of the ion-selective electrodes. The possibility of real life application of the optimized electrodes was assessed by determination of fluoride concentrations in tap water.

Summary Calcineurin B‐like interacting protein kinase (CIPKs) has been shown to be required for biotic stress tolerance of plants in plant‐pathogen interactions. However, the roles of CIPKs in immune signalling of cereal crops and an in‐depth knowledge of substrates of CIPKs in response to biotic stress are under debate. In this study, we identified and cloned a CIPK homologue gene TaCIPK10 from wheat. TaCIPK10 was rapidly induced by Puccinia striiformis f. sp. tritici (Pst) inoculation and salicylic acid (SA) treatment. In vitro phosphorylation assay demonstrated that the kinase activity of TaCIPK10 is regulated by Ca2+ and TaCBL4. Knockdown TaCIPK10 significantly reduced wheat resistance to Pst, whereas TaCIPK10 overexpression resulted in enhanced wheat resistance to Pst by the induction of defense response in different aspects, including hypersensitive cell death, ROS accumulation and pathogenesis‐relative genes expression. Moreover, TaCIPK10 physically interacted with and phosphorylated TaNH2, which was homologous to AtNPR3/4. Silencing of TaNH2 in wheat resulted in enhanced susceptibility to the avirulent Pst race, CYR23, indicating its positive role in wheat resistance. Our results demonstrate that TaCIPK10 positively regulate wheat resistance to Pst as molecular links between of Ca2+ and downstream components of defense response and TaCIPK10 interacts with and phosphorylates TaNH2 to regulate wheat resistance to Pst.

A series of PN-heterocycles and urea based cleft receptors containing hydrogen bond donor/acceptor groups complementary with hydrosulfide/hydrosulfate were used for the first time as ionophores to fabricate polymeric membrane hydrosulfide/hydrosulfate ISEs, while similar potentiometric sensors have rarely been reported. ISEs exhibiting Nernstian or near-Nernstian responses to hydrosulfide/hydrosulfate with improved selectivity over lipophilic anions and halides were obtained by optimizing the membrane component such as lipophilic additives and plasticizers. Selectivity for hydrosulfide or hydrosulfate can be manipulated simply by deploying the hydrogen bond donor/acceptor in a subtle way. For real-life applications, the optimized ISEs with good reversibility and improved detection limits were employed for hydrosulfide/hydrosulfate determination in water samples.

This study involved healthy community-living older adults in an investigation of the association between moderate alcohol consumption (AC) and acute changes in postural stability and whether the association differed according to pre-AC balance skills. Thirty-nine moderate drinkers aged ≥ 65 years (62% women; mean age: 73.9 ± 6.1 years) consumed a moderate dose of alcohol (0.4 g/kg; administered as two drinks). Breath alcohol concentration and postural stability were measured at five time points (pre-AC and 40, 80, 120, and 160 minutes post-AC) using unipedal stance time (UPST) and center of pressure (CoP) displacement. Pre-AC UPST was used to categorize participants into good-balance (≥30 seconds) and poor-balance (

7531 Background: Venetoclax (Ven) has synergistic activity with hypomethylating agents (eg, azacitidine [Aza] or decitabine [Dec]) or low-dose cytarabine (LDAC). These Ven-based combinations have demonstrated rapid median response times. This analysis describes the rapidity and likelihood of response to Ven treatments, and its associated characteristics, in older patients with newly diagnosed acute myeloid leukemia (AML). Methods: Included are data from two open-label trials of Ven, at label recommended doses, in combination with Aza, Dec (NCT02203773; phase 1b), or low-dose cytarabine (NCT02287233; phase 1/2) in newly diagnosed patients with AML. Patients were classified based on CR/CRi timing: within 2 cycles of therapy, after 2 cycles, or never achieving CR/CRi. Within each group, baseline and post-baseline characteristics were evaluated to determine impact on response timing. The percentage of patients in each category and duration of response (DOR) in each category were also evaluated. Results: Data cutoff was August 2018. Of 197 patients, 42% (n = 83) had CR/CRi in ≤2 cycles, 22% (n = 44) had CR/CRi in > 2 cycles, and 36% (n = 70) did not achieve CR/CRi. Median DOR was 21.2 mos. (95% CI 14.1-NR) for ≤2 cycle responders and 8.1 mos. (95% CI 5.3-14.9) for > 2 cycle responders. Baseline characteristics are shown in the Table. Patients with baseline IDH1/2 mutation were more likely to have CR/CRi in ≤2 cycles, while those with secondary AML and no response by the end of cycle 2 were more likely to never achieve CR/CRi. Of the patients who achieved CR/CRi after 2 cycles of therapy, 43% (19/44) achieved MLFS within the first two cycles. Of those who never achieved CR/CRi, 17% (12/70) of patients achieved MLFS within 2 cycles. In depth regression analyses of factors predictive of response, including analysis of biomarkers, will be available upon presentation. Conclusions: Over 1/3rd of patients that achieved CR/CRi on Ven combination therapy within these two studies required more than 2 cycles of treatment. Therefore, prior to discontinuing therapy for nonresponders, it is critical to assess key predictive patient characteristics. Clinical trial information: NCT02203773 and NCT02287233 . [Table: see text]

Cyclic nucleotide gated channels (CNGCs) play multifaceted roles in plants, particularly with respect to signaling processes associated with abiotic stress signaling and during host-pathogen interactions. Despite key roles during plant survival and response to environment, little is known about the activity and function of CNGC family in common wheat (Triticum aestivum L.), a key stable food around the globe. In this study, we performed a genome-wide identification of CNGC family in wheat and identified a total 47 TaCNGCs in wheat, classifying these genes into four major groups (I–IV) with two sub-groups (IVa and IVb). Sequence analysis revealed the presence of several conserved motifs, including a phosphate binding cassette (PBC) and a “hinge” region, both of which have been hypothesized to be critical for the function of wheat CNGCs. During wheat infection with Pst, the transcript levels of TaCNGC14 and TaCNGC16, both members of group IVb, showed significant induction during a compatible interaction, while a reduction in gene expression was observed in incompatible interactions. In addition, TaCNGC14 and TaCNGC16 mRNA accumulation was significantly influenced by exogenously applied hormones, including abscisic acid (ABA), methyl jasmonate (MeJA), and salicylic acid (SA), suggesting a role in hormone signaling and/or perception. Silencing of TaCNGC14 and TaCNGC16 limited Pst growth and increased wheat resistance against Pst. The results presented herein contribute to our understanding of the wheat CNGC gene family and the mechanism of TaCNGCs signaling during wheat-Pst interaction.

The gene, designated TaMADS2, was obtained from wheat leaves infected with the wheat stripe rust fungus by in silico cloning and RT-PCR. TaMADS2 encodes a predicted 159-amino-acid polypeptide that contains a highly conserved MADS domain. Phylogenetic analysis revealed that TaMADS2 is a type I MADS-box gene. The TaMADS2 transcript was detected in wheat leaves, stems, and roots. The expression of TaMADS2 was substantially down-regulated in the compatible interaction between wheat and Puccinia striiformis f. sp. tritici (Pst) at 36 and 48 h post-inoculation (hpi), whereas in the incompatible interaction the down-regulation was only observed at 48 hpi. Exogenous salicylic acid (SA) and abscisic acid (ABA) greatly induced the expression of TaMADS2 at 12 h post treatment (hpt), whereas methyl jasmonate (MeJA) down-regulated TaMADS2 at 6 hpt by approximately two-fold.

Purpose Clinicians use tamsulosin, an α1-adrenoceptor antagonist, to manage symptomatic benign prostatic hyperplasia (BPH). Because α1-adrenoceptors are also present in the brain, the potential exists for adverse effects on cognitive functions. We explored the association between tamsulosin use and dementia risk. Methods We used Medicare data (2006-2012) to conduct a cohort study among patients aged ≥65 years and diagnosed with BPH. Men taking tamsulosin (n = 253 136) were matched at a 1:1 ratio using propensity-scores to each of 6 comparison cohorts: patients who used no BPH-medication (n = 180 926), and patients who used the following alternative-BPH-medications: doxazosin (n = 28 581), terazosin (n = 23 858), alfuzosin (n = 17 934), dutasteride (n = 34 027), and finasteride (n = 38 767). Assessment began following the first fill of BPH-medication to identify incident dementia by ICD-9 diagnosis codes. We estimated hazard ratios (HR) and 95% confidence intervals (CI) for dementia using Cox proportional hazard regression for each of the 6 propensity-score-matched cohort-pairs. Results The median follow-up period for all cohorts was 19.8 months. After propensity-score matching, the tamsulosin cohort had an incidence of dementia of 31.3/1000 person-years compared with only 25.9/1000 person-years in the no-BPH-medication cohort. The risk of dementia was significantly higher in the tamsulosin cohort, when compared with the no-BPH-medication cohort (HR [95% CI]: 1.17 [1.14, 1.21]) and each of the alternative-BPH-medication cohorts: doxazosin (1.20 [1.12, 1.28]), terazosin (1.11 [1.04, 1.19]), alfuzosin (1.12 [1.03, 1.22]), dutasteride (1.26 [1.19, 1.34]), and finasteride (1.13 [1.07, 1.19]). The significance of these findings persisted in sensitivity analyses. Conclusion Tamsulosin may increase the risk of dementia in older men with BPH.

Members of the family of 70-kD heat shock proteins (HSP70 s) play various stress-protective roles in plants. In this study, a wheat HSP70 gene was isolated from a suppression subtractive hybridization (SSH) cDNA library of wheat leaves infected by Puccinia striiformis f. sp. tritici. The gene, that was designated as TaHSC70, was predicted to encode a protein of 690 amino acids, with a molecular mass of 73.54 KDa and a pI of 5.01. Further analysis revealed the presence of a conserved signature that is characteristic for HSP70s and phylogenetic analysis demonstrated that TaHSC70 is a homolog of chloroplast HSP70s. TaHSC70 mRNA was present in leaves of both green and etiolated wheat seedlings and in stems and roots. The transcript level in roots was approximately threefold less than in leaves but light–dark treatment did not charge TaHSC70 expression. Following heat shock of wheat seedlings at 40°C, TaHSC70 expression increased in leaves of etiolated seedlings but remained stable at the same level in green seedlings. In addition, TaHSC70 was differentially expressed during an incompatible and compatible interaction with wheat-stripe rust, and there was a transient increase in expression upon treatment with methyl jasmonate (MeJA) treatment. Salicylic acid (SA), ethylene (ET) and abscisic acid (ABA) treatments had no influence on TaHSC70 expression. These results suggest that TaHSC70 plays a role in stress-related responses, and in defense responses elicited by infection with stripe rust fungus and does so via a JA-dependent signal transduction pathway.

Calcium is a ubiquitous and essential secondary messenger in eukaryotic signal transduction pathways. Calcium binding protein, as a component of pathways, plays various roles in response to biotic and abiotic stresses, as well as in developmental processes in plants. In this study, a calcium binding protein gene, designated as TaCab1 (Triticum aestivum calcium binding EF-hand protein 1), was isolated and characterized from wheat leaves (cv. Suwon 11) infected by Puccinia striiformis f. sp. tritici by in silico cloning and reverse transcription PCR (RT-PCR). TaCab1 did not have an intron and was predicted to encode a 216 amino acid protein which possesses an N-terminal region with a signal peptide, a transmembrane domain, an EF-hand motif and a caleosin domain. The results of transient assays with constructs of TaCab1 with green fluorescent protein (GFP) gene indicated that TaCab1 encodes a transmembrane protein. Quantitative real-time PCR (qRT-PCR) analyses revealed that TaCab1 was highly expressed in leaves than roots and stems. Although up-regulated expression profiles of TaCab1 were quite similar in both incompatible and compatible interactions, its transcript accumulation in the compatible interaction was much higher than in the incompatible interaction. The transcription of TaCab1 was also up-regulated at different degrees after treated by phytohormones [abscisic acid, benzyl adenine, ethylene, methyl jasmonate and salicylic acid (SA)] and stress stimuli [wounding, low temperature, polyethylene glycol and high salinity]. These results suggest that TaCab1 is involved in the plant-pathogen recognition, symptom development, and the basal tolerance to biotic and abiotic stresses through the SA signaling pathway.