ALBERT

Description: Bioenergy from crops is expected to make a considerable contribution to climate change mitigation. However, bioenergy is not necessarily carbon neutral because emissions of CO 2 , N 2 O and CH 4 during crop production may reduce or completely counterbalance CO 2 savings of the substituted fossil fuels. These greenhouse gases (GHGs) need to be included into the carbon footprint calculation of different bioenergy crops under a range of soil conditions and management practices. This review compiles existing knowledge on agronomic and environmental constraints and GHG balances of the major European bioenergy crops, although it focuses on dedicated perennial crops such as M iscanthus and short rotation coppice species. Such second-generation crops account for only 3% of the current European bioenergy production, but field data suggest they emit 40% to 〉99% less N 2 O than conventional annual crops. This is a result of lower fertilizer requirements as well as a higher N-use efficiency, due to effective N-recycling. Perennial energy crops have the potential to sequester additional carbon in soil biomass if established on former cropland (0.44 Mg soil C ha −1  yr −1 for poplar and willow and 0.66 Mg soil C ha −1  yr −1 for M iscanthus ). However, there was no positive or even negative effects on the C balance if energy crops are established on former grassland. Increased bioenergy production may also result in direct and indirect land-use changes with potential high C losses when native vegetation is converted to annual crops. Although dedicated perennial energy crops have a high potential to improve the GHG balance of bioenergy production, several agronomic and economic constraints still have to be overcome.

Description: As already extensively discussed in Part I of this series, the ‘climax’ of the studies at the ETH on the synthesis of corrins was reached with the conception and experimental realization of the corrin synthesis via a final ring closure between rings A and D by the photochemical A / D -secocorrin corrin cycloisomerization. As it was the case for the ‘ old corrin synthesis ’, described in Part IV of this series [4], the ‘ new synthesis ’ was first explored in a model system, before it became the antetype of the photochemical variant of the synthesis of vitamin B 12 .

Description: Bioenergy from crops is expected to make a considerable contribution to climate change mitigation. However, bioenergy is not necessarily carbon neutral because emissions of CO 2 , N 2 O and CH 4 during crop production may reduce or completely counterbalance CO 2 savings of the substituted fossil fuels. These greenhouse gases (GHGs) need to be included into the carbon footprint calculation of different bioenergy crops under a range of soil conditions and management practices. This review compiles existing knowledge on agronomic and environmental constraints and GHG balances of the major European bioenergy crops, although it focuses on dedicated perennial crops such as M iscanthus and short rotation coppice species. Such second-generation crops account for only 3% of the current European bioenergy production, but field data suggest they emit 40% to 〉99% less N 2 O than conventional annual crops. This is a result of lower fertilizer requirements as well as a higher N-use efficiency, due to effective N-recycling. Perennial energy crops have the potential to sequester additional carbon in soil biomass if established on former cropland (0.44 Mg soil C ha −1  yr −1 for poplar and willow and 0.66 Mg soil C ha −1  yr −1 for M iscanthus ). However, there was no positive or even negative effects on the C balance if energy crops are established on former grassland. Increased bioenergy production may also result in direct and indirect land-use changes with potential high C losses when native vegetation is converted to annual crops. Although dedicated perennial energy crops have a high potential to improve the GHG balance of bioenergy production, several agronomic and economic constraints still have to be overcome.

Description: Mg 4.85 Rh 6 Si 13 was obtained from a mixture of the elements in an alumina crucible enclosed in a tantalum ampoule at 950 °C. The crystal structure was solved and refined from single crystal diffraction data [space group P 6 3 / mmc ; a = 8.709(1) Å, c = 22.240(1) Å]. The new structure type displays a three-dimensional [Rh 6 Si 13 ] framework, which contains Si 4 tetrahedra and Mg 2 @Si 18 polyhedra consisting of two magnesium centered truncated tetrahedra connected by a hexagonal face. The compound is a Pauli-paramagnetic metal with a high electrical resistivity.

Description: BACKGROUND: The median age for diagnosis of acute myeloid leukemia (AML) is 68 years. Elderly patients are often ineligible for intensive chemotherapy and have limited treatment options. Venetoclax (Ven), an oral agent that targets the antiapoptotic protein, BCL-2, has demonstrated high rates of remission (〉60%) when administered in combination with low-dose cytarabine (LDAC), and could represent a potent therapeutic option for patients ineligible for intensive chemotherapy. METHODS: This open-label, phase 1/2 study (NCT02287233) evaluated the safety and efficacy of venetoclax in combination with LDAC in patients with previously untreated AML who were ineligible for intensive chemotherapy due to comorbidities or age. Patients had an Eastern Cooperative Oncology Group (ECOG) performance score of 0-2, had adequate hepatic and renal function, and were enrolled from December 2014 to May 2017. In the dose escalation portion of the study, 600 mg venetoclax was determined to be the recommended phase 2 dose (RPTD). Venetoclax was initiated at 50 or 100 mg daily and dose escalated over 4-5 days to reach the RPTD. In subsequent 28 day cycles, venetoclax was administered at 600 mg on all days. LDAC (20 mg/m2 daily) was subcutaneously administered on days 1-10 of each cycle. At the beginning of the study, concominant strong and moderate CYP3A inhibitor use was prohibited; however, as additional safety and pharmacokinetic data became available, their use was allowed with appropriate venetoclax dose adjustments. Time to first response, rates of complete remission (CR), CR with incomplete blood count recovery (CRi), CR with partial hematologic recovery (CRh), duration of response, achievement of transfusion independence, overall survival (OS) and adverse events (AEs) were evaluated. Minimal residual disease (MRD) was evaluated centrally by multicolor flow cytometry at a cutoff of 10-3 leukemic cells. RESULTS: Data cutoff was November 8, 2017. Of 82 patients treated with 600 mg of venetoclax, 65% were male, 95% white race, 60% had intermediate and 32% had poor cytogenetic risk, and 49% had secondary AML (of whom 60% had prior HMA exposure). Transfusion dependence for red blood cells (RBC) and platelets within 8 weeks prior to venetoclax treatment was 65% (53/82) and 28% (23/82) of patients, respectively. Most common grade ≥3 AEs across all patients were febrile neutropenia (43%), thrombocytopenia (38%), neutropenia (27%), and anemia (27%). Laboratory evidence of grade 3 tumor-lysis syndrome (TLS) was observed in two patients; both patients achieved the target dose of venetoclax. Forty seven percent of patients received moderate (40%) or strong (7%) CYP3A inhibitors for at least 7 days (predominantly azole antifungals); no relevant differences in serious adverse event rates were observed. Key efficacy results are shown in the Table. Median time to first response was 1.4 months, and 54% and 46% of patients achieved CR/CRi and CR/CRh, respectively. The rates of CR/CRi for patients with secondary and de novo AML were 35% and 71%, respectively; median DOR for those with secondary and de novo AML was 8.1 and 11.6 months, respectively. Patients with selected genetic mutations achieved the following rates of CR/CRi: TP53, 30%; IDH1/2, 72%; FLT3, 44%; NPM1, 89%. MRD response below 10-3 cutoff was achieved by 32% of patients with CR/CRi; median OS has not yet been reached for these patients. Among patients that were RBC or platelet transfusion dependent at baseline, 49% (26/53) and 65% (15/23), respectively, achieved transfusion independence while on venetoclax therapy. CONCLUSIONS: Venetoclax in combination with LDAC led to rapid, deep, and durable responses in patients with AML who were ineligible for intensive chemotherapy. Venetoclax plus LDAC demonstrated an improved CR rate (26% vs. 8%), CR/CRi rate (54% vs. 11%) and median overall survival (10 months vs. 5 months) compared to the historical rates with LDAC alone. Furthermore, a majority of patients achieved transfusion independence during venetoclax therapy. Strong and moderate CYP3A inhibitors, including azole antifungals, were safely coadministered with appropriate venetoclax dose adjustments. These results demonstrate that venetoclax, in combination with LDAC, represents an effective therapeutic option for patients with AML who are not suitable for standard induction therapy. Disclosures Wei: Novartis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Servier: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding. Strickland:Boehringer Ingelheim: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas Pharma: Consultancy; Baxalta: Consultancy, Membership on an entity's Board of Directors or advisory committees; CTI Biopharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Tolero Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sunesis Pharmaceuticals: Consultancy, Research Funding. Fiedler:Amgen: Consultancy, Other: Meeting attendance, Patents & Royalties, Research Funding; ARIAD/Incyte: Consultancy; Novartis: Consultancy; Pfizer: Consultancy, Research Funding; Gilead: Other: Meeting attendance; GSO: Other: Meeting attendance; Teva: Other: Meeting attendance; JAZZ pharma: Other: Meeting attendance; Daiichi Sankyo: Other: Meeting attendance. Lin:Jazz Pharmaceuticals: Honoraria. Walter:Actinium Pharmaceuticals, Inc: Other: Clinical Trial support , Research Funding; Amgen Inc: Other: Clinical Trial Support, Research Funding; Amphivena Therapeutics, Inc: Consultancy, Other: Clinical Trial Support, Research Funding; Aptevo Therapeutics, Inc: Consultancy, Other: Clinical Trial Support, Research Funding; Covagen AG: Consultancy, Other: Clinical Trial Support, Research Funding; Seattle Genetics, Inc: Consultancy, Other: Clinical Trial Support, Research Funding; Pfizer, Inc: Consultancy; Boehringer Ingelheim Pharma GmbH & Co. KG: Consultancy. Hong:Genentech Inc/Roche: Employment, Other: Ownership interests PLC. Chyla:AbbVie, Inc: Employment, Equity Ownership. Popovic:AbbVie Inc: Employment, Equity Ownership. Fakouhi:AbbVie, Inc: Employment, Equity Ownership. Xu:AbbVie, Inc: Employment, Equity Ownership. Hayslip:AbbVie: Employment, Equity Ownership. Roboz:Bayer: Consultancy; Pfizer: Consultancy; Bayer: Consultancy; AbbVie: Consultancy; AbbVie: Consultancy; Orsenix: Consultancy; Cellectis: Research Funding; Aphivena Therapeutics: Consultancy; Otsuka: Consultancy; Roche/Genentech: Consultancy; Astex Pharmaceuticals: Consultancy; Orsenix: Consultancy; Roche/Genentech: Consultancy; Daiichi Sankyo: Consultancy; Jazz Pharmaceuticals: Consultancy; Eisai: Consultancy; Celgene Corporation: Consultancy; Sandoz: Consultancy; Novartis: Consultancy; Celgene Corporation: Consultancy; Cellectis: Research Funding; Argenx: Consultancy; Jazz Pharmaceuticals: Consultancy; Daiichi Sankyo: Consultancy; Sandoz: Consultancy; Janssen Pharmaceuticals: Consultancy; Astex Pharmaceuticals: Consultancy; Janssen Pharmaceuticals: Consultancy; Celltrion: Consultancy; Aphivena Therapeutics: Consultancy; Argenx: Consultancy; Celltrion: Consultancy; Pfizer: Consultancy; Novartis: Consultancy; Otsuka: Consultancy; Eisai: Consultancy.

Description: Background: Multiple studies have demonstrated the modest efficacy of low-dose cytarabine (LDAC) in older patients (≥65 years) with Acute Myeloid Leukemia(AML) who are unlikely to benefit from an anthracycline and cytarabine intensive induction [CR/CRi rates of 10 - 26%; (CRi = complete remission with incomplete marrow recovery)]. Venetoclax, a selective BCL-2 inhibitor has demonstrated single-agent activity in patients with relapsed and refractory AML [Konopleva et al., ASH 2014]. When administered with LDAC, the recommended phase 2 dose (RP2D) of venetoclax was 600 mg daily [Lin et al., ASCO 2016 (abstract 7007)]. Here we present the safety and efficacy data at RP2D of venetoclax from the dose escalation and expansion phases of the study (NCT02287233). Methods: Patients enrolled as of 15DEC2015 are included in this analysis with a data cut-off date of 31MAR2016. Patients were eligible if considered unfit for intensive chemotherapy, had an ECOG performance status of 0-2 and adequate renal and liver function. Patients treated with cytarabine for a pre-existing myeloid disorder, or those with acute promyelocytic leukemia or active CNS involvement with AML were excluded from the study. Venetoclax 600 mg was administered orally once daily on days 2 - 28 of Cycle 1 and days 1 - 28 of subsequent cycles. A 5-day dose ramp-up schedule was followed to reach the 600 mg dose. LDAC 20 mg/m2 was administered s.c. daily on days 1-10 in 28-day cycles. To mitigate the potential risk of tumor lysis syndrome (TLS), all patients were hospitalized and received prophylaxis commencing 48 hours prior to venetoclax during Cycle 1. Adverse events (AEs) were graded by NCI CTCAE Version 4.0. Results: Twenty patients were enrolled in the study (escalation, n=8; expansion, n=12). The median age was 74 years (range: 66 - 87). 8/20 (40%) patients had an antecedent hematologic disorder. Median time on venetoclax was 147.5 days (range: 8 - 455). Grade 3/4 AEs (≥10% patients) excluding cytopenias were febrile neutropenia (35%), hypertension (20%), hypophosphatemia (20%), decreased appetite, increased blood bilirubin, hyponatremia, hypoxia, hypotension, pneumonia, sepsis, syncope, urinary tract infection, and vomiting (10% each). No events of TLS occurred. Venetoclax exposures on Cycle 1 Day 10 (with LDAC) vs. Cycle 1 Day 18 (venetoclax alone) were comparable. The mean ± SD of maximum observed concentration (Cmax, µg/mL/mg) were 2.04 ± 1.45 vs. 2.92 ± 2.15, respectively. The mean ± SD of area under the curve (AUC24, µg*hr/mL) were 33.3 ± 27.5 vs. 46.1 ± 36.8, respectively. Similarly, co-administration of venetoclax did not markedly affect LDAC exposures. The mean ± SD of Cmax (ng/mL) of LDAC on Cycle 1 Day 1 (LDAC alone) vs. Cycle 1 Day 10 (with venetoclax) were 158.89 ± 79.08 vs 166.49 ± 32.06, respectively. Similarly, the mean ± SD of AUCinf (ng*hr/mL) were 170.64 ± 102.86 vs 246.51 ± 93.41, respectively. 15/20 (75%) patients achieved an objective response (CR+CRi+PR). Of them, 14/20 (70%) patients had a CR+CRi; all 14 patients belonged to a subset of 18 patients with no prior myeloproliferative neoplasm (MPN). 16/19 (84%) patients with available data had their bone marrow blast percentage reduced to below 5%. The 12-month overall survival (OS) estimate for all patients was 74.7% (95% CI=49.4 - 88.6) and that for the responders (n=15) was 86.7% (95% CI=56.4 - 96.5). The overall response rates and 12-month OS estimates for patients with or without prior hypomethylating agent (HMA) and with or without MPN are summarized in Table 1. A Kaplan-Meier curve showing OS for responders vs. non-responders is shown in Figure 1. The median time to best response was 30 days (range: 23 - 169). Only 2/14 patients who achieved CR/CRi have died [disease progression (n=1), acute hepatic failure (n=1)]. Conclusions: Venetoclax (600 mg RP2D) plus LDAC demonstrated an acceptable safety and pharmacokenitic profile in patients aged ≥65 years with treatment-naive AML who are not eligible for an intensive anthracycline-containing induction chemotherapy. Clinical remission was achieved in the majority of patients. The median OS has not been reached. A substantially better survival in responders as compared to non-responders suggests that the improvement is likely due to treatment with venetoclax plus LDAC. Updated responses and survival estimates for all patients, including those in dose expansion phase that were enrolled after the preliminary data cut, will be presented. Disclosures Wei: Novartis: Honoraria, Research Funding. Strickland:Boehringer Ingelheim: Consultancy, Research Funding; CTI Biopharma: Consultancy; Daiichi Sankyo: Consultancy; Sanofi: Research Funding; Sunesis Pharmaceuticals: Consultancy, Research Funding; Alexion Pharmaceuticals: Consultancy; Ambit: Consultancy; Baxalta: Consultancy; Abbvie: Research Funding; Astellas Pharma: Research Funding; Celator: Research Funding; Cyclacel: Research Funding; GlaxoSmithKline: Research Funding; Karyopharm Therapeutica: Research Funding. Roboz:Agios, Amgen, Amphivena, Astex, AstraZeneca, Boehringer Ingelheim, Celator, Celgene, Genoptix, Janssen, Juno, MEI Pharma, MedImmune, Novartis, Onconova, Pfizer, Roche/Genentech, Sunesis, Teva: Consultancy; Cellectis: Research Funding. Fiedler:Amgen: Consultancy, Other: Travel, Patents & Royalties, Research Funding; Kolltan: Research Funding; Novartis: Consultancy; Teva: Other: Travel; Ariad/Incyte: Consultancy; Gilead: Other: Travel; Pfizer: Research Funding; GSO: Other: Travel. Martinelli:MSD: Consultancy; Celgene: Consultancy, Speakers Bureau; Ariad: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Genentech: Consultancy; BMS: Speakers Bureau; Novartis: Speakers Bureau; Roche: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau. Fakouhi:AbbVie Inc.: Employment, Other: may own stock. Darden:AbbVie Inc.: Employment, Other: may own stock. Dunbar:AbbVie Inc.: Employment, Other: may own stock. Zhu:AbbVie Inc.: Employment, Other: may own stock. Agarwal:AbbVie Inc.: Employment, Other: may own stock. Salem:AbbVie Inc.: Employment, Other: Stocks or options. Mabry:AbbVie Inc.: Employment, Other: May own stock. Hayslip:AbbVie Inc.: Employment, Other: May own stock.

Description: Immunotherapy trials targeting the induction of tumor-reactive T-cell responses in cancer patients appear to hold significant promise. Because nonmutated lineage-specific antigens and mutated idiotypic antigens may be coexpressed by tumor cells, the use of autologous tumor material to promote the broadest range of antitumor T-cell specificities has significant clinical potential in cancer vaccination trials. As a model for vaccination in the cancer setting, we chose to analyze the promotion of T-cell responses against Epstein-Barr virus (EBV)-transformed B-lymphoblastoid cell line (B-LCL)–derived antigens in vitro. A series of bulk antigenic formats (freeze–thaw lysate, trifluoroacetic acid lysate, extracted membranes, affinity-purified MHC class I– and class II–presented peptides, acid-eluted peptides) prepared from EBV B-LCLs were tested for their ability to stimulate EBV B-LCL–reactive CD4+ and CD8+ T lymphocytes in vitro when pulsed onto autologous dendritic cells (DCs). DC presentation of freeze–thaw lysate material derived from (either autologous or allogeneic) EBV B-LCLs with an Mr of 10 kd or larger stimulated optimal anti-EBV B-LCL responsiveness from freshly isolated CD4+ and CD8+ peripheral blood T cells. These in vivo “memory” T-cell responses were observed only in EBV-seropositive donors. CD4+ T-cell responses to lysate-pulsed DCs were Th1 type (ie, strong interferon-γ and weak interleukin-5 responses). While CD8+ T-cell responses were also observed in interferon-γ Elispot assays and in cytotoxicity assays, these responses were of low frequency unless the DC stimulators were induced to “mature” after being fed with tumor lysates. Optimal-length, naturally processed, and MHC class I– or class II–presented tumor peptides were comparatively poorly immunogenic in this model system.