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We report final analysis results from the PILOT study (NCT0348303) after a median follow-up of 18.2 mo (range, 1.2–32.8).

Approximately 50% of acute myeloid leukemia (AML) patients do not respond to induction therapy (primary induction failure [PIF]) or relapse after <6 months (early relapse [ER]). We have recently shown an association between an immune-infiltrated tumor microenvironment (TME) and resistance to cytarabine-based chemotherapy but responsiveness to flotetuzumab, a bispecific DART antibody-based molecule to CD3ε and CD123. This paper reports the results of a multicenter, open-label, phase 1/2 study of flotetuzumab in 88 adults with relapsed/refractory AML: 42 in a dose-finding segment and 46 at the recommended phase 2 dose (RP2D) of 500 ng/kg per day. The most frequent adverse events were infusion-related reactions (IRRs)/cytokine release syndrome (CRS), largely grade 1-2. Stepwise dosing during week 1, pretreatment dexamethasone, prompt use of tocilizumab, and temporary dose reductions/interruptions successfully prevented severe IRR/CRS. Clinical benefit accrued to PIF/ER patients showing an immune-infiltrated TME. Among 30 PIF/ER patients treated at the RP2D, the complete remission (CR)/CR with partial hematological recovery (CRh) rate was 26.7%, with an overall response rate (CR/CRh/CR with incomplete hematological recovery) of 30.0%. In PIF/ER patients who achieved CR/CRh, median overall survival was 10.2 months (range, 1.87-27.27), with 6- and 12-month survival rates of 75% (95% confidence interval [CI], 0.450-1.05) and 50% (95% CI, 0.154-0.846). Bone marrow transcriptomic analysis showed that a parsimonious 10-gene signature predicted CRs to flotetuzumab (area under the receiver operating characteristic curve = 0.904 vs 0.672 for the European LeukemiaNet classifier). Flotetuzumab represents an innovative experimental approach associated with acceptable safety and encouraging evidence of activity in PIF/ER patients. This trial was registered at www.clinicaltrials.gov as #NCT02152956.

Somatic TP53 mutations and 17p deletions with genomic loss of TP53 occur in 37% to 46% of acute myeloid leukemia (AML) with adverse-risk cytogenetics and correlate with primary induction failure, high risk of relapse, and dismal prognosis. Herein, we aimed to characterize the immune landscape of TP53-mutated AML and determine whether TP53 abnormalities identify a patient subgroup that may benefit from immunotherapy with flotetuzumab, an investigational CD123 × CD3 bispecific dual-affinity retargeting antibody (DART) molecule. The NanoString PanCancer IO360 assay was used to profile 64 diagnostic bone marrow (BM) samples from patients with TP53-mutated (n = 42) and TP53-wild-type (TP53-WT) AML (n = 22) and 45 BM samples from patients who received flotetuzumab for relapsed/refractory (R/R) AML (15 cases with TP53 mutations and/or 17p deletion). The comparison between TP53-mutated and TP53-WT primary BM samples showed higher expression of IFNG, FOXP3, immune checkpoints, markers of immune senescence, and phosphatidylinositol 3-kinase-Akt and NF-κB signaling intermediates in the former cohort and allowed the discovery of a 34-gene immune classifier prognostic for survival in independent validation series. Finally, 7 out of 15 patients (47%) with R/R AML and TP53 abnormalities showed complete responses to flotetuzumab (<5% BM blasts) on the CP-MGD006-01 clinical trial (NCT #02152956) and had significantly higher tumor inflammation signature, FOXP3, CD8, inflammatory chemokine, and PD1 gene expression scores at baseline compared with nonresponders. Patients with TP53 abnormalities who achieved a complete response experienced prolonged survival (median, 10.3 months; range, 3.3-21.3 months). These results encourage further study of flotetuzumab immunotherapy in patients with TP53-mutated AML.

Somatic TP53mutations and 17p deletions with genomic loss of TP53occur in 37% to 46% of acute myeloid leukemia (AML) with adverse-risk cytogenetics and correlate with primary induction failure, high risk of relapse, and dismal prognosis. Herein, we aimed to characterize the immune landscape of TP53-mutated AML and determine whether TP53abnormalities identify a patient subgroup that may benefit from immunotherapy with flotetuzumab, an investigational CD123 × CD3 bispecific dual-affinity retargeting antibody (DART) molecule. The NanoString PanCancer IO360 assay was used to profile 64 diagnostic bone marrow (BM) samples from patients with TP53-mutated (n = 42) and TP53-wild-type (TP53-WT) AML (n = 22) and 45 BM samples from patients who received flotetuzumab for relapsed/refractory (R/R) AML (15 cases with TP53mutations and/or 17p deletion). The comparison between TP53-mutated and TP53-WT primary BM samples showed higher expression of IFNG, FOXP3, immune checkpoints, markers of immune senescence, and phosphatidylinositol 3-kinase-Akt and NF-κB signaling intermediates in the former cohort and allowed the discovery of a 34-gene immune classifier prognostic for survival in independent validation series. Finally, 7 out of 15 patients (47%) with R/R AML and TP53abnormalities showed complete responses to flotetuzumab (<5% BM blasts) on the CP-MGD006-01 clinical trial (NCT #02152956) and had significantly higher tumor inflammation signature, FOXP3, CD8, inflammatory chemokine, and PD1gene expression scores at baseline compared with nonresponders. Patients with TP53abnormalities who achieved a complete response experienced prolonged survival (median, 10.3 months; range, 3.3-21.3 months). These results encourage further study of flotetuzumab immunotherapy in patients with TP53-mutated AML.

•The overall response rate for low-dose subcutaneous decitabine was 33% in this prospective clinical trial of 21 patients with myelofibrosis.•A high International Prognostic Scoring System score, high fetal hemoglobin, and decrease in circulating CD34+cells were associated with response.

Background: For the 30%-40% of patients with large B-cell lymphoma (LBCL) who are not cured after first-line therapy, traditional second-line therapy has been high-dose chemotherapy (HDCT) and hematopoietic stem cell transplantation (HSCT). Recent studies have challenged this paradigm, showing a PFS/OS benefit to CAR T cell therapy over HDCT/HSCT in patients with high-risk, transplant-intended disease at first relapse. Given the lack of effective therapeutic options, outcomes have been historically poor for patients not intended to receive HDCT/HSCT. Lisocabtagene maraleucel (liso-cel) is an autologous, CD19-directed, 4-1BB CAR T cell product administered at equal target doses of CD8 +and CD4 +CAR +T cells. The open-label phase 2 PILOT study (NCT03483103) evaluated the efficacy and safety of liso-cel in patients with R/R LBCL not intended for HSCT after 1 prior line of therapy. In the primary analysis, the primary endpoint was met with an ORR of 80%. Here, we report the final analysis results from PILOT after a median follow-up of 18.2 mo (range, 1.2-32.8).

Background

Freytes: Sanofi: Speakers Bureau. Stevens:Amgen, MorphoSys: Consultancy. Varela:Neximmune: Consultancy, Current equity holder in private company. Cherry:Kite: Other: Ad Board; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Other: Ad Board; Epizyme: Other: Ad Board . Essell:Kite: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau. Courtright:AbbVie: Other: Investigator in AbbVie-sponsored clinical trials.. Fanning:Takeda: Consultancy, Speakers Bureau; Abbvie: Consultancy; Sanofi Aventis: Speakers Bureau; TG Therapeautics: Consultancy; Bristol Myers Squibb: Consultancy, Speakers Bureau; Prisma Health: Current Employment. Yimer:Sanofi: Speakers Bureau; AstraZeneca: Consultancy, 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; Janssen: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding, Speakers Bureau; BeiGene: Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding, Speakers Bureau; Epizyme: Consultancy, Divested equity in a private or publicly-traded company in the past 24 months; Karyopharm: Consultancy, Divested equity in a private or publicly-traded company in the past 24 months, 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: Consultancy, 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; Celgene, a Bristol-Myers Squibb Company: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Speakers Bureau; TG Therapeutics: Consultancy; Texas Oncology: Current Employment. Trede:Juno Therapeutics, a Bristol-Myers Squibb Company: Current Employment; Bristol-Myers Squibb Company: Current equity holder in publicly-traded company. Youssef:Bristol-Myers Squibb Company: Current Employment, Current equity holder in publicly-traded company. Lymp:Juno Therapeutics, a Bristol-Myers Squibb Company: Current Employment; Bristol-Myers Squibb Company: Current equity holder in publicly-traded company. Bachier:Juno Therapeutics, a Bristol-Myers Squibb Company: Honoraria; CRISPR: Honoraria; AlloVir: Honoraria; Sanofi: Speakers Bureau.

We have recently shown that bone marrow (BM) RNA profiles stratify patients with acute myeloid leukemia (AML) into immune-infiltrated and immune-depleted subtypes and that type I/II interferon (IFN)-related gene signatures associate with complete response to flotetuzumab (FLZ), an investigational CD123×CD3 bispecific DART molecule. Within the AML tumor microenvironment CD8+T cells exhibit features of immune exhaustion and senescence (IES). IES are dysfunctional states driven by metabolic alterations in the tumor microenvironment (TME) and emerging targets for cancer immunotherapy. The aim of the current study was to determine whether IES predicts response of relapsed-refractory (R/R) AML to FLZ in the CP-MGD006-01 clinical trial.

Introduction:CRS is a potentially life-threatening toxicity observed following T cell-redirecting therapies. CRS is associated with elevated cytokines, including IL6, IFNγ, TNFα, IL2 and GM-CSF. Glucocorticosteroids (GC) and the IL6 receptor blocking antibody tocilizumab (TCZ) can reduce CRS severity; however, CRS may still occur and limit the therapeutic window of novel immunotherapeutic agents. Disruption of cytokine signaling via Janus kinase (JAK) pathway interference may represent a complementary approach to blocking CRS. Ruxolitinib (RUX), an oral JAK1/2 inhibitor approved for the treatment of myelofibrosis and polycythemia vera, interferes with signaling of several cytokines, including IFNγ and IL6, via blockade of the JAK/STAT pathway. We hypothesized that RUX may reduce the frequency and severity of CRS in R/R AML patients (pts) undergoing treatment with flotetuzumab (FLZ), an investigational CD123 x CD3 bispecific DART® molecule.

Aldoss: abbvie: Consultancy, Research Funding; agios: Honoraria; kite: Consultancy; autolus limited: Consultancy; JAZZ: Honoraria, Speakers Bureau; Amgen: Consultancy; Agios: Consultancy. Uy:Genentech: Consultancy; Agios: Consultancy; Pfizer: Consultancy; Jazz Pharmaceuticals: Consultancy; Daiichi Sankyo: Consultancy; Astellas Pharma: Honoraria. Emadi:Amgen: Membership on an entity's Board of Directors or advisory committees; NewLink Genetics: Research Funding; Jazz Pharmaceuticals: Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; KinaRx: Other: co-founder and scientific advisor; Servier: Membership on an entity's Board of Directors or advisory committees. Walter:Aptevo Therapeutics: Research Funding. Foster:Daiichi Sankyo: Consultancy; Bellicum Pharmaceuticals: Research Funding; Macrogenics: Consultancy, Research Funding. Arellano:Hanmi: Research Funding; Gilead Sciences, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cephalon Oncology: Research Funding. Wieduwilt:Amgen: Research Funding; Macrogeneics: Research Funding; Leadiant: Research Funding; Merck: Research Funding; Shire: Research Funding; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees. Michaelis:Jazz Pharmaceuticals: Research Funding. Stiff:Kite, a Gilead Company: Research Funding; Gamida Cell: Research Funding; Atara: Research Funding; Unum: Research Funding; Delta-Fly: Research Funding; Macrogenics: Research Funding; Amgen: Research Funding. Advani:Novartis: Consultancy, Other: advisory board; Pfizer: Honoraria, Research Funding; Takeda: Research Funding; OBI: Research Funding; Kite: Other: Advisory board/ honoraria; Amgen: Consultancy, Other: steering committee/ honoraria, Research Funding; Seattle Genetics: Other: Advisory board/ honoraria, Research Funding; Immunogen: Research Funding; Glycomimetics: Consultancy, Other: Steering committee/ honoraria, Research Funding; Macrogenics: Research Funding; Abbvie: Research Funding. Wermke:MacroGenics: Honoraria. Erba:AbbVie, Daiichi Sankyo, Forma, ImmunoGen, Jazz Pharmaceuticals, MacroGenics, Novartis, PTC: Research Funding; Glycomimetics: Other: member of Scientific Steering Committee; Celgene: Other: chair of the Scientific Steering Committee; Covance (AbbVie): Other: chair of the Independent Review Committee; AbbVie, Agios, Celgene, Incyte, Jazz Pharmaceuticals, and Novartis: Speakers Bureau; AbbVie, Agios, Amgen, Astellas, Celgene, Daiichi Sankyo, Glycomimetics, ImmunoGen, Incyte, Jazz Pharmaceuticals, MacroGenics, Novartis, and Pfizer: Consultancy. Topp:Amgen, Boehringer Ingelheim, KITE, Regeneron, Roche: Research Funding; Amgen, KITE, Novartis, Regeneron, Roche: Consultancy. Ravandi:Abbvie: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Xencor: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Macrogenics: Research Funding; Celgene: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria; Orsenix: Consultancy, Honoraria, Research Funding. Muth:MacroGenics, Inc.: Current Employment, Current equity holder in publicly-traded company. Collins:IQVIA: Other: I have worked as a contractor for IQVIA in the past, within the past 24 months.; MacroGenics: Current equity holder in publicly-traded company, Other: I currently work as a contractor for MacroGenics. Guo:Macrogenics: Current Employment. Tran:MacroGenics: Current Employment. Kaminker:MacroGenics, Inc.: Current Employment, Current equity holder in publicly-traded company. Patel:MacroGenics: Current Employment. Bakkacha:MacroGenics: Current Employment. Jacobs:MacroGenics: Current Employment. Seiler:MacroGenics: Current Employment. Rutella:Kura Oncology: Research Funding; MacroGenics Inc.: Research Funding; NanoString Technologies Inc.: Research Funding. Bonvini:MacroGenics, Inc.: Current Employment, Current equity holder in publicly-traded company. Davidson-Moncada:Macrogenics: Current Employment. DiPersio:Magenta Therapeutics: Membership on an entity's Board of Directors or advisory committees.

AbstractHerbicide resistance to several of the most common weed species in US rice production, such as barnyardgrass and red rice, has made weed control extremely difficult with available herbicide options. No very-long-chain fatty acid–inhibiting herbicides are labeled for use in US rice; however, pethoxamid is one such herbicide under development for soil-applied use to control grasses and small-seeded broadleaves in rice and various row crops. Field trials were conducted in 2015 and 2016 near Stuttgart, AR, for rice tolerance and in 2016 near Colt, AR, and Lonoke, AR, for weed control with the use of pethoxamid-containing rice herbicide programs. Pethoxamid was applied alone and in a program at 420 and 560 g ai ha–1with other herbicides labeled in rice including clomazone, quinclorac, propanil, imazethapyr, and carfentrazone POST. Injury less than 10% was seen for all treatments 2 wk after application in 2015 and 2016, except for pethoxamid at 420 g ha–1to clomazone to one-leaf rice. Rice injury dissipated to less than 5% following all treatments by 4 wk after flood establishment. Barnyardgrass was controlled 95% or more near Colt and 93% or more near Lonoke for herbicide programs including clomazone PRE followed by pethoxamid plus quinclorac or imazethapyr at three- to four-leaf stage rice. Considering the minimal injury and high levels of barnyardgrass control associated with pethoxamid-containing weed control programs, pethoxamid provides a unique and effective site of action for use in US rice production.

AbstractThe evolution of herbicide resistance is making it extremely difficult for US rice producers to use chemical control on weed species such as barnyardgrass and red rice. To combat herbicide resistance, it is imperative that alternative herbicide sites of action (SOAs) be incorporated into rice whenever possible. There are currently no very-long-chain fatty acid–inhibiting herbicides (WSSA Group 15) labeled for use in US rice; however, pethoxamid is one such herbicide currently under development. If appropriate rice tolerance and weed control can be established, pethoxamid would represent a unique herbicide SOA for use in US rice. We conducted field trials near Stuttgart, AR, in 2015 and near Colt and Lonoke, AR, in 2016 to assess selectivity of pethoxamid and weed control alone and in combination with other herbicides as a delayed preemergence (DPRE) application in drill-seeded rice. Pethoxamid was applied at 0, 420, or 560 g ai ha–1alone and in combination with clomazone, imazethapyr, pendimethalin, and quinclorac. Minimal rice injury occurred with any treatment assessed. A reduction in rice shoot density and plant height compared to the nontreated control followed the use of pethoxamid; however, no decrease in yield resulted. The highest levels of barnyardgrass control followed the use of imazethapyr at 91% and quinclorac at 89% regardless of the presence of pethoxamid near Lonoke; however, pethoxamid applied at both rates in combination with clomazone and quinclorac increased barnyardgrass control compared to clomazone and quinclorac applied alone. Near Colt, barnyardgrass control of 92% and 96% resulted from pethoxamid alone, averaged over the high and low rates. Based on these data, rice can tolerate pethoxamid when applied DPRE, and adequate levels of barnyardgrass control can be achieved at the rates evaluated within a program; hence, pethoxamid appears to be a viable option for use in rice to allow for increased rotation of herbicide SOAs to combat herbicide-resistant and difficult-to-control weeds.

Prior to novel targeted agents for chronic lymphocytic leukemia (CLL), the best chemoimmunotherapy regimen in patients with non-del(11q) disease was unclear. The role of lenalidomide was also not defined. This phase 2 study randomized 342 untreated patients with non-del(11q) CLL requiring therapy to fludarabine plus rituximab (FR; n = 123), FR plus lenalidomide consolidation (FR+L; n = 109), or FR plus cyclophosphamide (FCR; n = 110) and compared 2-year progression-free survival (PFS) rates of each to the historical control rate with FC (60%). Patients with del(11q) in at least 20% of pretreatment cells continued with FCR (n = 27) or were reassigned to FCR+L (n = 31) and excluded from the primary analysis. Among non-del(11q) patients, 2-year PFS rates were 64% (90% confidence interval [CI], 57-71; FR), 72% (90% CI, 65-79; FR+L), and 74% (90% CI, 66-80; FCR); FR+L and FCR had rates significantly greater than historical control. Median PFS was significantly shorter with FR compared with FR+L (P= .04) and FCR (P< .001): 43 (95% CI, 33-50), 61 (95% CI, 45-71), and 97 (95% CI, 61 to not reached) months, respectively. Median follow-up was 73 months and median overall survival (OS) was only reached with FCR (101 months; 95% CI, 96 to not reached). With FR+L, the risk of death decreased over time and was lower than with FR at later time points (P= .01), but not significantly different from FCR (P= .21). Future studies incorporating short courses of lenalidomide into other novel treatment regimens are justified.

ABSTRACTIsland ecosystems are highly threatened by invasive rats and mice. Currently, the only effective technology for eradicating rodents from islands is toxicants. Though effective, they are expensive and have high failure rates. They are not species-specific and are potentially dangerous to humans. Gene drive technology is one alternative to toxicants for rodent eradication. Gene drive methods of rodent eradication offer an alternative to killing that has the potential to be more species-specific, more humane, and more biologically safe for use around humans. Technologies in development aim to apply either natural meiotic drive or clustered regularly interspersed short palindromic repeats to influence offspring development so that all offspring are phenotypically male, eventually creating a population that is not reproductively viable. Implementing this technology would involve releasing laboratory-developed engineered mice into wild populations. Some areas for further research include assessing the ecological effects of releasing engineered mice, the potential risks for the accidental or deliberate release of genetically modified organisms into mainland mouse populations, and the social, ethical, and regulatory acceptability of the technology.

The recent vehicle management systems have been developing to improve the quality of the combustion process and transmission systems. In thermodynamic approach, the water molecule can exists in different phases like ice, water, wet steam, dry steam, and superheated steam. The phase change occurs in the steam formation process can be compared to the various stages of any vehicle dynamic system such starting, idling, normal speed, high speed and very high speed. There may be an identical value in the increment of energy level in both steam formation process and any vehicle dynamic system. Thermodynamic approach always deals with system, surroundings, boundary and energy transformation across boundaries. Entropy is a very good property which is used to find the energy degradation in a particular system, and this property existence in the vehicle dynamics of automobiles will be used to improve the efficiency of the control module of a vehicle management system. This paper initiates a new angle research in the field of vehicle dynamics to study and investigate the kinetic energy transformation and distance moved by the vehicle thermodynamically. From this paper, Entropy is found as a very good property for increasing the mileage of the vehicle. In the vehicle health monitoring, there should be an entropy measurement to reduce the unavailability of energy as it is the measure of the distance travelled by the vehicle per unit energy supplied to the same vehicle at various operating speeds. In manual transmission method, it has been found that driver is not able to press the accelerator pedal continuously due to body strain. Driver has to run the vehicle at constant speed by pressing the accelerator pedal continuously. In automatic transmission, the data required for the ECU module is given by the thermodynamic relations such as enthalpy, entropy and internal energy. This paper aims thermodynamically to describe the speed, acceleration, fuel consumption, kinetic energy and various resistances offered to the vehicles. Generally, Thermodynamic system deals with heat and mass transfer, likewise vehicle dynamics deals with work and vehicle’s motion.