Standard Schedule Research Articles

ТЕХНОЛОГИЯ АВТОМАТИЗИРОВАННОЙ КОРРЕКТИРОВКИ НОРМАТИВНЫХ ГРАФИКОВ ДВИЖЕНИЯ ПОЕЗДОВ С ПРИМЕНЕНИЕМ ПРОГРАММНЫХ РОБОТОВ

The article discusses the technological aspects of automated adjustment of standard train schedules using software robots. The information environment and existing technology for main-taining standard freight train schedules are considered. Information is provided on the implemen-tation of robotic process automation in corporate information systems operated in traffic control directorates. The stages and results of automating the adjustment of standard train schedules using software robots are considered. A generalized diagram of the process of adjusting standard train schedules using a software robot and a special data converter is presented. A fragment of the robot code for uploading the standard schedule into the Elbrus hardware and software complex is given. The issues of using Python programming language libraries to automate processes are considered. An assessment was made of the effectiveness of using software robots to adjust standard sched-ules. The possibilities of joint robotic and intelligent automation for adjusting train schedules are considered.

Flexible job-shop scheduling problem with parallel batch machines based on an enhanced multi-population genetic algorithm

AbstractThe flexible job-shop scheduling problem (FJSP) with parallel batch processing machine (PBM) is one of those long-standing issues that needs cutting-edge approaches. It is a recent extension of standard flexible job shop scheduling problems. Despite their wide application and prevalence in practical production, it seems that current research on these types of combinatorial optimization problems remains limited and uninvestigated. More specifically, existing research mainly concentrates on the flow shop scenarios in parallel batch machines for job shop scheduling but few literature emphasis on the flexible job shop integration in these contexts. To directly address the above mentioned problems, this paper establishes an optimization model considering parallel batch processing machines, aiming to minimize the maximum completion time in operating and production environments. The proposed solution merges variable neighborhood search with multi-population genetic algorithms, conducting a neighborhood search on the elite population to reduce the likelihood of falling into local optima. Subsequently, its applicability was evaluated in computational experiments using real production scenarios from a partnering enterprise and extended datasets. The findings from the analyses indicate that the enhanced algorithm can decrease the objective value by as much as 15% compared to other standard algorithms. Importantly, the proposed approach effectively resolves flexible job shop scheduling problems involving parallel batch processing machines. The contribution of the research is providing substantial theoretical support for enterprise production scheduling.

Cost and performance aware scheduling technique for cloud computing environment

Recently, lot of interest have been put forth by researchers to improve workload scheduling in cloud platform. However, execution of scientific workflow on cloud platform is time consuming and expensive. As users are charged based on hour of usage, lot of research work have been emphasized in minimizing processing time for reduction of cost. However, the processing cost can be reduced by minimizing energy consumption especially when resources are heterogeneous in nature; very limited work have been done considering optimizing cost with energy and processing time parameters together in meeting task quality of service (QoS) requirement. This paper presents cost and performance aware workload scheduling (CPA-WS) technique under heterogeneous cloud platform. This paper presents a cost optimization model through minimization of processing time and energy dissipation for execution of task. Experiments are conducted using two widely used workflow such as Inspiral and CyberShake. The outcome shows the CPA-WS significantly reduces energy, time, and cost in comparison with standard workload scheduling model.

Continuous PEGasparaginase Dosing Reduces Hypersensitivity Reactions in Pediatric ALL: A Dutch Childhood Oncology Group ALL11 Randomized Trial.

The primary objective of this randomized study was to determine whether a continuous dosing schedule (without the asparaginase-free interval) would result in less hypersensitivity reactions to PEGasparaginase (PEGasp) compared with the standard noncontinuous dosing schedule. Eight hundred eighteen patients (age 1-18 years) with ALL were enrolled in the Dutch Childhood Oncology Group-ALL11 protocol and received PEGasp. Three hundred twelve patients stratified in the medium-risk arm were randomly assigned to receive 14 individualized PEGasp doses once every two weeks in either a noncontinuous or continuous schedule after the first three doses in induction (EudraCT: 2012-000067-25). Hypersensitivity reactions were defined as allergies, allergic-like reactions, and silent inactivation. Secondary end points were other asparaginase-related toxicities, asparaginase activity and antibody levels, and outcome. During induction, 27 of 818 patients (3.3%) experienced hypersensitivity reactions. After random assignment, 4 of 155 (2.6%) in the continuous treatment arm versus 17 of 157 (10.8%) patients in the noncontinuous treatment arm had hypersensitivity reactions (P < .01), of which two (1.3%) versus 13 (8.3%) were inactivating reactions (P < .01). The occurrence of inactivating hypersensitivity reactions was seven times lower in the continuous arm (odds ratio, 0.15 [0.032-0.653]). In addition, antibody levels were significantly lower in the continuous arm (P < .01). With exception of a lower incidence of increased amylase in the continuous arm, there were no significant differences in total number of asparaginase-associated toxicities between arms. However, the timing of the toxicities was associated with the timing of the asparaginase administrations. No difference in 5-year cumulative incidence of relapse, death, or disease-free survival was found between both treatment arms. A continuous dosing schedule of PEGasp is an effective approach to prevent antibody formation and inactivating hypersensitivity reactions. The continuous PEGasp schedule did not increase toxicity and did not affect the efficacy of the therapy.

THE SECRETS OF SPEAKING THE LANGUAGE FLUENTLY

Language is the way to explore new knowledge, culture and people. And most people want to learn English which becomes International language around the World and speak fluently in this language. The problem is that most schools have a lot of pressure to go very fast. They are always pushing the students to learn more and more vocabulary and new grammar. This article illustrates some connections of language with repetition. Furthermore, if language teachers' training collaborated with not only standard lesson schedule, but also deep learning method, in today's world that is becoming more than easy to reach success in language learning.

Work hours, weekend working, nonstandard work schedules and sleep quantity and quality: findings from the UK household longitudinal study

BackgroundAtypical temporal work patterns such as working longer than the standard 35–40 h/ week, weekend working, and nonstandard work schedules (i.e. outside of the typical 9–5, including but not restricted to shiftwork) are increasingly prevalent in the UK. Aside from occupation-specific studies, little is known about the effects of these atypical temporal work patterns on sleep among workers in the UK, even though poor sleep has been linked to adverse health problems, lower workplace productivity, and economic costs.MethodWe used regression models to investigate associations between three types of atypical temporal work patterns (long and short weekly work hours, weekend working, and nonstandard schedules) and sleep duration and disturbance using data from over 25,000 employed men and women from 2012–2014 and/or 2015–2017 in the UK Household Longitudinal Study, adjusting for potential confounders and psychosocial work factors.ResultsWe found that relative to a standard 35–40 h/week, working 55 h/week or more was related to short sleep (less than 7 h/night) and sleep disturbance. Working most/all weekends compared to non-weekends was associated with short sleep, long sleep (more than 8 h/night), and sleep disturbance, as was working nonstandard schedules relative to standard schedules (fixed day-time schedules). Further analyses suggested some gender differences.ConclusionsThese results should prompt employers and policymakers to recognise the need for rest and recovery, consider how the timing and scheduling of work might be improved to better support workers’ health and productivity, and consider appropriate compensation for anyone required to work atypical temporal work patterns.

Reduced Cytokine Release Syndrome and Improved Outcomes with Earlier Immunosuppressive Therapy in Haploidentical Stem Cell Transplantation

The optimal timing of immunosuppression and post-transplantation cyclophosphamide (PTCy) in haploidentical hematopoietic stem cell transplantation (haplo-HSCT) is unknown. However, cytokine release syndrome (CRS) following haplo-HSCT is associated with worse transplantation outcomes, and the incidence of CRS may be affected by the timing of immunosuppression and PTCy. In this study, we compared CRS and other transplantation outcomes in 2 cohorts receiving different immunosuppression and PTCy schedules following haplo-HSCT. This was a retrospective cohort study of 91 patients who underwent haplo-HSCT at the Intermountain Health Blood and Marrow Transplant Program. The original or standard haplo-HSCT GVHD prophylaxis regimen included PTCy on days +3 and +4, with mycophenolate mofetil (MMF) and tacrolimus starting on day +5. The modified regimen adopted in November 2020 changed PTCy to days +3 and +5, with earlier introduction of tacrolimus and MMF, on day -1 and day 0, respectively. Grade ≥1 CRS occurred in 32% of patients in the modified regimen, in 82% of patients in the standard regimen (P <.0001), and 65% overall. Likewise, grade ≥2 CRS was lower with the modified regimen (16% versus 57%; P = .0002). The mean duration of CRS symptoms was longer with the standard regimen (3.14 days versus 1.44 days; P = .0003). The incidence of acute graft-versus-host disease grade III-IV or extensive chronic GVHD (cGVHD) at 1 year was lower in the modified regimen (6% versus 32%; P = .0068). No differences between the standard and modified regimens were seen in overall survival, relapse, or GVHD-free relapse-free survival (GRFS), although there appeared to be a trend toward improved GRFS with the modified regimen. Post hoc analysis comparing GRFS in patients with CRS and those without CRS found that CRS was associated with lower GRFS at 1 year (36% versus 63%; P = .0138). The duration of broad-spectrum antibiotic therapy was decreased by 7.5 days (P = .0017) and the time to hospital discharge was reduced by 7.1 days (P = .0241) with the modified regimen. This is the first analysis to evaluate and find a difference in CRS with early initiation of immunosuppressive therapy in haplo-HSCT. Our results suggest that this modified GVHD regimen benefits patients by reducing CRS and high-grade GVHD compared to the standard PTCy-based GVHD prophylaxis regimen in haplo-HSCT. Additionally, this novel regimen did not appear to negatively impact outcomes.

A phase I dose-escalation study of an all-in-one 5-fluorouracil and leucovorin co-formulation administered after failure of standard treatment.

140 Background: 5-fluorouracil (5-FU) and its biomodulator leucovorin (LV) are an efficacious treatment option for various solid tumours, and are considered the backbone of therapy for colorectal cancer. Standard administration schedules require sequential administration of the two agents due to their chemical incompatibility; given the importance of LV in modulating 5-FU activity, their simultaneous administration is expected to enhance anti-tumour efficacy. Deflexifol is an all-in-one injectable reformulation of 5-FU and LV at physiological pH. An initial phase I trial demonstrated the safety and efficacy of Deflexifol when administered as a bolus or infusion, with a maximum tolerated dose (MTD) of ≥25% more 5-FU than established for standard regimens. This subsequent phase I study sought to investigate Deflexifol administered as a combined bolus and infusion schedule. Methods: Patients with advanced malignancy who had failed standard treatment were administered Deflexifol as a bolus followed by a continuous 46-hr infusion. The infusional dose was escalated across four levels (2400 mg/m2 to 3800 mg/m2) in the absence of Dose Limiting Toxicity using a traditional 3+3 design; the bolus dose was fixed at the previously declared MTD of 525 mg/m2. The stated Deflexifol dose represents the dose of standard 5-FU delivered. Primary trial objectives were to determine the safety and tolerability of a bolus plus infusion regimen of Deflexifol, with a secondary objective to determine the pharmacokinetics and MTD. Efficacy was an exploratory objective. Results: Nineteen patients with mainly colorectal (n=13) and breast (n=4) cancers were enrolled and treated with Deflexifol. Approximately two-thirds of patients had previously received fluoropyrimidine treatment. Deflexifol was generally well tolerated, with the MTD declared as a 525 mg/m2 bolus plus 3400 mg/m2 infusion. Treatment-related toxicities were consistent with standard 5-FU/LV therapy; the most frequent Grade 1/2 adverse events were fatigue, mucositis, and diarrhea. Grade ≥3 adverse events were reported in 6/19 patients, including mucositis (2/19) and haematological toxicity (5/19). One treatment-related death occurred at the highest infusion dose level of 3800 mg/m2 due to haematological toxicity. Quantifiable 5-FU and LV concentrations were exhibited at all time-points. Disease control, including one partial response, was achieved in 9/13 evaluable patients. Conclusions: Deflexifol is safe and well tolerated at doses of 5-FU up to 40% higher than typically administered by the standard modified de Gramont regimen. 5-FU and LV co-exposure extended throughout the entire dosing period, substantially longer than reported for standard treatment. Disease control was achieved in 69% of patients. Clinical trial information: ACTRN12619001533189 .

Traffic rate agnostic end-to-end delay optimization using receiver-based adaptive link scheduling in 6TiSCH networks

Link scheduling is a key component in 6TiSCH networks. It mainly specifies a node is allowed to transmit packets through which link at what time and in which channel. There exist many link scheduling schemes in the literature for 6TiSCH networks. Among the distributed schemes, the Self-healing distributed scheduling for end-to-end delay optimization (Stratum) was specifically devised to minimize end-to-end latency. However, it performs worse in case of higher traffic rates. On the other hand, the de-facto link scheduling standard Minimal Scheduling Function (MSF) allocates cells (i.e. timeslot and channel) randomly in a slotframe for scheduling transmissions, and thus its end-to-end delay performance is not good under all traffic rates. Therefore, this paper proposes a traffic rate agnostic distributed link scheduling function (RTDS) for 6TiSCH networks. The RTDS follows a receiver-based cell selection and allocation strategy to reduce the waiting time of a packet in the buffer of receiving node before forwarding the packet towards final destination. Unlike MSF, the RTDS uses lesser number of control packet exchanges to adapt the schedule of a link based on the present network condition and traffic rate. The proposed RTDS scheme minimizes end-to-end latency under any traffic rate. RTDS is implemented in the 6TiSCH simulator. Simulation results show that RTDS can significantly improve the end-to-end latency compared to the benchmark schemes. For example, in an 80-node network, the RTDS reduces end-to-end latency by 58% and 43% in low and high traffic rates, respectively, compared to that in MSF. Further, it outperforms Stratum by 77% and 75% under the low and high traffic rates, respectively.

Supervision of The People's Representative Council of Aceh Besar District on The Direct Cash Assistance Program in Lhoong District

The aim of this research is to analyze and describe the implementation of the DPRK's supervisory policy on the realization ofthe BLT program in Lhoong sub-district, Aceh Besardistrict and to analyze and describe the supporting and inhibiting factors in implementing the DPRK's supervisory role on the realization of the BLT program in Lhoong sub-district, Aceh Besar district. The method used in this research is a qualitative approach with data analysis techniques using an interactive analysis process model. The results of this research indicate that the process of implementing DPRK supervision of the realization of the BLT programin Lhong District, Aceh Besar Regency prioritizeslocal wisdom so that the process can run well. However, regarding the supervision procedures of the Aceh Besar DPRK, it seems that this is still not the case because the mechanism is tentative and preventive because it is only carried out during initial planning and is not accompanied by a standard schedule.

Impact of Climate Change on Crop and Dairy Farming in Telangana: Agricultural Scientists Perspective

Climate change has comprehensive consequences on agriculture and livestock that will directly impact farmers, the perception of Agricultural scientists concerning climate change regionally is crucial in addressing its negative impacts effectively, thus the study was purposively conducted in the state of Telangana during 2021-2022 in nine major Indian institutes viz., ICRISAT, CRIDA, IIMR, IIOR, NIPHM, PJTSAU, NAARM, NIRD &amp; PR, and MANAGE to assess the perception of Agriculturalscientists on causes of climate change, changes in climatic parameters, and on the impact of climate change on crop and dairy farming, random sampling procedure was followed and the total respondents for the study was 150. Pre-tested and standardized interview schedules were used to obtain data. The study through scientists’ perception identified the most important causes of climate change, the most observed changes in climatic parameters, and, the greatest impact of climate change on crop and dairy farming. The composite index developed using Principal Component Analysis showed that most of the respondents had a medium level of perception. Thus, the perceptions of agricultural scientists should be tapped to their fullest potential by policymakers in framing suitable solutions for adverse climate change impacts.

The Psychological Security of an Individual in the Urban Environment: Definition of the Construct

The article analyzes the basic definitions of psychological security, the approaches to this phenomenon, and reviews the concepts of security psychology. It also provides a brief overview of how this concept emerged. Psychological security is examined in the context of environmental and urban settings, linking psychological security to individual characteristics of urban dwellers. The study shows that psychological security is considered in a variety of contexts, and the semantic field of psychological security has changed over time, psychological security of urban dwellers has mainly been studied in relation to overcoming fear of crime. A series of narrative interviews was performed to analyze the semantic field of the concept “psychological security of urban residents” in the individual consciousness of the respondents and to identify the indicators of psychological security. The respondents (n = 28) participating in the study represent Yekaterinburg residents with different levels of education, income, and length of residence in the city. The interviews collected information on the characteristics of the respondents (gender, age, education, income level, city residence time). It did not follow a standardized interview schedule, but included questions such as: “What do you think about the city you are living in now?”, “What is it like to live here?”, “Do you ever feel scared, worried, panicked or afraid in your daily life in this city?”, “Can you describe you sensations when you feel safe in your daily life?” The analysis of the interviews enabled us to obtain a representation of the state of psychological security of city dwellers and to identify universals that constitute the indicators of psychological security of city dwellers: “freedom”, “comfort”, “self-efficacy”, “trustworthy relationships”, “control over the environment” and “reliability”, which cover three different forms of experiences and reactions of individuals with regard to the city: affective, cognitive and behavioral. The definition of psychological security of the individual in the urban environment is formulated. This can serve as a basis for the development of recommendations for designing a safe urban environment.

The effect of a dynamic lighting schedule on neurobehavioral performance during a 45-day simulated space mission.

We previously reported that during a 45-day simulated space mission, a dynamic lighting schedule (DLS) improved circadian phase alignment and performance assessed once on selected days. This study aimed to evaluate how DLS affected performance on a 5-minute psychomotor vigilance task (PVT) administered multiple times per day on selected days. Sixteen crewmembers (37.4 ± 6.7 years; 5F) underwent six cycles of 2 × 8-hour/night followed by 5 × 5-hour/night sleep opportunities. During the DLS (n = 8), daytime white light exposure was blue-enriched (~6000K; Level 1: 1079, Level 2: 76 melanopic equivalent daytime illuminance (melEDI) lux) and blue-depleted (~3000-4000K; L1: 21, L2: 2 melEDI lux) 3 hours before bed. In the standard lighting schedule (SLS; n = 8), lighting remained constant (~4500K; L1: 284, L2 62 melEDI lux). Effects of lighting condition (DLS/SLS), sleep condition (5/8 hours), time into mission, and their interactions, and time awake on PVT performance were analyzed using generalized linear mixed models. The DLS was associated with fewer attentional lapses (reaction time [RT] > 500 milliseconds) compared to SLS. Lapses, mean RT, and 10% fastest/slowest RTs were worse following 5 compared to 8 hours of sleep but not between lighting conditions. There was an effect of time into mission on RTs, likely due to sleep loss. Overall performance differed by time of day, with longer RTs at the beginning and end of the day. There were more lapses and slower RTs in the afternoon in the SLS compared to the DLS condition. Future missions should incorporate DLS to enhance circadian alignment and performance. This paper is part of the Sleep and Circadian Rhythms: Management of Fatigue in Occupational Settings Collection.

Definitive chemo-radiotherapy in cervical oesophageal cancer: a comprehensive review of literature.

Despite decades of experience with definitive chemo-radiotherapy (CRT) in cervical oesophageal cancer (CEC), the loco-regional control and survival outcomes are dismal. This review evaluated the outcomes of various treatment strategies being commonly utilized. A literature review was conducted to identify relevant articles on CEC published from years 2000-2023 addressing the predefined key questions. These questions focussed on the comparative outcomes of various primary treatment approaches (surgery, CRT, or trimodality treatment) and the radiation dose schedules, volumes, and techniques. CRT is the standard approach for treatment for CEC so far. The potential role of surgery and trimodality approach in settings of evolving surgical approaches needs to be validated. The high dose schedules that are preferentially practiced in CEC have not shown any benefit in improving the disease outcomes over the standard dose schedule of 50.4 Gy. The target volume delineation practice of elective nodal irradiation (ENI) does not have a proven benefit over the involved field irradiation (IFI). The limited evidence on radiation techniques suggests that intensity-modulated radiotherapy/volumetric-modulated arc therapy (IMRT/VMAT) techniques can improve toxicity profile over three-dimensional conformal radiotherapy (3DCRT), but no advantage proven in disease outcomes so far. This review will guide clinicians in decision-making for the management of this relatively rare entity and the directions for future research in these areas. Future large-scale multicentre prospective studies are needed for validating and standardizing our current practices and exploring potential options to improve the outcomes.

Achieving better Resource Utilization by Implementing a High-Performance Intelligent Framework in a Distributed Environment

Multi-distributed high-performance computers from many companies are aggregated into a single computing platform to provide handlers with uniform contact besides convention outlines. Job arrangement strategies in High-Performance Computing (HPC) environments are lacking in flexibility, so an enhanced computational intelligence automated system in the task ready queue, refinement of the principal planner aimed at every job, and increased arrangement of the job setting up plan are proposed in this paper, which introduces an improved task scheduling model. The swarm intelligence method is used in core task scheduling to reduce the average scheduling time for completing tasks by assigning jobs to each node in the most efficient manner possible. The suggested scheduling technique outperforms the standard work scheduling approach in simulations. Task waiting times can be reduced, system throughput increased, task response times improved, and system resources better utilized by using a job setting up method created on group Acumen systems

From Aviation to Web Standarts: Transformation of SSIM Files into JSON Format

Considering dynamic changes in the aviation sector, successful data exchange and integration planning plays a pivotal role in maintaining operational efficiency of airlines. Although the SSIM (Standard Schedules Information Manual) file is considered a reliable format, it has certain limitations regarding interaction and compatibility with other web technologies and programs due to its text format strictly defined by the specification. In this work, we propose an approach to convert SSIM files into the JSON (JavaScript Object Notation) format. One of the central aspects of this work is a detailed transformation model that considers all the important structures and levels of information of the SSIM file, conducts their syntactic analysis, and converts them into a flexible and easily recoverable JSON format. To transform a set of aviation flights into a combined flying line, a modified branch and bound method is used. With a series of examples and experiments, the article aims to demonstrate the effectiveness of this methodology in terms of preserving data integrity and ensuring their accuracy. In particular, the problems faced during the transformation, for example, how to consider the consistency of data rows with fixed width in the SSIM file, are considered. The transition from aviation-oriented formats, such as the SSIM file, to global web formats, such as JSON, is a process that goes beyond technologies and aims to increase the flexibility and convenience of collaboration, as well as data processing in the aviation industry. This research helps to implement this change, offering a simple, effective, and scalable approach for converting airline schedules into a format that by its nature meets the needs of modern information applications and systems.

Планирование и содержание воспитательной работы в образовательных организациях системы МВД России

Introduction. The relevance of the research is determined by amendments to Federal Law No. 273-FZ dated December 29, 2012 «On Education in the Russian Federation», which fixed general requirements for the organization of educational activitiesfor students. In accordance with these changes, it became necessary to work on the creation and approval of a standard work program for education and a standard calendar plan for educational activities and trainingin educational organizations of the Ministry of Internal Affairs of the Russian Federation.&#x0D; Research methods. The author used a set of general scientific methods of cognition (analysis, synthesis, induction, deduction).&#x0D; The results of the research. The analysis of regulatory legal acts of the Russian Federation regulating educational activities in educational institutions of higher education is carried out. Based on this analysis and taking into account the orientation of educationalactivities in the system of the Ministry of Internal Affairs of the Russian Federation, an approximate structure and content of a standard work program of educational activities and a standard calendar schedule of educational activities are proposed, as well as legal, organizational, methodological and methodological foundations for their development are outlined. The proposed guidelines for planning educational activities with cadets and students of educational organizations of the Ministry of Internal Affairs of Russia are recommended to be used by members of the educational process. The article presents a detailed list of educational activities. The following modules are highlighted: patriotic education, professional education, legal education, moral and ethical education, aesthetic education, spiritual and moral education, scientific and educationalactivity, physical education, environmental education.The allocation of the abovementioned modules is justified by the logic of building educational activities and the need to create an educational environment in educational organizations of the Ministry of Internal Affairs of Russia, as well as the requirements of legislation in the field of education and moral and psychological support for the activities of internal affairs bodies of the Russian Federation.

Implementation of Continuous Pegasparaginase Dosing without an Asparaginase-Free Interval Reduces Hypersensitivity in Children with Newly Diagnosed Acute Lymphoblastic Leukemia: Results of the DCOG ALL11 Pegasparaginase Randomization

Background: Asparaginase is key in the treatment of pediatric acute lymphoblastic leukemia (ALL). Hypersensitivity is one of its major side effects and hamper its use. Most hypersensitivity reactions occur after an asparaginase-free interval, as neutralizing anti-drug antibodies increase during these intervals. Thus we hypothesized that a continuous PEGasparaginase dosing schedule (without an asparaginase-free interval) would result in less hypersensitivity to PEGasparaginase compared to the standard non-continuous PEGasparaginase dosing schedule. Methods: Medium risk (MR) patients (aged 1-18 yrs) with ALL enrolled in the DCOG ALL11 protocol, were randomized to receive 14 individualized PEGasparaginase doses after an asparaginase-free interval of 3 months or to continue PEGasparaginase treatment following the first 3 doses in induction (EudraCT:2012-000067-25; Dutch Trial Register NL3227). Hypersensitivity included allergies, allergic-like reactions, and silent inactivations, where inactivating hypersensitivity reactions comprised the sum of allergies and silent inactivations. Secondary endpoints included other asparaginase-related adverse event (AEs) (CTCAE &amp;gt;grade 3), such as febrile neutropenia, infection, a thromboembolic event, pancreatitis, and avascular necrosis, as well as antibody levels and treatment outcome. Cumulative incidence of relapse (CIR), cumulative incidence of death (CID) in CR1 and disease-free survival (DFS) were compared between both treatment arms. Results: 312 MR patients were randomized to receive PEGasparaginase in a continuous (n=155) and non-continuous (n=157) dosing schedule. Hypersensitivity reactions occurred in 4 out of 155 (2.6%) patients in the continuous treatment arm versus 17 out of 157 (10.8%) patients in the non-continuous treatment arm (P&amp;lt;0.01), of which 2 (1.3%) versus 13 (8.3%) were inactivating reactions (Figure 1; P&amp;lt;0.01). Patients in de continuous treatment arm were significantly less likely to get an inactivating hypersensitivity reaction (odds ratio: 0.15 (0.032-0.653), P=0.012). Antibody levels were significantly lower in the continuous arm compared to the non-continuous arm (P&amp;lt;0.01). Without the asparaginase-free interval, the antibody levels slightly increased by 1.1-fold between dose 3 and 4 whereas antibody levels in the non-continuous arm increased by 2.5-fold during the asparaginase-free interval. We did not find any significant differences in the total number of asparaginase-associated AEs between the treatment arms (Figure 1). However, the generalized Poisson model analysis revealed that the occurrence of specific AEs, such as a thromboembolic event and pancreatitis, was influenced by both treatment phase and arm. These correlations can be attributed to the timing of asparaginase administrations, since at start of randomization asparaginase treatment was interrupted in the non-continuous arm but uninterrupted in the continuous arm. Consequently, thromboembolic events and pancreatitis occurred more frequently at the beginning of randomization in the continuous arm compared to the non-continuous arm (Table 1). This pattern reversed when the non-continuous arm resumed asparaginase treatment after the asparaginase-free period, while the continuous arm concluded their treatment. The occurrence of infections was not associated with treatment phase and treatment arm. The median duration of treatment phases was comparable between the two arms, with the exception of a longer duration of protocol M in the continuous versus non-continuous arm (median 10.3 versus 9.4 weeks respectively instead of the planned 9 weeks; P&amp;lt;0.01) Estimated median follow-up time was 57.2 months (95%-CI 51.9-61.3). The 5-yr CIR, CID in CR1 and DFS were 5.6% (SE 2.1%), 1.9% (SE 1.1%) and 91.9% (SE 2.4%) for continuous treatment vs 4.0% (SE 1.8%), 0.6% (SE 0.6%) and 95.3% (SE 1.9%) for non-continuous treatment (P=0.710; P=0.308; P=0.289), respectively. Conclusion: A continuous dosing schedule of PEGasparaginase resulted in a 7 times lower incidence of inactivating hypersensitivity reactions and lower anti-drug antibody levels compared with a non-continuous dosing schedule with an asparaginase-free interval. The continuous schedule of asparaginase treatment did not increase toxicity but changed the timing of toxicities and did not affect the efficacy of the therapy.

Safety and Tolerability of Magrolimab Combinations in Patients with Relapsed/Refractory Multiple Myeloma (RRMM): Safety Run-in Results from a Phase 2 Study

Background Outcomes remain poor for patients (pts) with RRMM; thus, novel combinations incorporating standard-of-care (SOC) regimens with new drugs possessing unique mechanisms of action and nonoverlapping toxicity are needed. Magrolimab (Magro) is a first-in-class monoclonal immunoglobulin G4 antibody blocking CD47, an antiphagocytic signal overexpressed in cancer cells, including MM, enabling them to evade phagocytosis. In vitro, blocking CD47 resulted in elimination of MM cells, and preclinical data suggested that Magro may synergize with commonly used agents in MM. Reported here are initial safety and tolerability data from 3 safety run-in (SRI) cohorts of our phase 2, open-label, multiarm study (NCT04892446) in which Magro-based combinations were evaluated in pts with RRMM. Methods Adult pts with RRMM were eligible if they had received ≥3 prior lines of therapy for MM, including an immunomodulatory drug and a proteasome inhibitor. In the SRI cohorts, pts received Magro in the following combinations: with daratumumab (Magro + D), pomalidomide/dexamethasone (Magro + Pd), or carfilzomib/dexamethasone (Magro + Kd). At the initial dose level tested, Magro was given intravenously as a 1-mg/kg priming dose, followed by a maintenance dose of 30 mg/kg every week during the first 2 cycles and then every 2 weeks starting in cycle 3. All other therapies were administered at standard doses and schedules per clinical guidelines. Dose-limiting toxicities (DLTs) were evaluated throughout cycle 1 (35 days); cycles were 28 days thereafter. Primary end points of the SRI included incidence of adverse events (AEs) and DLTs. Pts were included in the DLT-evaluable population if they met 1 of 2 criteria: (1) experienced a DLT during cycle 1 or (2) completed cycle 1 and received ≥3 Magro infusions and ≥2 (D, d, K) or ≥10 (P) doses of the SOC agents. DLTs were generally defined as grade (gr) ≥3 AEs that worsened from baseline and were at least possibly Magro-related (with a few exceptions, including gr 3 anemia and gr 3 neutropenia resolving within 2 weeks). Dose de-escalation of Magro was planned in the event of &amp;gt;2 DLTs per 6 DLT-evaluable pts. Results Of the 25 pts treated in the SRI (Magro + D, n = 9 [6 DLT evaluable]; Magro + Pd, n = 9 [6 DLT evaluable]; Magro + Kd, n = 7 [5 DLT evaluable]), all were treated at the Magro initial dose level. Median (range) age was 59 (55-78) years for Magro + D, 69 (46-79) years for Magro + Pd, and 64 (57-82) years for Magro + Kd. The mean (range) number of prior lines of therapy received was 5.2 (3-9). Two DLTs were reported: gr 3 febrile neutropenia (Magro + D) and gr 3 dyspnea (Magro + Pd) experienced in a context of probable infusion-related reaction (IRR). No DLTs were reported in the Magro + Kd arm. All pts experienced ≥1 treatment-emergent AE (TEAE); all but 2 experienced ≥1 Magro-related TEAE ( Table 1). The most common Magro-related TEAE observed in each cohort was anemia; other common Magro-related TEAEs were headache (Magro + D), fatigue (Magro + D, Magro + Pd), and thrombocytopenia (Magro + Kd). Magro-related anemia was reported in 13 of 25 pts (gr ≥3, n = 6). There were 3 pts with Magro-related IRRs (all gr 1-2: Magro + Kd, n = 1; Magro + D, n = 2) and 1 pt with a subcutaneous D-related IRR. Gr 3-4 Magro-related TEAEs reported in &amp;gt;1 pt in any cohort were anemia (Magro + D, n = 3; Magro + Pd, n = 2), decreased neutrophil count (Magro + Pd, n = 2), and decreased platelet count (Magro + Pd, n = 2). Serious Magro-related TEAEs occurred in 3 of 9 pts in the Magro + D cohort (febrile neutropenia, a DLT, on day 12; anemia on day 21; bacteremia on day 135), 1 of 9 pts in the Magro + Pd cohort (dyspnea, a DLT, on day 9 followed by febrile neutropenia on day 22 occurring in the same pt), and 1 of 7 pts in the Magro + Kd cohort (pneumonia on day 75). One pt (in the Magro + Pd arm) discontinued treatment due to Magro-related TEAEs reported on day 15 (gr 1 fatigue, gr 3 decreased neutrophil count, gr 3 decreased white blood cell count). No TEAEs leading to death occurred. Conclusion Magro demonstrated an acceptable safety profile with minimal additive toxicity when given in combination with SOC regimens for pts with heavily pretreated RRMM.

Zanubrutinib and Venetoclax As Initial Therapy for CLL/SLL with Obinutuzumab Triplet Consolidation in Patients with Minimal Residual Disease Positivity (BruVenG)

Background: Bruton's tyrosine kinase inhibitors (BTKi), anti-CD20 antibodies, and B cell lymphoma 2 inhibitors (BCL-2i) are essential therapeutic drug classes in the treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Clinical synergy of BTKi and BCL-2i combinations have been observed, which allow for an oral regimen, that can be safely administered in a clinic setting for most patients (Tam et al., 2022; Wierda et al., 2021). Still, it remains uncertain if anti-CD20 antibodies meaningfully add to the effectiveness of oral combination therapy. Recent reports of triplet regimens demonstrate modest improvement in minimal residual disease (MRD) negativity with similar response rates when compared to oral doublets (Davids et al., 2021; Soumerai et al., 2021; Wierda et al., 2021). Additionally, anti-CD20 antibody use causes significant B cell depletion resulting in prolonged immune suppression. Recent reports suggest BTKi use may in fact impair clinical activity of anti-CD20 antibodies, which can be mitigated by using selective BTKi and incorporating anti-CD20 later in the treatment course when lower disease burden is present (Da Roit et al., 2015; Flinsenberg et al., 2020; Pavlasova et al., 2016; Rawstron et al., 2018). Therefore, anti-CD20 therapy may not be required for all patients and could be optimized within a response-adapted strategy. This trial has been developed to assess efficacy and safety of a response adapted consolidative treatment approach utilizing obinutuzumab triplet consolidation in CLL/SLL patients who remain MRD positive after an oral doublet fixed duration treatment with zanubrutinib and venetoclax. This approach looks to maximize MRD negative remissions, spare toxicity by limiting anti-CD20 exposure, and provide a finite therapy. This study will utilize once daily zanubrutinib for which there is limited data in regard to safety and efficacy particularly in combination with venetoclax. Study Design and Endpoints: This is a single center, open label, phase II, investigator initiated clinical trial enrolling 50 subjects evaluating the efficacy and safety of zanubrutinib and venetoclax with obinutuzumab triplet consolidation in subjects who remain MRD positive (BruVenG). Eligible patients must have treatment naïve CLL/SLL and treatment indications per the International Workshop on CLL 2018 guidelines. Subjects with Richter's transformation are excluded. Treatment will consist of lead-in, combination, and consolidation phases. All subjects will be treated with a 3-cycle lead-in of 320mg oral, once daily zanubrutinib monotherapy. Venetoclax will be incorporated at cycle 4, per the standard prescriber insert ramp-up schedule. A final dose of 400mg oral, once daily venetoclax, in combination with 320mg oral, once daily zanubrutinib will be used in all subsequent cycles after ramp-up. At cycle 16, MRD will be assessed in the peripheral blood (PB) and bone marrow (BM) via clonoSEQ (Adaptive Biotechnologies). Subjects who are MRD negative (&amp;lt;1x10 -4 ) in both compartments will stop therapy. Subjects who are MRD positive in PB or BM will continue zanubrutinib and venetoclax for an additional 6 cycles. Obinutuzumab will be added to the oral doublet starting at cycle 17. Standard intravenous obinutuzumab lead-in will occur during cycle 17, followed by standard monthly intravenous dosing of 1000mg through cycle 22. Depending on MRD status, subjects will be treated for 16 or 22 cycles. All subjects who receive consolidation will stop treatment at cycle 23 regardless of end of treatment MRD status. The primary endpoint is cycle 16 PB and BM MRD negativity rates. A co-primary endpoint will be cycle 23 PB and BM MRD negativity rates in subjects who were MRD positive at C16 and who went on to receive at least 1 dose of obinutuzumab. Key secondary endpoints will include cycle 16 overall response rate, 36-month progression free survival, 36-month overall survival, 36-month time to next treatment, 24- and 36-month PB MRD negativity rates, tumor lysis risk reduction rates, and safety. Exploratory endpoints will assess the positive predicative value of the ∆400 biomarker (Soumerai et al., 2021) on MRD negativity at cycle 16. This biomarker will be assessed between cycle 4 and 6. The MRD negative rates at cycle 16 and cycle 23 will be estimated with a 90% confidence interval using the Clopper-Pearson method based on exact binomial distribution.