Multi-agent Protocol Research Articles

Space-time graph path planner for unsignalized intersection management with a V2V agent coordination architecture

Reducing traffic congestion and increasing passenger safety are important objectives for emerging automated transportation systems. Autonomous intersection management systems (AIMS) enable large scale optimization of vehicle trajectories with connected and autonomous vehicles (CAVs). We propose a novel approach for computing the fastest waypoint trajectory in intersections using graph search in a discretized space-time graph that produces collision-free paths with variable vehicle speeds that comply with traffic rules and vehicle dynamical constraints. To assist our planner algorithm in decentralized scenarios, we also propose a multi-agent protocol architecture for vehicle coordination for trajectory planning using a vehicle-to-vehicle (V2V) network. The trajectories generated allow a much higher evacuation rate and congestion threshold, with lower O(N) algorithm runtime compared to the state of the art conflict detection graph platoon path planning method, even for large scenarios with vehicle arrival rate of 1/s and thousands of vehicles.

Use of Lomustine and Prednisolone as First-Line Treatment in Canine Multicentric Lymphoma.

Multiagent chemotherapy is considered the most effective treatment for canine high-grade lymphoma; however, due to cost and time requirements, single-agent protocols have also been described. The aim of our study was to evaluate the outcome and prognostic factors of dogs affected by multicentric lymphoma treated with lomustine and prednisolone as first-line treatment. Cases of medium-large-cell multicentric lymphoma treated with lomustine and prednisolone were included in the study. Response to therapy, time to progression (TTP), median disease-free interval (MDFI) and median survival time (MST) were retrospectively described. Thirty cases were included. Eleven (36.67%) were T cell, 11 (36.67%) were B cell and 8 (26.66%) had unknown immunophenotype. The overall response rate (RR) was 87%, with 15 patients achieving CR (50%) and 11 patients PR (37%). The median TTP, MDFI and MST were 42, 63 and 90 days, respectively. The only factor significantly associated with MDFI and MST was the stage. Dogs with multicentric lymphoma treated with lomustine and prednisolone have lower RR, TTP, MDFI and MST compared with dogs receiving multiagent protocols. Based on the short-lasting response, this study confirms that this protocol might have minimal utility beyond palliation.

THE MANAGEMENT OF LYMPHOPROLIFERATIVE NEOPLASIA IN FOUR NORTHERN SEA OTTERS (ENHYDRA LUTRIS KENYONI).

Lymphoproliferative neoplasia has been reported in both free-ranging sea otters and those in managed care, but little information is available on the management of this neoplastic disease in this species. This case series describes clinical lymphoma in four northern sea otters (Enhydra lutris kenyoni) in managed care. Two otters presented with Stage 5 lymphoma with evidence of hematologic spread resulting in leukemia. Two additional otters presented with Stage 3 disease. Immunophenotypes in these cases included disseminated large B-cell lymphoma and lymphoblastic lymphoma of potential T-cell origin. Cases were managed with multiagent chemotherapy protocols including prednisone, L-asparaginase, cyclophosphamide, vincristine, cytosine arabinoside, lomustine, and doxorubicin. Unique approaches included the use of a vascular access port in one case and development of an autologous vaccine in another. Survival time ranged from 81 to 409 days. Diagnosis, staging, and treatment with multiagent protocols is recommended for the management of lymphoma in sea otters.

Alternating rabacfosadine and doxorubicin for treatment of naïve canine lymphoma.

The current standard of care treatment for canine lymphoma is a multi-agent, CHOP-based chemotherapy protocol. Single agent doxorubicin (DOX) is less burdensome; however, multi-agent chemotherapy protocols are often superior. The recently approved drug rabacfosadine (RAB, Tanovea) provides an attractive option for combination therapy with DOX, as both drugs demonstrate efficacy against lymphoma and possess different mechanisms of action. A previous study evaluating alternating RAB/DOX reported an overall response rate (ORR) of 84%, with a median progression-free survival time (PFS) of 194 days. The aim of this prospective trial was to evaluate the same protocol in an additional population of dogs. Fifty-nine dogs with treatment naïve lymphoma were enrolled. RAB (1.0 mg/kg IV) was alternated with DOX (30 mg/m2 IV) every 21 days for up to six total treatments (3 cycles). Response assessment and adverse event (AE) evaluation were performed every 21 days using VCOG criteria. The ORR was 93% (79% CR, 14% PR). The median time to maximal response was 21.5 days; median PFS was 199 days. T cell immunophenotype and lack of treatment response were predictive of inferior outcomes. AEs were mostly gastrointestinal. Six dogs developed presumed or confirmed pulmonary fibrosis; four were grade 5. One dog experienced grade 3 extravasation injury with RAB that resolved with supportive treatment. These data mirror those of the previously reported RAB/DOX study, and support the finding that alternating RAB/DOX is a reasonable treatment option for canine lymphoma.

Evaluation of a multiagent chemotherapy protocol combining vincristine, cyclophosphamide, mitoxantrone and prednisolone (CMOP) for treatment of feline intermediate-large cell lymphoma.

The aim of this study was to determine response rates, median progression-free intervals (PFIs) and median survival times (MSTs) for cats with intermediate-large cell lymphoma treated with a vincristine, cyclophosphamide, mitoxantrone and prednisolone (CMOP) protocol. A secondary objective was to determine the tolerability of mitoxantrone used within this multiagent protocol. The medical records of 31 cats treated at a single institution between 2009 and 2022 were reviewed to identify suitable cases. Cats were included in the study if they had a confirmed diagnosis of intermediate-large cell lymphoma, had received a CMOP protocol as first-line treatment and had completed at least one 4-week cycle of this protocol. Modifications allowed in the protocol included the use of l-asparaginase, vinblastine substitution for vincristine, chlorambucil substitution for cyclophosphamide and dexamethasone or methylprednisolone substitution for prednisolone. The overall response rate was 74% (n = 23), with 45% (n = 14) achieving complete remission (CR), 29% (n = 9) achieving partial remission (PR) and 26% (n = 8) achieving stable disease (SD). The Kaplan-Meier median PFI and MST were 139 days and 206 days, respectively. Responders (CR or PR) had a significantly longer (P <0.001) median PFI and MST compared with non-responders (SD) (176 days vs 62 days, and 251 days vs 61 days, respectively). Cats that achieved CR had a significantly longer median PFI and MST (P <0.001) at 178 days and 1176 days, respectively. The 6-month and 1- and 2-year survival rates in cats with CR were 64%, 57% and 35%, respectively. Treatment with mitoxantrone was generally well tolerated, with no cats experiencing Veterinary Cooperative Oncology Group adverse effects above grade 2. The CMOP protocol is an alternative and well-tolerated treatment for cats with intermediate-large cell lymphoma. As demonstrated with previous chemotherapy protocols, cats that respond to treatment, particularly those that achieve CR, are likely to have more durable responses.

Expressive Multi-Agent Communication via Identity-Aware Learning

Information sharing through communication is essential for tackling complex multi-agent reinforcement learning tasks. Many existing multi-agent communication protocols can be viewed as instances of message passing graph neural networks (GNNs). However, due to the significantly limited expressive ability of the standard GNN method, the agent feature representations remain similar and indistinguishable even though the agents have different neighborhood structures. This further results in the homogenization of agent behaviors and reduces the capability to solve tasks effectively. In this paper, we propose a multi-agent communication protocol via identity-aware learning (IDEAL), which explicitly enhances the distinguishability of agent feature representations to break the diversity bottleneck. Specifically, IDEAL extends existing multi-agent communication protocols by inductively considering the agents' identities during the message passing process. To obtain expressive feature representations for a given agent, IDEAL first extracts the ego network centered around that agent and then performs multiple rounds of heterogeneous message passing, where different parameter sets are applied to the central agent and the other surrounding agents within the ego network. IDEAL fosters expressive communication between agents and generates distinguishable feature representations, which promotes action diversity and individuality emergence. Experimental results on various benchmarks demonstrate IDEAL can be flexibly integrated into various multi-agent communication methods and enhances the corresponding performance.

Design and comprehensive analysis of improved Proportional-Integral-Retarded protocol for second-order multi-agent systems

BackgroundThe attractive characteristics of an innovative delay-based controller called Proportional-Integral-Retarded (PIR) controller are reported in many fields. However, a detailed investigation of the merits of the PIR controller for multi-agent systems (MASs) is still missing. MethodsTo bridge this gap, we propose an improved PIR protocol for a general class of second-order MASs. This protocol, using multiple intentional delays and heterogeneous gains as tunable parameters, realizes the optimal spectrum assignment of each subsystem in a completely independent way without affecting the stability of other subsystems. We then present a systematic and flexible parameter tuning strategy for the PIR protocol such that the desired exponential decay rate of the consensus system can be achieved. Specifically, this strategy achieves an arbitrary dominant root assignment in the domain of non-negative real numbers and enables enhanced control flexibility by adjusting an additionally introduced free variable in the analytical parameter formulae. To unveil the superiority of our proposed PIR protocol, we develop a comprehensive comparison of the PIR protocol with the Proportional-Integral-Derivative (PID) scheme and the Proportional-Retarded (PR) protocol. Significant findingsThe numerical simulations show that our PIR protocol outperforms the PID scheme regarding the noise attenuation property. Besides, this protocol can attain faster consensus, stronger robustness against parameter uncertainties, and superior disturbance resistance than the PR protocol. Our paper provides a valuable reference for the design of an effective and implementable multi-agent consensus protocol.

Multi-Agent Reinforcement Learning-Based Routing Protocol for Underwater Wireless Sensor Networks With Value of Information

Multi-Agent Reinforcement Learning-Based Routing Protocol for Underwater Wireless Sensor Networks With Value of Information

Pathogenic Variants Associated with Epigenetic Control and the NOTCH Pathway Are Frequent in Classic Hodgkin Lymphoma.

Classic Hodgkin lymphoma (cHL) constitutes a B-cell neoplasm derived from germinal center lymphocytes. Despite high cure rates (80-90%) obtained with the current multiagent protocols, a significant proportion of cHL patients experience recurrences, characterized by a lower sensitivity to second-line treatments. The genomic background of chemorefractory cHL is still poorly understood, limiting personalized treatment strategies based on molecular features. In this study, using a targeted next-generation sequencing (NGS) panel specifically designed for cHL research, we compared chemosensitive and chemorefractory diagnostic tissue samples of cHL patients. Furthermore, we longitudinally examined paired diagnosis-relapsesamples of chemorefractory cHL in order to define patterns of dynamic evolution and clonal selection. Pathogenic variants in NOTCH1 and NOTCH2 genes frequently arise in cHL. Mutations in genes associated with epigenetic regulation (CREBBP and EP300) are particularly frequent in relapsed/refractory cHL. The appearance of novel clones characterized by mutations previously not identified at diagnosis is a common feature in cHL cases showing chemoresistance to frontline treatments. Our results expand current molecular and pathogenic knowledge of cHL and support the performance of molecular studies in cHL prior to the initiation of first-line therapies.

Treatment of feline intermediate to high-grade alimentary lymphoma: A retrospective evaluation of 55 cats treated with the VAPC combination chemotherapy protocol (2017-2021).

The most commonly utilized protocols to treat lymphoma in cats employ vincristine, cyclophosphamide and prednisone; with additional drugs sometimes used including L-asparaginase and doxorubicin. Medical records were reviewed for 55 cats with alimentary lymphoma treated with a novel multiagent protocol using prednisolone, L-asparaginase, doxorubicin, vinblastine instead of vincristine, a higher dosage of cyclophosphamide and oral procarbazine (VAPC protocol). Outcomes evaluated were response to therapy, toxicity and progression-free survival (PFS). Grade 3 or 4 neutropenia was the most common treatment-related reason for chemotherapy dosage adjustment, occurring in 8 of 52 cats receiving vinblastine, 7 of 55 cats receiving cyclophosphamide and 1 of 40 cats receiving doxorubicin, but febrile neutropenia was identified in only two cats. Of 38 cats receiving chemotherapy for measurable disease, 26 (68.4%) achieved complete response (CR). Three cats achieved a partial response and 9 cats failed to achieve a remission. There were no identified factors influencing whether a cat was likely to achieve CR. For all 55 cats (including those receiving chemotherapy and surgery), median PFS was 184 days with 1, 2 and 3-year survival rates of 35.4%, 26.5% and 26.5%, respectively. On multivariate analysis, 40 cats that achieved CR had a median survival time of 341 days (78 days for PR, 45 days for NR); PFS times were also significantly affected by lymphocyte:monocyte L:M ratio (>3.4 = 700 days vs. ≤3.4 = 126 days) and B-cell versus T-cell phenotype (220 days vs. 42 days, respectively).

Central Retinal Vein Occlusion (CRVO) in Acute Lymphoblastic Leukaemia (ALL) Adult Patient Treated with Peg Asparaginase

ntroduction Asparaginase, available as native asparaginase or polyethylene glycol (Peg-aspa), is an essential component of multi-agent treatment protocols for Acute Lymphoblastic Leukaemia (ALL). It works by deaminating L-asparagine, leading to apoptosis and cell cycle arrest in leukemic cells. However, peg-asp is associated with various toxicities, including thrombotic complications mainly cavernous sinuses thrombosis and venous thrombosis. Methods and Results: We report a 48-year-old Indian gentleman, known to be hypertensive, diagnosed to have Precursor T-Lymphoblastic leukaemia/ lymphoma (NOS), when he presented with bicytopenia and a mediastinal mass. He was treated as per ALL protocol for adult at National centre for cancer care and research (NCCCR)Doha, which is adopted from UKALL-14 protocol. He received induction treatment (1A&amp; 1B) and has achieved a morphological remission. He received prophylactic anticoagulation with low molecular weight heparin (LMWH) which was stopped only in the cytopenic nadir. During the ascending phase of induction 1B, He presented with acute onset of floaters and blurred vision in the left eye. Urgent CT head scan revealed vitreous haemorrhage. Full blood count was normal except Platelets of 20*10 9ul. Coagulation screen, fibrinogen level and anti-thrombin level was within normal limit. Ophthalmological evaluation revealed vitreous and retinal haemorrhages, indicating Central Retinal Vein Occlusion (CRV). MRI/MRV brain ruled out intracranial venous thrombosis. CSF analysis excluded CNS disease. He received supportive transfusion; however, he has progressed to permanent loss of vision in the left eye. Therapeutic anticoagulation is not indicated in his case. Thrombotic events can occur during induction therapy for ALL mainly cavernous sinuses thrombosis and venous thrombosis, yet CRVO is an unusual site for thrombotic events and associated predominately with age-associated vasculopathies. In the reported case, several factors contribute to thrombosis, including acute leukaemia, prolonged hospitalization, age, presentation with a mediastinal mass, steroid use as well as Peg-aspa and the patient was managed with prophylactic anticoagulation while on therapy. Asparaginase induces a hypercoagulable state by decreasing antithrombin III, protein C, and protein S levels, leading to hypofibrinogenemia and augmenting the risk of thrombotic events. Thrombosis can negatively impact disease-free survival and long-term outcomes, resulting in complications such as therapy delays, post-thrombotic syndrome, and central nervous system-related issues (seizures, neurocognitive deficits, blindness). While these complications may lead to hesitancy or discontinuation of peg-asp use, early recognition and vigilant monitoring of antithrombin III and fibrinogen levels can help to guide management. In cases where the treatment course is complicated by thrombotic events, a high index of suspicion should arise considering strongly the causative agent to be Asparaginase. Thromboprophylaxis with low-molecular-weight heparin (LMWH) is widely accepted as supportive therapy in ALL management. Conclusion: ALL patients receiving Asparaginase therapy are at risk of developing thrombotic events. Early identification of symptoms and risk stratification are essential for improved disease outcomes. Awareness and understanding of peg-asp-induced thrombosis, including unusual site thrombosis can help guide treatment decisions and improve patient outcomes in ALL therapy.

Multi-valued model checking IoT and intelligent systems with commitment protocols in multi-source data environments

In today’s world of connectivity, various domains use different multi-sensor Internet of Things (IoT) and Intelligent Systems (IS) applications. These applications involve extensive interactions between thousands or millions of components in open environments, which challenges verifying their reliability and efficiency. This paper introduces the first investigation in verifying IoT applications and intelligent systems in multi-source data settings with multi-agent commitment protocols in uncertain or inconsistent environments. Specifically, we present original and efficient solutions for modeling and verifying these systems with conditional and unconditional commitment protocols under uncertain or inconsistent settings. We introduce 4v-CTLc and 4v-CTLcc, multi-valued logics of commitment for reasoning about inconsistency over these systems that expand 3v-CTLc and 3v-CTLcc for reasoning about uncertainty. Moreover, we introduce new reduction algorithms for reducing our multi-valued model checking problems to the two-valued ones. To implement these algorithms, we develop two new automatic verification tools. The first tool translates the multi-valued logics to CTL and automatically interacts with the NuSMV model checker. The second tool translates these logics to the two-valued versions, CTLc and CTLcc, and automatically interacts with the MCMAS+ model checker. We apply our verification approaches to a Smart Home, a Smart Hospital and a Smart Mortgage system with multi-source data as case studies using sets of properties, including safety, liveness and reachability. The experimental results obtained by the proposed multi-valued model checking techniques proved these techniques’ high efficiency and applicability to modeling and verifying intelligent and autonomous multi-source data systems.

Clinical characterisation and long-term survival of paediatric and juvenile lymphoma in cats: 33 cases (2008-2022).

The aims of this study were to describe the clinical presentation, tumour characteristics, responses to chemotherapy protocols and toxicity in a cohort of cats with lymphoma up to 18 months of age. In addition, the probability of long-term (>2 years) survival was explored. The medical records of client-owned cats aged up to 18 months diagnosed with lymphoma between 2008 and 2022 at five UK-based veterinary referral hospitals were reviewed. Thirty-three cats were included. The most common anatomical forms were mediastinal (42%), disseminated disease (30%) and renal (15%), with all cats having intermediate to large cell lymphoma. Three out of 29 cats tested were positive for FeLV but none for FIV. Twenty-six cats were treated with multi-agent chemotherapy protocols with complete and partial responses seen in 46% and 50% of cats, respectively. For this group, median progression-free survival was 133 days (95% confidence interval [Cl] 67 to 199) and median survival time was 268 days (95% Cl 106 to 430). Complete response to chemotherapy was associated with a longer progression-free survival. Seven cats were considered long-term survivors (>2 years). Chemotherapy was generally well tolerated with none of the long-term survivors suffering from chronic sequelae from cytotoxic treatment. Paediatric and juvenile cats with lymphoma showed a high response rate to multi-agent chemotherapy protocols with rare significant toxicities. The presence of long-term survivors may suggest a more favourable outcome in a subset of patients.

Hypersensitivity Reactions to Native E. coli L-asparaginase in Children With Acute Lymphoblastic Leukemia Treated in Trial ALL-BFM 2000: Impact of Treatment Schedule and Type of Glucocorticoid in Induction.

Hypersensitivity Reactions to Native E. coli L-asparaginase in Children With Acute Lymphoblastic Leukemia Treated in Trial ALL-BFM 2000: Impact of Treatment Schedule and Type of Glucocorticoid in Induction.

Multiagent Distributed Secondary Control for Energy Storage Systems With Lossy Communication Networks in DC Microgrid

For the energy storage system (ESS) with lossy communication networks of packet loss in DC microgrid, the multiagent distributed secondary control strategy is proposed to manage the ESS. The multiagent dynamic-tracking consensus protocol (DCP) based on the random packet loss model is constructed to estimate the global information for the dynamic network with lossy communication. Then the adaptive current sharing algorithm (ACSA) is designed to balance the state of charge (SoC) for ESSs with different capacities. Furthermore, the data-driven model-free adaptive control (MFAC) scheme is proposed for the single-input multiple-output (SIMO) nonlinear ESS to provide accurate voltage tracking and current sharing. Finally, the real-time simulation tests of different case studies are carried out through the OPAL-RT platform to verify the effectiveness of the designed control strategy. Simulation results can prove that the favorable capabilities of current sharing and voltage regulation as well as robustness to communication packet loss and communication faults can be achieved.

Enhancing Local Decisions in Agent-Based Cartesian Genetic Programming by CMA-ES

Cartesian genetic programming is a popular version of classical genetic programming, and it has now demonstrated a very good performance in solving various use cases. Originally, programs evolved by using a centralized optimization approach. Recently, an algorithmic level decomposition of program evolution has been introduced that can be solved by a multi-agent system in a fully distributed manner. A heuristic for distributed combinatorial problem-solving was adapted to evolve these programs. The applicability of the approach and the effectiveness of the used multi-agent protocol as well as of the evolved genetic programs for the case of full enumeration in local agent decisions has already been successfully demonstrated. Symbolic regression, n-parity, and classification problems were used for this purpose. As is typical of decentralized systems, agents have to solve local sub-problems for decision-making and for determining the best local contribution to solving program evolution. So far, only a full enumeration of the solution candidates has been used, which is not sufficient for larger problem sizes. We extend this approach by using CMA-ES as an algorithm for local decisions. The superior performance of CMA-ES is demonstrated using Koza’s computational effort statistic when compared with the original approach. In addition, the distributed modality of the local optimization is scrutinized by a fitness landscape analysis.

Retrospective analysis of immunosuppressive and anti-thrombotic protocols in nonassociative immune mediated hemolytic anemia in dogs.

Evidence supporting the effectiveness of therapeutic protocols for nonassociative immune-mediated hemolytic anemia (na-IMHA) is weak. Investigate the efficacy of various drugs in na-IMHA. Two hundred forty-two dogs. Multi-institutional retrospective study (2015-2020). Immunosuppressive effectiveness was determined by time to packed cell volume (PCV) stabilization and duration of hospitalization through analysis by mixed model linear regression. Occurrence of disease relapse, death, and antithrombotic effectiveness, were analyzed using mixed model logistic regression. Use of corticosteroids vs a multi-agent protocol had no effect on time to PCV stabilization (P=.55), duration of hospitalization (P=.13), or case fatality (P=.06). A higher rate of relapse (P=.04; odds ratio: 3.97; 95% confidence interval [CI]: 1.06-14.8) was detected in dogs receiving corticosteroids (11.3%) during follow-up (median: 28.5 days, range: 0-1631 days) compared to multiple agents (3.1%) during follow up (median: 47.0 days, range: 0-1992 days). When comparing drug protocols, there was no effect on time to PCV stabilization (P=.31), relapse (P=.44), or case fatality (P=.08). Duration of hospitalization was longer, by 1.8 days (95% CI: 0.39-3.28 days), for the corticosteroid with mycophenolate mofetil group (P=.01) compared to corticosteroids alone. Use of clopidogrel vs multiple agents had no effect on development of thromboses (P ≥ .36). Addition of a second immunosuppressive agent did not alter immediate outcome measures but might be associated with a reduction in relapse. Use of multiple antithrombotic agents did not reduce incidence of thrombosis.

Self-esteem of acute leukemic children undergoing chemotherapy

Background Acute leukemia is a major malignancy in children. Multiagent chemotherapy protocols are the main treatment option for acute leukemia. Still chemotherapy has a significant effect on children's well-being, improving the physical, psychological, and social status of children, and also, it has a remarkable effect on self-image and self-esteem. Aim The aim was to assess self-esteem of acute leukemic children undergoing chemotherapy. Patients and methods A descriptive exploratory research design was used. The study was conducted at two pediatric oncology outpatient clinics at Tanta Cancer Center and National Cancer Institute at Cairo University. A purposive sample of 80 children with acute lymphoblastic leukemia was recruited. Their ages were between 10 and 16 years old. A structured interview questionnaire and Coopersmith Self-esteem Inventory were used, and IRB approval was obtained from the National Cancer Institute for performing this study. Results The age of half of the children (50%) ranged between 14 and 16 years, with mean±SD age of 13.21±1.62 years. Overall, 61.3% were males. Less than half of the children (47.5%) received intravenous chemotherapy, whereas 46.2% of the children had both oral and intravenous chemotherapy. More than half of the children (62.5%) had low self-esteem regarding general self, whereas the vast majority of children (90%) had low self-esteem regarding their social self-peers. All children had low self-esteem toward their home parents, whereas the highest percent (98.8%) of children had low self-esteem regarding their school academic. The vast majority children (98.8%) had low self-esteem regarding the lie scale. All dimensions of self-esteem were significantly correlated with total score of self-esteem. Conclusion Children with acute leukemia undergoing chemotherapy had low self-esteem regarding general self, home parents, school academic, and social peers. Self-esteem was negatively affected among school age and adolescent children with acute leukemia who underwent chemotherapy. Regarding the lie domain, most children always told the truth. Recommendations Training programs should be designed and constructed for nurses in how to assess self-esteem for children with acute leukemia. Empowerment program should be directed to children with acute leukemia and their caregivers to improve their self-esteem.

Association of Inherited Genetic Factors With Drug-Induced Hepatic Damage Among Children With Acute Lymphoblastic Leukemia

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. Hepatotoxic effects, including hyperbilirubinemia and elevated alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, are common during all phases of therapy and are linked to several chemotherapeutic agents, including asparaginase, mercaptopurine, and methotrexate. To determine which genetic variants were associated with hyperbilirubinemia and elevated ALT and AST levels in children, adolescents, and young adults treated for ALL. This retrospective analysis of a multiethnic genome-wide association study was conducted between January 1, 2019, and April 15, 2022, including patients treated as part of Children's Oncology Group (COG) trials with centers in the United States, Canada, and Australia, which accrued data from December 29, 2003, to January 21, 2011 (AALL0232), and from January 22, 2007, to July 24, 2014 (AALL0434). Germline genotypes were interrogated using genome-wide arrays and imputed using a National Institutes of Health TOPMed Imputation server. Mixed-effects logistic regressions were used to account for multiple episodes for an individual patient. Genotype × treatment phase interaction was tested to uncover phase-specific genetic risk factors. Total duration of multiagent protocol chemotherapy ranging from 2.5 to 3.5 years. The primary outcomes were National Cancer Institute Common Terminology Criteria for Adverse Events (version 4) hyperbilirubinemia of grade 3 or higher and elevated liver ALT and AST levels. A total of 3557 participants were included in the analysis (2179 [61.3%] male; median age, 11.1 [range, 1-30] years). Among 576 known variants associated with these liver function test results in the general population, UGT1A1 variant rs887829 and PNPLA3 variant rs738409 were associated with increased risk of hyperbilirubinemia (odds ratio [OR], 2.18 [95% CI, 1.89-2.53]; P = 6.7 × 10-27) and ALT and AST levels (OR, 1.27 [95% CI, 1.15-1.40]; P = 3.7 × 10-7), respectively, during treatment for ALL. Corresponding polygenic risk scores were associated with hepatotoxic effects across all therapy phases and were largely driven by UGT1A1 and PNPLA3 variants. Genome-wide association analysis revealed an age-specific variant near the CPT1A gene that was only associated with elevated ALT and AST levels among patients younger than 10 years (OR, 1.28 [95% CI, 1.18-1.39]; P = 8.7 × 10-10). These results suggest a strong genetic basis for interpatient variability in hyperbilirubinemia and aminotransferase level elevations during leukemia chemotherapy.

Hypersensitivity Reactions to Native E. coli L-Asparaginase in Children with Acute Lymphoblastic Leukemia May Vary By Treatment Schedule and Type of Glucocorticoid in Induction: Results of Trial ALL-BFM 2000

Background: Asparaginase (ASNase) has become a key component of treatment for acute lymphoblastic leukemia (ALL). The ability of this agent to eliminate leukemic blasts by utilizing the special feature that such cells are largely unable to synthesize the otherwise non-essential amino acid asparagine means that blasts cannot survive in an environment in which this amino acid has been depleted. Currently, there are three ASNase products commercially available sharing the same mechanism of action. The oldest one is the purified native enzyme extracted from E. coli. This product was further developed and refined by conjugation with polyethylene glycol (PEG-L-Asparaginase, PEG-ASNase) to prolong half-life and to reduce immunogenicity. A third ASNase product derived from the bacterium Erwinia chrysanthemi (Erwinase) is structurally different from the E. coli ASNase products. The main reason for limitation in the use of ASNase is the rather frequent occurrence of hypersensitivity reactions (HSR). Such reactions require the replacement of the ASNase product used with alternative preparations. The incidence of clinical HSR to ASNase varies with the type of ASNase product, the treatment schedule (number of ASNase doses, extended ASNase-free intervals) and the administration route (intravenously [IV] or intramuscularly [IM]). This retrospective study was primarily performed to demonstrate the dynamics and the interdependence when using ASNase in a complex multiagent treatment protocol. It aimed to evaluate the incidence of clinically apparent HSR in the ALL-BFM 2000 trial which was part of the cooperative trial AIEOP-BFM ALL 2000. Methods: Clinical hypersensitivity reactions (HSR) to native E. coli ASNase were retrospectively analyzed in a cohort of children with acute lymphoblastic leukemia (ALL) focusing on the impact of concurrent chemotherapy schedules in the risk-adapted and randomized treatment protocol and evaluating the prognostic relevance of asparaginase discontinuation. Patients: Patients with ALL aged 1-18 years were treated risk-stratified with standard-risk (SR), medium-risk (MR) and high-risk (HR) regimens in trial ALL-BFM 2000. Schedule of intravenously administered native E. coli ASNase varied by risk group and randomization arm. Randomizations compared the glucocorticoids prednisolone and dexamethasone in induction and different reintensification regimens (Möricke A et al, BLOOD 127(17): 2101-2112 (2016)). In this trial, native E. coli ASNase was administered IV as first-line product during the induction and reinduction phases. In the high-risk arm, the phase of intensified consolidation included additional E. coli ASNase doses. PEG-ASNase (IV) or Erwinase (IM) were used as second- or third-line products after HSR occurring with native E. coli ASNase or the respective second-line product. Results: HSR occurred in 40% (492/1207) of all evaluable patients. One-year cumulative incidence (CI-HSR±standard error) was 42.3±1.5% (40.6±2.5% in SR, 37.0±1.9% in MR, 65.2±3.8% in HR). Dexamethasone-treated SR and MR patients had significantly higher CI-HSR (48.5±4.3% and 45.9±3.2%) than prednisolone-treated patients (32.3±3.7% [p=0.007] and 31.2±2.9% [p<0.001]); no such difference was seen among HR patients who underwent multiple exposures to the drug (Fig. 1). Post-induction randomizations showed that one week of dexamethasone before asparaginase re-exposition in reinduction did not protect from clinical HSR in the SR/MR arm. Randomization in HR revealed an effect of the type of concurrent chemotherapeutic drugs on the risk of HSR. Discontinuation of ASNase occurred in 6.1% of all patients. No disadvantage in leukemia outcome could be detected for these patients. Conclusion: The results in our study demonstrate the complex interdependencies contributing to the risk of HSR to E. coli asparaginase in a multiagent chemotherapy protocol. The differential effects of dexamethasone and prednisolone in induction generated new hypotheses about the role of glucocorticoids in sensitization or achievement of immune tolerance to asparaginase. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal