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Future Oncology (London, England) Dec 2014Outcomes for children with acute lymphoblastic leukemia (ALL) have improved significantly in recent decades, primarily due to dose-intensified, multi-agent chemotherapy... (Review)
Review
Outcomes for children with acute lymphoblastic leukemia (ALL) have improved significantly in recent decades, primarily due to dose-intensified, multi-agent chemotherapy regimens, of which asparaginase has played a prominent role. Despite this success, hypersensitivity remains a significant problem, often requiring the termination of asparaginase. Failure to complete the entire asparaginase therapy course due to clinical hypersensitivity, subclinical hypersensitivity (i.e., silent inactivation), or other treatment-related toxicity is associated with poor ALL outcomes. Thus, it is critical to rapidly identify patients who develop clinical/subclinical hypersensitivity and switch these patients to an alternate asparaginase formulation. This article provides an overview of asparaginase hypersensitivity, identification and management of hypersensitivity and subclinical hypersensitivity, and issues related to switching patients to asparaginase Erwinia chrysanthemi following hypersensitivity reaction.
Topics: Antineoplastic Agents; Asparaginase; Chemistry, Pharmaceutical; Child; Dickeya chrysanthemi; Humans; Hypersensitivity; Precursor Cell Lymphoblastic Leukemia-Lymphoma
PubMed: 24983955
DOI: 10.2217/fon.14.138 -
Anti-cancer Agents in Medicinal... 2022Microbial L-asparaginase is the most effective first-line therapy used in the treatment protocols of paediatric and adult leukemia. Leukemic cells' auxotrophy for... (Review)
Review
Microbial L-asparaginase is the most effective first-line therapy used in the treatment protocols of paediatric and adult leukemia. Leukemic cells' auxotrophy for L-asparagine is exploited as a therapeutic strategy to mediate cell death through metabolic blockade of L-asparagine using L-asparaginase. Escherichia coli and Erwinia chrysanthemi serve as the major enzyme deriving sources accepted in clinical practice, and the enzyme has bestowed improvements in patient outcomes over the last 40 years. However, an array of side effects generated by the native enzymes due to glutamine co-catalysis and short serum stays augmenting frequent dosages intended a therapeutic switch towards developing bio better alternatives for the enzyme, including the formulations resulting in sustained local depletion of Lasparagine. In addition, the treatment with L-asparaginase in a few cancer types has proven to elicit drug-induced cytoprotective autophagy mechanisms and therefore warrants concern. Although the off-target glutamine hydrolysis has been viewed as contributing to the drug-induced secondary responses in cells deficient with asparagine synthetase machinery, the beneficial role of glutaminase-asparaginase in proliferative regulation of asparagine prototrophic cells has been looked forward. The current review provides an overview of the enzyme's clinical applications in leukemia and possible therapeutic implications in other solid tumours, recent advancements in drug formulations, and discusses the aspects of two-sided roles of glutaminase-asparaginases and drug-induced cytoprotective autophagy mechanisms.
Topics: Asparaginase; Asparagine; Child; Escherichia coli; Glutaminase; Glutamine; Humans; Leukemia
PubMed: 34994334
DOI: 10.2174/1871520622666220106103336 -
Molecular Genetics and Metabolism Jul 2023Hyperammonemia has been reported following asparaginase administration, consistent with the mechanisms of asparaginase, which catabolizes asparagine to aspartic acid and...
Hyperammonemia has been reported following asparaginase administration, consistent with the mechanisms of asparaginase, which catabolizes asparagine to aspartic acid and ammonia, and secondarily converts glutamine to glutamate and ammonia. However, there are only a few reports on the treatment of these patients, which varies widely from watchful waiting to treatment with lactulose, protein restriction, sodium benzoate, and phenylbutyrate to dialysis. While many patients with reported asparaginase-induced hyperammonemia (AIH) are asymptomatic, some have severe complications and even fatal outcomes despite medical intervention. Here, we present a cohort of five pediatric patients with symptomatic AIH, which occurred after switching patients from polyethylene glycolated (PEG)- asparaginase to recombinant Crisantaspase Pseudomonas fluorescens (4 patients) or Erwinia (1 patient) asparaginase, and discuss their subsequent management, metabolic workup, and genetic testing. We developed an institutional management plan, which gradually evolved based on our local experience and previous treatment modalities. Because of the significant reduction in glutamine levels after asparaginase administration, sodium benzoate should be used as a first-line ammonia scavenger for symptomatic AIH instead of sodium phenylacetate or phenylbutyrate. This approach facilitated continuation of asparaginase doses, which is known to improve cancer outcomes. We also discuss the potential contribution of genetic modifiers to AIH. Our data highlights the need for increased awareness of symptomatic AIH, especially when an asparaginase with higher glutaminase activity is used, and its prompt management. The utility and efficacy of this management approach should be systematically investigated in a larger cohort of patients.
Topics: Humans; Child; Asparaginase; Phenylbutyrates; Hyperammonemia; Sodium Benzoate; Glutamine; Ammonia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Treatment Outcome; Antineoplastic Agents
PubMed: 37327713
DOI: 10.1016/j.ymgme.2023.107627 -
Leukemia & Lymphoma Aug 2018Asparaginase is an integral component of multiagent chemotherapy regimens for the treatment of acute lymphoblastic leukemia (ALL). Adequate asparagine depletion is... (Review)
Review
Asparaginase is an integral component of multiagent chemotherapy regimens for the treatment of acute lymphoblastic leukemia (ALL). Adequate asparagine depletion is believed to be an important factor in achieving optimal therapeutic outcomes. Measurement of asparaginase activity allows practitioners to evaluate the potential effectiveness of therapy in real time. Asparaginase activity levels can be used to identify patients with silent inactivation and modify therapy in these patients. Patients with silent inactivation to asparaginase who are switched to therapy with an immunologically distinct asparaginase exhibit outcomes similar to patients who never developed silent inactivation. Despite these benefits, there exists no universally agreed-upon guideline for treatment adjustments based on asparaginase activity levels. The goal of this manuscript is to review the clinical evidence linking asparaginase activity levels to outcomes in patients with ALL and to provide an overview of how asparaginase activity levels may be used to guide treatment.
Topics: Antineoplastic Agents; Asparaginase; Asparagine; Drug Monitoring; Humans; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Treatment Outcome
PubMed: 29045165
DOI: 10.1080/10428194.2017.1386305 -
Molecules (Basel, Switzerland) Dec 2020l-asparaginase (ASNase, EC 3.5.1.1) is an aminohydrolase enzyme with important uses in the therapeutic/pharmaceutical and food industries. Its main applications are as... (Review)
Review
l-asparaginase (ASNase, EC 3.5.1.1) is an aminohydrolase enzyme with important uses in the therapeutic/pharmaceutical and food industries. Its main applications are as an anticancer drug, mostly for acute lymphoblastic leukaemia (ALL) treatment, and in acrylamide reduction when starch-rich foods are cooked at temperatures above 100 °C. Its use as a biosensor for asparagine in both industries has also been reported. However, there are certain challenges associated with ASNase applications. Depending on the ASNase source, the major challenges of its pharmaceutical application are the hypersensitivity reactions that it causes in ALL patients and its short half-life and fast plasma clearance in the blood system by native proteases. In addition, ASNase is generally unstable and it is a thermolabile enzyme, which also hinders its application in the food sector. These drawbacks have been overcome by the ASNase confinement in different (nano)materials through distinct techniques, such as physical adsorption, covalent attachment and entrapment. Overall, this review describes the most recent strategies reported for ASNase confinement in numerous (nano)materials, highlighting its improved properties, especially specificity, half-life enhancement and thermal and operational stability improvement, allowing its reuse, increased proteolysis resistance and immunogenicity elimination. The most recent applications of confined ASNase in nanomaterials are reviewed for the first time, simultaneously providing prospects in the described fields of application.
Topics: Asparaginase; Biosensing Techniques; Biotechnology; Drug Development; Food Industry; Humans; Nanotechnology; Protein Engineering; Structure-Activity Relationship
PubMed: 33321857
DOI: 10.3390/molecules25245827 -
Biotechnology & Genetic Engineering... Apr 2017L-asparaginase is a vital enzyme of medical importance, and renowned as a chemotherapeutic agent. The relevance of this enzyme is not only limited as an anti-cancer... (Review)
Review
L-asparaginase is a vital enzyme of medical importance, and renowned as a chemotherapeutic agent. The relevance of this enzyme is not only limited as an anti-cancer agent, it also possesses a wide range of medical application. The application includes the antimicrobial property, treatment of infectious diseases, autoimmune diseases, canine and feline cancer. Apart from the health care industry, its significance is also established in the food sector as a food processing agent to reduce the acrylamide concentration. L-asparaginase is known to be produced from various bacterial, fungal and plant sources. However, there is a huge market demand due to its wide range of application. Therefore, the industry is still in the search of better-producing source in terms of high yield and low immunogenicity. It can be produced by both submerged and solid state fermentation, and each fermentation process has its own merits and demerits. This review paper focuses on its improved production strategy by adopting statistical experimental optimization techniques, development of recombinant strains, through mutagenesis and nanoparticle immobilization, adopting advanced and cost-effective purification techniques. Available research literature proves the competence and therapeutic potential of this enzyme. Therefore, research orientation toward the exploration of this clinical significant enzyme has to be accelerated. The objectives of this review are to discuss the high yielding sources, current production strategies, improvement of production, effective downstream processing and therapeutic application of L-asparaginase.
Topics: Acrylamide; Animals; Asparaginase; Bacteria; Fermentation; Food Industry; Fungi; Health Care Sector; Humans; Plants
PubMed: 28766374
DOI: 10.1080/02648725.2017.1357294 -
Pediatric Blood & Cancer Aug 2019Asparaginase is a critical component of lymphoblastic leukemia therapy, with intravenous pegaspargase (PEG) as the current standard product. Acute adverse events (aAEs)...
BACKGROUND
Asparaginase is a critical component of lymphoblastic leukemia therapy, with intravenous pegaspargase (PEG) as the current standard product. Acute adverse events (aAEs) during PEG infusion are difficult to interpret, representing a mix of drug-inactivating hypersensitivity and noninactivating reactions. Asparaginase Erwinia chrysanthemi (ERW) is approved for PEG hypersensitivity, but is less convenient, more expensive, and yields lower serum asparaginase activity (SAA). We began a policy of universal premedication and SAA testing for PEG, hypothesizing this would reduce aAEs and unnecessary drug substitutions.
PROCEDURE
Retrospective chart review of patients receiving asparaginase before and after universal premedication before PEG was conducted, with SAA performed 1 week later. We excluded patients who had nonallergic asparaginase AEs. Primary end point was substitution to ERW. Secondary end points included aAEs, SAA testing, and cost.
RESULTS
We substituted to ERW in 21 of 122 (17.2%) patients pre-policy, and 5 of 68 (7.4%) post-policy (RR, 0.427; 95% CI, 0.27-0.69, P = 0.028). All completed doses of PEG yielded excellent SAA (mean, 0.90 units/mL), compared with ERW (mean, 0.15 units/mL). PEG inactivation post-policy was seen in 2 of 68 (2.9%), one silent and one with breakthrough aAE. The rate of aAEs pre/post-policy was 17.2% versus 5.9% (RR, 0.342; 95% CI, 0.20-0.58, P = 0.017). Grade 4 aAE rate pre/post-policy was 15% versus 0%. Cost analysis predicts $125 779 drug savings alone per substitution prevented ($12 402/premedicated patient).
CONCLUSIONS
Universal premedication reduced substitutions to ERW and aAE rate. SAA testing demonstrated low rates of silent inactivation, and higher SAA for PEG. A substantial savings was achieved. We propose universal premedication for PEG be standard of care.
Topics: Administration, Intravenous; Adolescent; Adult; Antineoplastic Agents; Asparaginase; Child; Child, Preschool; Drug Hypersensitivity; Drug Monitoring; Drug Substitution; Female; Follow-Up Studies; Hematologic Neoplasms; Humans; Infant; Male; Premedication; Prognosis; Retrospective Studies; Tissue Distribution; Young Adult
PubMed: 31099154
DOI: 10.1002/pbc.27797 -
Pediatric Blood & Cancer Oct 2021Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. Bacterial L-asparaginase has played an important role in ALL treatment for several decades;... (Review)
Review
Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. Bacterial L-asparaginase has played an important role in ALL treatment for several decades; however, hypersensitivity reactions to Escherichia coli-derived asparaginases often preclude their use. Inability to receive asparaginase due to hypersensitivities is associated with poor patient outcomes. Erwinia chrysanthemi-derived asparaginase (ERW) is an effective, non-cross-reactive treatment option, but is limited in supply. Consequently, alternative asparaginase preparations are needed to ensure asparaginase availability for patients with hypersensitivities. Recombinant technology can potentially address this unmet need by programming cells to produce recombinant asparaginase. JZP-458, a recombinant Erwinia asparaginase derived from a novel Pseudomonas fluorescens expression platform with no immunologic cross-reactivity to E. coli-derived asparaginases, has the same primary amino acid sequence as ERW, with comparable activity based on in vitro measurements. The efficient manufacturing of JZP-458 would provide an additional asparaginase preparation for patients with hypersensitivities.
Topics: Antineoplastic Agents; Asparaginase; Child; Dickeya chrysanthemi; Drug Hypersensitivity; Escherichia coli; Humans; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pseudomonas fluorescens; Technology
PubMed: 34105243
DOI: 10.1002/pbc.29169 -
World Journal of Microbiology &... Sep 2019L-asparaginase is a critical part of the treatment of acute lymphoblastic leukaemia in children and adolescents, and has contributed to the improvement in patient... (Review)
Review
L-asparaginase is a critical part of the treatment of acute lymphoblastic leukaemia in children and adolescents, and has contributed to the improvement in patient outcomes over the last 40 years. The main products used in clinical treatment are L-asparaginase enzymes derived from Escherichia coli and Erwinia chrysanthemi. However, a very active area of research is the identification and characterisation of potential new L-asparaginase therapeutics, from existing or novel prokaryotic and eukaryotic sources, including mutations to improve function. In this review, we discuss the critical factors necessary to adequately characterise novel L-asparaginase therapeutic products, including enzyme kinetic parameters, glutaminase activity, and toxicity. One critical consideration is to ensure that the substrate affinity of novel enzymes, as measured by the Michaelis constant K, is sufficiently low to enable efficient reaction rates in human clinical use. The activity of L-asparaginases towards glutamine as a substrate is discussed and reviewed in detail, as there is much debate in the scientific literature about the importance of this feature for therapeutic enzymes. The recent research in the area is reviewed, including identification of new sources of the enzyme, modulating glutaminase activity, and improving the thermal stability and immunogenic response. New research in the area may benefit from these considerations, to enable the next generation of therapeutic product design. Critical to future work in this area is a complete characterisation of novel enzymes with respect to performance for both L-asparagine and L-glutamine as substrates.
Topics: Animals; Asparaginase; Enzyme Stability; Humans; Kinetics; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Substrate Specificity
PubMed: 31552479
DOI: 10.1007/s11274-019-2731-9 -
Cancer Reports (Hoboken, N.J.) Aug 2022The survival of children with acute lymphoblastic leukemia (ALL) has improved due to changes in the treatment and the disease diagnosis. A significant advance was the... (Observational Study)
Observational Study
BACKGROUND
The survival of children with acute lymphoblastic leukemia (ALL) has improved due to changes in the treatment and the disease diagnosis. A significant advance was the incorporation of asparaginase. However, hypersensitivity reactions are a common cause of early discontinuation of this drug.
AIM
The proposed study aims to evaluate early interruptions and the influence of the number of asparaginase doses effectively administered on the prognosis of patients with ALL.
METHODS AND RESULTS
An observational cohort study was carried out, with retrospective data collection, in medical records. The prognostic variables indicated in the protocol applied were used, and the principal outcomes were 5 years event-free survival (EFS) and 5 years of overall survival (OS) probability. Statistical analyzes were performed using SPPS 20.0 and R. In Cox's proportional hazards model for EFS and OS, variables of prognostic importance (n = 126 children) were: high-risk group (HGR), by the protocol classification, and less than 10 doses of asparaginase. The increased risk of events and death in HGR, who did less than 10 doses, was 3.6 and 7 times, respectively. The study did not show statistical significance for the number of asparaginase doses in patients who were not at high risk.
CONCLUSIONS
We demonstrated that the early interruption of asparaginase treatment could negatively impact the prognosis of patients with ALL, especially HGR, reinforcing the need for careful diagnosis of reactions and the availability of alternative types of asparaginase.
Topics: Antineoplastic Agents; Asparaginase; Child; Humans; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; Proportional Hazards Models; Retrospective Studies
PubMed: 34431241
DOI: 10.1002/cnr2.1533