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Cancer Medicine Dec 2023The clinicopathologic characteristics and prognosis of nasal and nonnasal extranodal natural killer T-cell lymphoma (ENKTL) are considered to be different. However, the...
BACKGROUND
The clinicopathologic characteristics and prognosis of nasal and nonnasal extranodal natural killer T-cell lymphoma (ENKTL) are considered to be different. However, the underlying features responsible for these differences are not well clarified especially in the era of asparaginase therapy.
METHODS
In total, 1007 newly diagnosed ENKTL patients from 11 medical centers were included in this study. Clinicopathologic characteristics and survival data were collected. The chi-squared test and Kruskal-Wallis test were utilized for the comparison of different groups. Univariable and multivariable Cox proportional hazards models were used to screen prognostic factors.
RESULTS
Overall, 869 (86.3%) patients were nasal forms. Compared to patients with nasal ENKTL, nonnasal patients were at more advanced stages and had poor performance status, bone marrow involvement, elevated serum lactate dehydrogenase (LDH), and CD56-negative status (p < 0.05). The 5-year overall survival (OS) for nasal and nonnasal patients were 65.6% and 45.0%, respectively. The OS of nasal forms patients were superior to nonnasal patients, especially in Eastern Cooperative Oncology Group performance status (ECOG PS) (≥2), advanced stage, KPI (HIR/HR), IPI (HIR/HR), PINK (HR), and high EBV DNA load groups. In patients treated with pegaspargase/L-asparaginase-based regimens, the OS of nasal patients was better than that of nonnasal patients. After adjusting the covariates of age, stage, ECOG PS score, LDH, B symptoms, and BM involvement, results showed that the nonnasal site was associated with poor survival of ENKTL.
CONCLUSIONS
The clinicopathologic characteristics and prognosis of nasal and nonnasal ENKTL patients are different. Nasal forms patients had superior OS than nonnasal patients, especially in the era of asparaginase.
Topics: Humans; Asparaginase; Lymphoma, Extranodal NK-T-Cell; Neoplasm Staging; Prognosis; Retrospective Studies
PubMed: 37902266
DOI: 10.1002/cam4.6674 -
Cancer Chemotherapy and Pharmacology Oct 2021We evaluated effects of asparaginase dosage, schedule, and formulation on CSF asparagine in children with acute lymphoblastic leukemia (ALL). (Comparative Study)
Comparative Study Randomized Controlled Trial
PURPOSE
We evaluated effects of asparaginase dosage, schedule, and formulation on CSF asparagine in children with acute lymphoblastic leukemia (ALL).
METHODS
We evaluated CSF asparagine (2114 samples) and serum asparaginase (5007 samples) in 482 children with ALL treated on the Total XVI study (NCT00549848). Patients received one or two 3000 IU/m IV pegaspargase doses during induction and were then randomized in continuation to receive 2500 IU/m or 3500 IU/m IV intermittently (four doses) on the low-risk (LR) or continuously (15 doses) on the standard/high risk (SHR) arms. A pharmacokinetic-pharmacodynamic model was used to estimate the duration of CSF asparagine depletion below 1 uM.
RESULTS
During induction, CSF asparagine depletion after two doses of pegaspargase was twice as long as one dose (median 30.7 vs 15.3 days, p < 0.001). During continuation, the higher dose increased the CSF asparagine depletion duration by only 9% on the LR and 1% in the SHR arm, consistent with the nonlinear pharmacokinetics of serum asparaginase. Pegaspargase caused a longer CSF asparagine depletion duration (1.3-5.3-fold) compared to those who were switched to erwinase (p < 0.001). The median (quartile range) serum asparaginase activity needed to maintain CSF asparagine below 1 µM was 0.44 (0.20, 0.99) IU/mL. Although rare, CNS relapse was higher with decreased CSF asparagine depletion (p = 0.0486); there was no association with relapse at any site (p = 0.3).
CONCLUSIONS
The number of pegaspargase doses has a stronger influence on CSF asparagine depletion than did dosage, pegaspargase depleted CSF asparagine longer than erwinase, and CSF asparagine depletion may prevent CNS relapses.
Topics: Antineoplastic Agents; Asparaginase; Asparagine; Child; Dose-Response Relationship, Drug; Drug Administration Schedule; Humans; Models, Biological; Polyethylene Glycols; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prospective Studies
PubMed: 34170389
DOI: 10.1007/s00280-021-04315-0 -
IUBMB Life May 2020It is generally accepted that L-asparagine is an important amino acid required for the fast growth of cells. Cancerous cells receive this amino acid from extracellular...
It is generally accepted that L-asparagine is an important amino acid required for the fast growth of cells. Cancerous cells receive this amino acid from extracellular sources. The depletion of L-asparagine from its surrounding environments by asparaginase enzyme can be used as a therapeutic strategy in cancer patients. This therapeutic enzyme is produced commercially mainly from bacteria such as Escherichia coli and Erwinia chrysanthemi. The side effects of such drugs have persuaded scientists to find new enzyme sources. In this study, in silico approach was applied to investigate L-asparaginase producing endophytic bacteria that produce more compatible enzymes within the body. Protein-protein basic local alignment search tool with E. coli and E. chrysanthemi asparaginase enzyme sequences against 262 endophytic bacteria were performed. The results with identity more than 35%, coverage more than 80%, and E-value less than 10 were selected. Then, some of bioinformatics tools were used to characterize them. A total of nine sequences consisting of seven known and two hypothetical proteins were identified in six bacterial species. The results showed that some of the asparaginase enzymes produced by endophytic bacteria possess more suitable immunological indices compared with asparaginase enzymes of E. coli and E. chrysanthemi. Herbaspirillum rubrisubalbicans was predicted to produce a nonallergen and nonantigen asparaginase enzyme. The number of antigenic determinants was predicted to be lower in asparaginase enzymes produced by Bacillus amyloliquefaciens, H. rubrisubalbicans, and H. seropedicae. Moreover, the number of high-scored B-cell epitopes was lower in enzyme sequences related to the mentioned bacteria and Paenibacillus polymyxa. The number of discontinuous epitopes and the number of T-cell epitopes were lower in B. amyloliquefaciens produced enzymes. Therefore, the therapeutic use of these enzymes is possible.
Topics: Allergens; Amino Acid Sequence; Antigens, Bacterial; Antineoplastic Agents; Asparaginase; Bacillus amyloliquefaciens; Bacterial Proteins; Computer Simulation; Dickeya chrysanthemi; Epitopes; Escherichia coli; Herbaspirillum; Humans; Paenibacillus polymyxa; Protein Structure, Quaternary
PubMed: 31981306
DOI: 10.1002/iub.2237 -
International Journal of Pharmaceutics Feb 2023l-asparaginase is a first-line medicine used for the treatment of acute lymphoblastic leukemia. Differing quality of marketed l-asparaginase biosimilars has been... (Review)
Review
l-asparaginase is a first-line medicine used for the treatment of acute lymphoblastic leukemia. Differing quality of marketed l-asparaginase biosimilars has been reported to adversely influence treatment outcomes. Herein, the quality of l-asparaginase biosimilars intended for clinical use was reviewed in sight of quality assurance parameters using English and Chinese language database searching, which provided information for possible improvements to the manufacture of this medicine. Ten articles met inclusion criteria, and quality attributes that measured potency, specific activity, purity and host cell proteins (HCPs) were identified. Biosimilars manufactured in high-income countries represented good quality in all aspects. Biosimilars manufactured in high-middle/middle-income countries, however, suggested poorer quality control particularly over removal of HCPs. Future work should now focus on establishing pharmacopeia monographs to establish equivalent quality assurance for l-asparaginase biosimilars manufactured between countries. Standardization of the quality profile, analytical methods and the limits of critical quality parameters, are essential to ensure appropriated efficacy and safety of clinical grade l-asparaginase.
Topics: Humans; Asparaginase; Biosimilar Pharmaceuticals; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Treatment Outcome; Antineoplastic Agents
PubMed: 36581108
DOI: 10.1016/j.ijpharm.2022.122523 -
PloS One 2019L-asparaginase (ASNase) from Escherichia coli is currently used in some countries in its PEGylated form (ONCASPAR, pegaspargase) to treat acute lymphoblastic leukemia...
L-asparaginase (ASNase) from Escherichia coli is currently used in some countries in its PEGylated form (ONCASPAR, pegaspargase) to treat acute lymphoblastic leukemia (ALL). PEGylation refers to the covalent attachment of poly(ethylene) glycol to the protein drug and it not only reduces the immune system activation but also decreases degradation by plasmatic proteases. However, pegaspargase is randomly PEGylated and, consequently, with a high degree of polydispersity in its final formulation. In this work we developed a site-specific N-terminus PEGylation protocol for ASNase. The monoPEG-ASNase was purified by anionic followed by size exclusion chromatography to a final purity of 99%. The highest yield of monoPEG-ASNase of 42% was obtained by the protein reaction with methoxy polyethylene glycol-carboxymethyl N-hydroxysuccinimidyl ester (10kDa) in 100 mM PBS at pH 7.5 and PEG:ASNase ratio of 25:1. The monoPEG-ASNase was found to maintain enzymatic stability for more days than ASNase, also was resistant to the plasma proteases like asparaginyl endopeptidase and cathepsin B. Additionally, monoPEG-ASNase was found to be potent against leukemic cell lines (MOLT-4 and REH) in vitro like polyPEG-ASNase. monoPEG-ASNase demonstrates its potential as a novel option for ALL treatment, being an inventive novelty that maintains the benefits of the current enzyme and solves challenges.
Topics: Asparaginase; Binding Sites; Cell Line, Tumor; Cell Survival; Chromatography, Gel; Enzyme Stability; Humans; Polyethylene Glycols; Precursor Cell Lymphoblastic Leukemia-Lymphoma
PubMed: 30753228
DOI: 10.1371/journal.pone.0211951 -
International Journal of Environmental... Jan 2022Endobiotic fungi are considered as a reservoir of numerous active metabolites. Asparaginase is used as an antileukemic drug specially to treat acute lymphoblastic...
Endobiotic fungi are considered as a reservoir of numerous active metabolites. Asparaginase is used as an antileukemic drug specially to treat acute lymphoblastic leukaemia. The presented study aims to optimize the media conditions, purify, characterize, and test the antileukemic activity of the asparaginase induced from . The culture medium was optimized using an experiment designed by The Taguchi model with an activity ranging from 10 to 175 IU/mL. Asparaginase was induced with an activity of 315 IU/mL. Asparaginase was purified with a specific activity of 468.03 U/mg and total activity of 84.4 IU/mL. The purified asparaginase showed an approximate size of 70 kDa. The purified asparaginase showed an optimum temperature of 37 °C and an optimum pH of 6. SDS reduced the activity of asparaginase to 0.65 U/mL while the used ionic surfactants enhanced the enzyme activity up to 151.92 IU/mL. The purified asparaginase showed a K of 9.37 µM and V of 127.00 µM/mL/min. The purified asparaginase showed an IC of 35.2 ± 0.7 IU/mL with leukemic M-NFS-60 cell lines and CC of 79.4 ± 1.9 IU/mL with the normal WI-38 cell line. The presented study suggests the use of endophytic fungi as a sustainable source for metabolites such as asparaginase, provides an opportunity to develop a facile, eco-friendly, cost-effective, and rapid synthesis of antileukemic drugs, which have the potential to be used as alternative and reliable sources for potent anticancer agents.
Topics: Antineoplastic Agents; Ascomycota; Asparaginase; Temperature
PubMed: 35055502
DOI: 10.3390/ijerph19020680 -
FEMS Yeast Research Oct 2022The study of nitrogen assimilation in yeast is of interest from genetic, evolutionary, and biotechnological perspectives. Over the course of evolution, yeasts have...
The study of nitrogen assimilation in yeast is of interest from genetic, evolutionary, and biotechnological perspectives. Over the course of evolution, yeasts have developed sophisticated control mechanisms to regulate nitrogen metabolism, with domesticated lineages sometimes displaying particular specialisation. The focus of this study was on assimilation of asparagine, which is a significant nutritional source for some alcoholic fermentations. We were particularly interested in ASP3, which encodes a periplasmic asparaginase and that was proposed to have been acquired relatively recently in S. cerevisiae by horizontal gene transfer. We examined 1680 S. cerevisiae genome assemblies to evaluate the distribution and evolutionary trajectory of ASP3. Our findings suggest an alternative hypothesis that ASP3 is an ancient Saccharomyces gene that has generally been lost over the course of evolution but has been retained in certain fermentative environments. As asparagine is the major nitrogen source in apple juice, we explored whether the presence of ASP3 would confer a growth advantage. Interestingly, we found that although ASP3 enhances growth when asparagine is the sole nitrogen source, the same effect is not seen in apple juice. These data indicate that growth in pure culture may not reflect the original selective environment for ASP3+ strains and highlight the role that complex regulation may play in optimising nitrogen assimilation in yeasts.
Topics: Asparaginase; Asparagine; Fermentation; Nitrogen; Saccharomyces cerevisiae
PubMed: 36040324
DOI: 10.1093/femsyr/foac044 -
Haematologica Oct 2023For several decades, asparaginase has been considered world-wide as an essential component of combination chemotherapy for the treatment of childhood acute lymphoblastic...
For several decades, asparaginase has been considered world-wide as an essential component of combination chemotherapy for the treatment of childhood acute lymphoblastic leukemia (ALL). Discovered over 60 years ago, two main unmanipulated asparaginase products originated from primary bacteria sources, namely Escherichia coli and Erwinia chrysanthemi, have been available for clinical use. A pegylated product of the Escherichia coli asparaginase was subsequently developed and is now the main product used by several international co-operative groups. The various asparaginase products all display the same mechanism of action (hydrolysis of circulating asparagine) and are associated with similar efficacy and toxicity patterns. However, their different pharmacokinetics, pharmacodynamics and immunological properties require distinctive modalities of application and monitoring. Erwinia chrysanthemi asparaginase was initially used as a first-line product, but subsequently became a preferred second-line product for children who experienced immunological reactions to the Escherichia coli asparaginase products. An asparaginase product displaying the same characteristics of the Erwinia chrysanthemi asparaginase has recently been produced by use of recombinant technology, thus securing a preparation available for use as an alternative, or as a back-up in case of shortages, for the non-recombinant product. The long journey of the Erwinia chrysanthemi asparaginase product as it has developed throughout the last several decades has made it possible for almost every child and adult with ALL to complete the asparaginase-based protocol treatment when an immunological reaction has occurred to any Escherichia coli asparaginase product.
Topics: Child; Adult; Humans; Asparaginase; Dickeya chrysanthemi; Drug Hypersensitivity; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Escherichia coli; Antineoplastic Agents
PubMed: 37470157
DOI: 10.3324/haematol.2022.282324 -
ESMO Open Sep 2020Insufficient exposure to asparaginase therapy is a barrier to optimal treatment and survival in childhood acute lymphoblastic leukaemia (ALL). Three important reasons... (Review)
Review
Insufficient exposure to asparaginase therapy is a barrier to optimal treatment and survival in childhood acute lymphoblastic leukaemia (ALL). Three important reasons for inactivity or discontinuation of asparaginase therapy are infusion related reactions (IRRs), pancreatitis and life-threatening central nervous system (CNS). For IRRs, real-time therapeutic drug monitoring (TDM) and premedication are important aspects to be considered. For pancreatitis and CNS thrombosis one key question is if patients should be re-exposed to asparaginase after their occurrence.An expert panel met during the Congress of the International Society for Paediatric Oncology in Lyon in October 2019 to discuss strategies for diminishing the impact of these three toxicities. The panel agreed that TDM is particularly useful for optimising asparaginase treatment and that when a tight pharmacological monitoring programme is established premedication could be implemented more broadly to minimise the risk of IRR. Re-exposure to asparaginase needs to be balanced against the anticipated risk of leukemic relapse. However, more prospective data are needed to give clear recommendations if to re-expose patients to asparaginase after the occurrence of severe pancreatitis and CNS thrombosis.
Topics: Antineoplastic Agents; Asparaginase; Child; Humans; Neoplasm Recurrence, Local; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prospective Studies
PubMed: 32967920
DOI: 10.1136/esmoopen-2020-000977 -
Haematologica Mar 2016L-asparaginase is an integral component of therapy for acute lymphoblastic leukemia. However, asparaginase-related complications, including the development of...
L-asparaginase is an integral component of therapy for acute lymphoblastic leukemia. However, asparaginase-related complications, including the development of hypersensitivity reactions, can limit its use in individual patients. Of considerable concern in the setting of clinical allergy is the development of neutralizing antibodies and associated asparaginase inactivity. Also problematic in the use of asparaginase is the potential for the development of silent inactivation, with the formation of neutralizing antibodies and reduced asparaginase activity in the absence of a clinically evident allergic reaction. Here we present guidelines for the identification and management of clinical hypersensitivity and silent inactivation with Escherichia coli- and Erwinia chrysanthemi- derived asparaginase preparations. These guidelines were developed by a consensus panel of experts following a review of the available published data. We provide a consensus of expert opinions on the role of serum asparaginase level assessment, indications for switching asparaginase preparation, and monitoring after change in asparaginase preparation.
Topics: Antibodies, Neutralizing; Antineoplastic Agents; Asparaginase; Consensus; Dickeya chrysanthemi; Disease Management; Drug Hypersensitivity; Drug Monitoring; Drug Substitution; Escherichia coli; Gene Expression; Humans; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recombinant Proteins
PubMed: 26928249
DOI: 10.3324/haematol.2015.137380