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Pediatric Blood & Cancer Aug 2021PEG-asparaginase is critical in pediatric acute lymphoblastic leukemia (ALL) therapy but is highly immunogenic. Severe allergic reactions lead to substitution of further...
BACKGROUND
PEG-asparaginase is critical in pediatric acute lymphoblastic leukemia (ALL) therapy but is highly immunogenic. Severe allergic reactions lead to substitution of further PEG-asparaginase with Erwinia. Erwinia is associated with more frequent dosing, increased expense, and limited availability. Premedication may reduce rates of allergic reactions.
PROCEDURES
This Markov model evaluated the cost-effectiveness of three strategies: premedication plus therapeutic drug monitoring (TDM), TDM alone, and no premedication or TDM. We modeled two scenarios: a standard-risk (SR) B-ALL patient receiving two asparaginase doses and a high-risk (HR) patient receiving seven asparaginase doses. The model incorporated costs of asparaginase, premedication, TDM and clinic visits, and lost parental wages associated with each additional Erwinia dose. We incorporated a five-year time horizon with a societal perspective. Outcomes were Erwinia substitutions avoided and differences in quality-adjusted life years (QALYs). Probabilistic and one-way sensitivity analyses evaluated model uncertainty.
RESULTS
In both scenarios, premedication was the least costly strategy. In SR and HR scenarios, premedication with monitoring resulted in 8% and 7% fewer changes to Erwinia compared with monitoring alone and 3% and 2% fewer changes compared with no premedication/monitoring, respectively. Premedication resulted in the most QALYs gained in the SR patients. Individual variation of model inputs did not change premedication/monitoring favorability for either scenario. In probabilistic sensitivity analyses, premedication/monitoring was favored in >87% of iterations in both scenarios.
CONCLUSION
Compared with other strategies, premedication use and asparaginase level monitoring in children with B-ALL is potentially cost-saving.
Topics: Antineoplastic Agents; Asparaginase; Child; Cost-Benefit Analysis; Erwinia; Humans; Hypersensitivity; Polyethylene Glycols; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Premedication
PubMed: 33860989
DOI: 10.1002/pbc.29051 -
Leukemia Mar 2024Adolescents and young adult (AYA) patients with acute lymphoblastic leukemia (ALL) face worse outcomes than children. While pediatric-inspired protocols have improved...
Treatment completion, asparaginase completion, and oncologic outcomes among children, adolescents and young adults with acute lymphoblastic leukemia treated with DFCI Consortium Protocols.
Adolescents and young adult (AYA) patients with acute lymphoblastic leukemia (ALL) face worse outcomes than children. While pediatric-inspired protocols have improved outcomes, the ability of patients to complete these intensive regimens and the reasons for discontinuation are unknown. We analyzed a cohort of 332 AYA patients (aged 15-49 years) and 1159 children (aged 1-14 years) with Ph-negative ALL treated on DFCI consortium protocols. We found that AYA patients completed treatment at lower rates than children (60.8% vs. 89.7%, p < 0.001), primarily due to higher rates of early treatment failure (14.5% vs. 2.4%, p < 0.001). Withdrawal from treatment for toxicity, social/personal, or unknown reasons was uncommon, but higher among AYA patients (9.3% vs 4.7%, p = 0.001). Patients who remained on assigned therapy for one year had favorable overall survival (AYA 5-year OS 88.9%; children 5-year OS 96.4%; p < 0.001). Among patients who continued treatment for 1 year, AYA patients completed asparaginase (defined as receiving 26+ weeks) at lower rates than children (79.1% vs. 89.6%, p < 0.001). Patients who received more weeks of consolidation asparaginase had higher overall and event-free survival. Efforts should focus on identifying patients at risk for early treatment failure and optimizing asparaginase delivery.
Topics: Child; Humans; Adolescent; Young Adult; Asparaginase; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Antineoplastic Combined Chemotherapy Protocols
PubMed: 38177437
DOI: 10.1038/s41375-023-02115-4 -
Journal of Oncology Pharmacy Practice :... Jan 2020The incorporation of L-asparaginase and pegylated asparaginase into pediatric-inspired regimens has conferred a survival advantage in treatment of adults with acute...
The incorporation of L-asparaginase and pegylated asparaginase into pediatric-inspired regimens has conferred a survival advantage in treatment of adults with acute lymphoblastic leukemia. Use of asparaginase products requires careful prevention, monitoring, and management of adverse effects including hypersensitivity, hepatotoxicity, pancreatitis, coagulopathy, and thrombosis. Currently, there is limited published literature to offer guidance on management of these toxicities. At the University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, a standard of practice guideline was created to prevent and manage asparaginase-related adverse events. By sharing our long-term experience with asparaginase products and clinical management of asparaginase-induced toxicities, this article aims to improve patient safety and optimize treatment outcomes.
Topics: Adult; Antineoplastic Agents; Asparaginase; Cancer Care Facilities; Child, Preschool; Disease Management; Dose-Response Relationship, Drug; Drug Monitoring; Humans; Polyethylene Glycols; Practice Guidelines as Topic; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Thrombosis; Treatment Outcome
PubMed: 30917738
DOI: 10.1177/1078155219838316 -
Journal of Microbiology and... May 2022L-asparaginase (E.C. 3.5.1.1) purified from bacterial cells is widely used in the food industry, as well as in the treatment of childhood acute lymphoblastic leukemia....
L-asparaginase (E.C. 3.5.1.1) purified from bacterial cells is widely used in the food industry, as well as in the treatment of childhood acute lymphoblastic leukemia. In the present study, the L-asparaginase gene was cloned into the pGEX-2T DNA plasmid, expressed in BL21 (DE3) pLysS, and purified to homogeneity using Glutathione Sepharose chromatography with 7.26 purification fold and 16.01% recovery. The purified enzyme exhibited a molecular weight of ~33.6 kDa with SDS-PAGE and showed maximal activity at 50°C and pH 8.0. It retained 95.1, 89.6%, and 70.2% initial activity after 60 min at 30°C, 40°C, and 50°C, respectively. The enzyme reserved its activity at 30°C and 37°C up to 24 h. The enzyme had optimum pH of 8 and reserved 50% activity up to 24 h. The recombinant enzyme showed the highest substrate specificity towards L-asparaginase substrate, while no detectable specificity was observed for L-glutamine, urea, and acrylamide at 10 mM concentration. THP-1, a human leukemia cell line, displayed significant morphological alterations after being treated with recombinant L-asparaginase and the IC of the purified enzyme was recorded as 0.8 IU. Furthermore, the purified recombinant L-asparaginase improved cytotoxicity in liver cancer HepG2 and breast cancer MCF-7 cell lines, with IC values of 1.53 and 18 IU, respectively.
Topics: Asparaginase; Burkholderia pseudomallei; Enzyme Stability; Escherichia coli; Humans; Recombinant Proteins; Substrate Specificity
PubMed: 35354764
DOI: 10.4014/jmb.2112.12050 -
Expert Review of Hematology Nov 2019: Natural killer (NK)/T-cell lymphomas are aggressive malignancies that present predominantly in nasal and adjacent sites (nasal subtype), occasionally in skin,... (Review)
Review
: Natural killer (NK)/T-cell lymphomas are aggressive malignancies that present predominantly in nasal and adjacent sites (nasal subtype), occasionally in skin, gastrointestinal tract and other tissues (non-nasal), and rarely as disseminated disease with a leukemic phase (aggressive NK-cell leukemia, or leukemia/lymphoma, subtype).: The diagnosis and treatment of NK/T-cell lymphoma are discussed, based on a PubMed literature search. The diagnostic criteria for NK/T-cell lymphoma are highlighted, followed by an update of the diagnostic and prognostic importance (on presentation, at interim and end-of-treatment) of plasma EBV DNA as a surrogate biomarker of lymphoma load. Prognostic models based on clinicopathologic features and EBV DNA load are discussed. For stage I/II NK/T-cell lymphomas, combined chemotherapy, and radiotherapy gives the best results, with their concomitant or sequential administration equally efficacious. For stage III/IV NK/T-cell lymphoma, chemotherapy is the mainstay of treatment. Conventional anthracycline-based regimens for B-cell lymphomas are ineffective. Recommended regimens combine L-asparaginase with other drugs not affected by P-glycoprotein. For relapsed/refractory patients, immune checkpoint blockade with antibodies against programmed cell death protein 1 has shown much promise.: Current strategies result in durable remissions in a significant proportion of NK/T-cell lymphomas. Immune checkpoint inhibition and other novel approaches are promising for relapsed/refractory cases.
Topics: Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Humans; Lymphoma, Extranodal NK-T-Cell; Models, Biological; Neoplasm Staging; Prognosis
PubMed: 31487202
DOI: 10.1080/17474086.2019.1660640 -
BioDrugs : Clinical Immunotherapeutics,... Jun 2020Engineered red blood cells (RBCs) appear to be a promising method for therapeutic drug and protein delivery. With a number of agents in clinical trials (e.g.,... (Review)
Review
Engineered red blood cells (RBCs) appear to be a promising method for therapeutic drug and protein delivery. With a number of agents in clinical trials (e.g., dexamethasone 21-phosphate in ataxia telangiectasia, asparaginase in pancreatic cancer/acute lymphoblastic leukemia, thymidine phosphorylase in mitochondrial neurogastrointestinal encephalomyopathy, RTX-134 in phenylketonuria, etc.), this leading article summarizes the ongoing efforts in developing these agents, focuses on the clinical progress, and provides a brief background into engineered RBCs and the different ways in which they can be exploited for therapeutic/diagnostic purposes. References to available data on safety, efficacy, and tolerability are reported. Due to the continuous progress in this field, the information is updated as of January 2020 from databases, websites, and press releases of the involved companies and information that is in the public domain.
Topics: Asparaginase; Cell Engineering; Clinical Trials as Topic; Dexamethasone; Drug Carriers; Erythrocytes; Humans; Phenylalanine Ammonia-Lyase; Thymidine Phosphorylase
PubMed: 32198632
DOI: 10.1007/s40259-020-00415-0 -
Recent Patents on Biotechnology 2021L-asparaginase (L-ASNase, L-asparagine amidohydrolase, E.C.3.5.1.1) is an enzyme with wide therapeutic applicability. Currently, the commercialized L-ASNase comes from... (Review)
Review
BACKGROUND
L-asparaginase (L-ASNase, L-asparagine amidohydrolase, E.C.3.5.1.1) is an enzyme with wide therapeutic applicability. Currently, the commercialized L-ASNase comes from mesophilic organisms, presenting low specificity to the substrate and limitations regarding thermostability and active pH range. Such factors prevent the maximum performance of the enzyme in different applications. Therefore, extremophilic organisms may represent important candidates for obtaining amidohydrolases with particular characteristics desired by the biotechnological market.
OBJECTIVES
The present study aims to carry out a technological prospecting of patents related to the L-asparaginases derived from extremophilic organisms, contributing to pave the way for further rational investigation and application of such enzymes.
METHODS
This patent literature review used six patents databases: The LENS, WIPO, EPO, USPTO, Patent Inspiration, and INPI.
RESULTS
It was analyzed 2860 patents, and 14 were selected according to combinations of descriptors and study criteria. Approximately 57.14% of the patents refer to enzymes obtained from archaea, especially from the speciesPyrococcus yayanosii (35.71% of the totality).
CONCLUSION
The present prospective study has singular relevance since there are no recent patent reviews for L-asparaginases, especially produced by extremophilic microorganisms. Although such enzymes have well-defined applications, corroborated by the patents compiled in this review, the most recent studies allude to new uses, such as the treatment of infections. The characterization of the catalytic profiles allows us to infer that there are potential sources still unexplored. Hence, the search for new L-ASNases with different characteristics will continue to grow in the coming years and, possibly, ramifications of the technological routes will be witnessed.
Topics: Asparaginase; Asparagine; Biotechnology; Extremophiles; Patents as Topic; Prospective Studies
PubMed: 34353277
DOI: 10.2174/1872208315666210805162459 -
Pediatric Blood & Cancer Aug 2023Acute lymphoblastic leukemia is the commonest form of cancer in children and adolescents worldwide, and asparaginase is an essential component of successful chemotherapy...
Acute lymphoblastic leukemia is the commonest form of cancer in children and adolescents worldwide, and asparaginase is an essential component of successful chemotherapy for this disease associated with long-term survival rates often exceeding 90% in high-income countries. Demonstrably defective preparations of asparaginase, distributed from China and India, increase the burden of morbidity and mortality, reducing attainable survival rates. This adverse outcome is enabled by inadequate regulation and oversight, especially in resource-poor settings in low- and middle-income countries where the great majority of children and adolescents with cancer live. The pediatric oncology community must rise to the challenge.
Topics: Adolescent; Child; Humans; Asparaginase; Antineoplastic Agents; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Survival Rate; Medical Oncology
PubMed: 37218459
DOI: 10.1002/pbc.30403 -
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 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