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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 -
Journal of Hematology & Oncology Oct 2021Asparaginase is an important drug to treat childhood haematological malignancies. Data on the association between human leukocyte antigens (HLA) and asparaginase...
Asparaginase is an important drug to treat childhood haematological malignancies. Data on the association between human leukocyte antigens (HLA) and asparaginase hypersensitivity among Chinese are lacking. We conducted a retrospective study to identify HLA alleles associated with asparaginase hypersensitivity among Chinese children with acute lymphoblastic leukaemia (ALL), mixed phenotype leukaemia and non-Hodgkin lymphoma (NHL), who received asparaginases with HLA typing performed between 2009 and 2019. 107 Chinese patients were analysed. 66.3% (71/107) developed hypersensitivity to at least one of the asparaginases. HLA-B*46:01 (OR 3.8, 95% CI 1.4-10.1, p < 0.01) and DRB1*09:01 (OR 4.3, 95% CI 1.6-11.4, p < 0.01) were significantly associated with L-asparaginase hypersensitivities, which remained significant after adjustment for age, gender and B cell ALL [HLA-B*46:01 (adjusted OR 3.5, 95% 1.3-10.5, p = 0.02) and DRB1*09:01 (OR 4.4, 95% CI 1.6-13.3, p < 0.01)].
Topics: Alleles; Antineoplastic Agents; Asian People; Asparaginase; Child; Child, Preschool; China; Drug Hypersensitivity; Female; Genetic Predisposition to Disease; HLA Antigens; Humans; Lymphoma, Non-Hodgkin; Male; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Retrospective Studies
PubMed: 34717720
DOI: 10.1186/s13045-021-01201-3 -
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 -
Seminars in Thrombosis and Hemostasis Jul 2021Bleeding and thrombosis are well-known complications to hematological malignancies, and changes in fibrinolysis impact both these issues. In the present systematic...
Bleeding and thrombosis are well-known complications to hematological malignancies, and changes in fibrinolysis impact both these issues. In the present systematic review, we provide an overview and discussion of the current literature in regards to clinical manifestations, diagnosis, and treatment of altered fibrinolysis in patients suffering from hematological malignancies, beyond acute promyelocytic leukemia. We performed a systematic literature search employing the databases Pubmed, Embase, and Web of Science to identify original studies investigating fibrinolysis in hematological malignancies. Studies investigating fibrinolysis in acute promyelocytic leukemia or disseminated intravascular coagulation were excluded. We identified 32 studies fulfilling the inclusion criteria. A majority of the studies were published more than two decades ago, and none of the studies examined all available markers of fibrinolysis or used dynamic clot lysis assays. In acute leukemia L-asparaginase treatment induced a hypofibrinolytic state, and prior to chemotherapy there seemed to be little to no change in fibrinolysis. In studies examining fibrinolysis during chemotherapy results were ambiguous. Two studies examining multiple myeloma indicated hypofibrinolysis prior to chemotherapy, and in another plasma cell disease, amyloid light chain-amyloidosis, clear signs of hyperfibrinolysis were demonstrated. In myeloproliferative neoplasms, the studies reported signs of hypofibrinolysis, in line with the increased risk of thrombosis in this disease. Only one study regarding lymphoma was identified, which indicated no alterations in fibrinolysis. In conclusion, this systematic review demonstrated that only sparse, and mainly old, evidence exists on fibrinolysis in hematological malignancy. However, the published studies showed a tendency toward hypofibrinolysis in myeloproliferative disorders, an increased risk of hyperfibrinolysis, and bleeding in patients with AL-amyloidosis, whereas studies regarding acute leukemias were inconclusive except with regard to L-asparaginase treatment, which induced a hypofibrinolytic state.
Topics: Amyloidosis; Asparaginase; Blood Coagulation Disorders; Fibrinolysis; Hematologic Neoplasms; Hemorrhage; Humans; Leukemia, Promyelocytic, Acute; Thrombosis
PubMed: 34058766
DOI: 10.1055/s-0041-1725099 -
Biotechnology and Applied Biochemistry Jul 2020l-Asparaginase (E.C.3.5.1.1.) is a vital enzyme that hydrolyzes l-asparagine to l-aspartic acid and ammonia. This property of l-asparaginase inhibits the protein... (Review)
Review
l-Asparaginase (E.C.3.5.1.1.) is a vital enzyme that hydrolyzes l-asparagine to l-aspartic acid and ammonia. This property of l-asparaginase inhibits the protein synthesis in cancer cells, making l-asparaginase a mainstay of pediatric chemotherapy practices to treat acute lymphoblastic leukemia (ALL) patients. l-Asparaginase is also recognized as one of the important food processing agent. The removal of asparagine by l-asparaginase leads to the reduction of acrylamide formation in fried food items. l-Asparaginase is produced by various organisms including animals, plants, and microorganisms, however, only microorganisms that produce a substantial amount of this enzyme are of commercial significance. The commercial l-asparaginase for healthcare applications is chiefly derived from Escherichia coli and Erwinia chrysanthemi. A high rate of hypersensitivity and adverse reactions limits the long-term clinical use of l-asparaginase. Present review provides thorough information on microbial l-asparaginase bioprocess optimization including submerged fermentation and solid-state fermentation for l-asparaginase production, downstream purification, its characterization, and issues related to the clinical application including toxicity and hypersensitivity. Here, we have highlighted the bioprocess techniques that can produce improved and economically viable yields of l-asparaginase from promising microbial sources in the current scenario where there is an urgent need for alternate l-asparaginase with less adverse effects.
Topics: Animals; Asparaginase; Dickeya chrysanthemi; Escherichia coli; Escherichia coli Proteins; Humans; Precursor Cell Lymphoblastic Leukemia-Lymphoma
PubMed: 31954377
DOI: 10.1002/bab.1888 -
Journal of Clinical Pharmacy and... Dec 2022Diabetic ketoacidosis (DKA) may occur during asparaginase use. However, limited by the study population, the association between asparaginase and DKA has not been... (Review)
Review
WHAT IS KNOWN AND OBJECTIVE
Diabetic ketoacidosis (DKA) may occur during asparaginase use. However, limited by the study population, the association between asparaginase and DKA has not been elucidated. The purpose of this study was to determine the potential association between asparaginase and DKA and analyse related clinical characteristics and possible risk factor.
METHODS
Disproportionality analysis with the reporting odd ratio (ROR) was used to detect the adverse reaction signals of asparaginase-associated DKA in Food and Drug Administration Adverse Event Reporting System (FAERS). A literature review was conducted to further analyse clinical characteristics, possible risk factor and something noteworthy in asparaginase-associated DKA.
RESULTS AND DISCUSSION
A total of 12 reports of DKA associated with l-asparaginase (l-asp) and 6 reports associated with pegaspargase (PEG-asp) were extracted in FAERS, more than 50% of the cases were classified as serious adverse events. DKA was a positive signal of l-asp (ROR = 2.397, 95% CI 1.360-4.226), while not closely related to the use of PEG-asp (ROR = 1.602, 95% CI 0.719-3.570). Searched in PubMed, Embase and Web of Science, a total of eight patients were collected. The patients were mainly adolescent patients, aged between 11 and 25 years old with a median age of 16 years. Drug dosage form distribution is unbalanced, 7 patients received l-asp and only 1 received PEG-asp.
WHAT IS NEW AND CONCLUSIONS
The ROR of KDA caused by l-asp was statistically significant, but there was not a statistical association for DKA caused by PEG-asp. Asparaginase dosage form may affect the occurrence of DKA, but further research is needed.
Topics: Adolescent; United States; Humans; Child; Young Adult; Adult; Asparaginase; Diabetic Ketoacidosis; Risk Factors; United States Food and Drug Administration; Odds Ratio; Diabetes Mellitus
PubMed: 36411584
DOI: 10.1111/jcpt.13782 -
British Journal of Haematology Aug 2022Osteonecrosis (ON) is a complication of acute lymphoblastic leukaemia (ALL) treatment with patient- (age, female sex, genetic polymorphisms, presence of metabolic... (Review)
Review
Osteonecrosis (ON) is a complication of acute lymphoblastic leukaemia (ALL) treatment with patient- (age, female sex, genetic polymorphisms, presence of metabolic syndrome) and treatment-specific (glucocorticoid type and schedule) risk factors described. The potential role of asparaginase in increasing risk of ON via effects on coagulation, lipid metabolism, and steroid clearance is now also recognised. Paediatric studies consistently identify age as a key risk factor for ON, with adolescents at higher risk than young children. Fewer studies comprehensively report on risk of ON in adults, but available evidence suggests that adolescents and young adults (AYAs) treated with corticosteroid and asparaginase-containing paediatric-inspired regimens are more at risk than older adults treated with paediatric-inspired or traditional adult regimens. There are few proven strategies to prevent or mitigate the severity of ON and other orthopaedic complications of ALL therapy. Future clinical trials should carefully ascertain orthopaedic adverse events in adults. Evidence-based guidelines should be developed for management of orthopaedic adverse events in adults being treated for ALL, especially high-risk AYAs being treated with paediatric-inspired regimens.
Topics: Adolescent; Adult; Asparaginase; Female; Humans; Orthopedics; Osteonecrosis; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Treatment Outcome; Young Adult
PubMed: 35312041
DOI: 10.1111/bjh.18093 -
BMC Genomics Nov 2021Trichoderma is a genus of fungi in the family Hypocreaceae and includes species known to produce enzymes with commercial use. They are largely found in soil and...
BACKGROUND
Trichoderma is a genus of fungi in the family Hypocreaceae and includes species known to produce enzymes with commercial use. They are largely found in soil and terrestrial plants. Recently, Trichoderma simmonsii isolated from decaying bark and decorticated wood was newly identified in the Harzianum clade of Trichoderma. Due to a wide range of applications in agriculture and other industries, genomes of at least 12 Trichoderma spp. have been studied. Moreover, antifungal and enzymatic activities have been extensively characterized in Trichoderma spp. However, the genomic information and bioactivities of T. simmonsii from a particular marine-derived isolate remain largely unknown. While we screened for asparaginase-producing fungi, we observed that T. simmonsii GH-Sj1 strain isolated from edible kelp produced asparaginase. In this study, we report a draft genome of T. simmonsii GH-Sj1 using Illumina and Oxford Nanopore technologies. Furthermore, to facilitate biotechnological applications of this species, RNA-sequencing was performed to elucidate the transcriptional profile of T. simmonsii GH-Sj1 in response to asparaginase-rich conditions.
RESULTS
We generated ~ 14 Gb of sequencing data assembled in a ~ 40 Mb genome. The T. simmonsii GH-Sj1 genome consisted of seven telomere-to-telomere scaffolds with no sequencing gaps, where the N50 length was 6.4 Mb. The total number of protein-coding genes was 13,120, constituting ~ 99% of the genome. The genome harbored 176 tRNAs, which encode a full set of 20 amino acids. In addition, it had an rRNA repeat region consisting of seven repeats of the 18S-ITS1-5.8S-ITS2-26S cluster. The T. simmonsii genome also harbored 7 putative asparaginase-encoding genes with potential medical applications. Using RNA-sequencing analysis, we found that 3 genes among the 7 putative genes were significantly upregulated under asparaginase-rich conditions.
CONCLUSIONS
The genome and transcriptome of T. simmonsii GH-Sj1 established in the current work represent valuable resources for future comparative studies on fungal genomes and asparaginase production.
Topics: Asparaginase; Genome; Hypocreales; Telomere; Trichoderma
PubMed: 34789157
DOI: 10.1186/s12864-021-08162-4 -
International Journal of Oncology Apr 2021L‑asparaginase enzymes have been a vital component of acute lymphoblastic leukemia therapy for >40 years. L‑asparaginase acts by depleting plasma L‑asparagine,... (Review)
Review
L‑asparaginase enzymes have been a vital component of acute lymphoblastic leukemia therapy for >40 years. L‑asparaginase acts by depleting plasma L‑asparagine, which is essential to the survival of leukemia cells. In contrast to normal cells, tumor cells cannot synthesize L‑asparagine and thus depend on its external uptake for growth. Currently, three bacterial L‑asparaginases are used in therapy; however, they are associated with severe side‑effects related to high toxicity and immunogenicity. The introduction of human L‑asparaginase‑like protein 1 in acute lymphoblastic leukemia treatment would avoid the problems caused by the bacterial enzymes; however, a major difficulty in the therapeutic use of the human enzyme comes from the fact that human L‑asparaginase must be activated through an autoprocessing step, which is a low‑efficiency process in vitro that results in reduced enzymatic activity. The present review article aimed to contribute to the understanding of the enzyme self‑activation process and focuses on the efforts made for the development of a therapeutic variant of human L‑asparaginase.
Topics: Asparaginase; Autoantigens; Enzyme Activation; Humans; Precursor Cell Lymphoblastic Leukemia-Lymphoma
PubMed: 33649831
DOI: 10.3892/ijo.2021.5191