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Clinical Hematology International 2023Asparaginase-associated pancreatitis complicates 2-10% of patients treated for acute lymphoblastic leukemia, causing morbidity and discontinuation of asparaginase...
Asparaginase-associated Pancreatitis Complicated by Pancreatic Fluid Collection Treated with Endoscopic Cistogastrostomy in Pediatric Acute Lymphoblastic Leukemia: A Case Report and Systematic Review of the Literature.
Asparaginase-associated pancreatitis complicates 2-10% of patients treated for acute lymphoblastic leukemia, causing morbidity and discontinuation of asparaginase administration. Among acute complications, pancreatic fluid collections can be managed conservatively, but intervention is indicated when associated with persistent insulin therapy need and recurrent abdominal pain. Endoscopic treatment has become the standard approach in adult patients, with increasing favorable evidence in children. This work compares the characteristics of a pediatric oncology patient treated at our institution with reported literature experiences, showing feasibility, safety and effectiveness of endoscopic approach.
PubMed: 38817959
DOI: 10.46989/001c.90958 -
Critical Reviews in Oncology/hematology May 2024Asparaginase is essential in the initial management of acute lymphoblastic leukemia (ALL) but frequently leads to venous thromboembolism (VTE). Using anticoagulants for... (Meta-Analysis)
Meta-Analysis Review
A systematic review and meta-analysis of the effectiveness of primary thromboprophylaxis in acute lymphoblastic leukemia during early-phase therapy including asparaginase or its prolonged form.
Asparaginase is essential in the initial management of acute lymphoblastic leukemia (ALL) but frequently leads to venous thromboembolism (VTE). Using anticoagulants for primary VTE prevention has been studied with no consensus. We conducted a systematic literature search in PubMed, Scopus, and Web of science and performed random-effect meta-analysis using Mantel-Haenszel method in RevMan 5.4 to analyze primary pharmacological thromboprophylaxis during asparaginase treatment in early-phase (induction, consolidation, or intensification phase) therapy in patients with ALL with all ages and followed with subgroup analysis by age. Meta-analysis of 13 articles describing the effect of antithrombin supplementation in 1375 patients showed that antithrombin prophylaxis decreases the risk of VTE by 43% (RR, 0.57; 95% CI, 0.38 - 0.83; p=0.004), with mild heterogeneity (I=35%, p=0.10) and moderate certainty by GRADE. 8 articles included for meta-analysis of low-molecular weight heparin (LMWH) treatment in 612 patients showed that it decreased the risk of VTE by nearly 40% (RR, 0.61; 95% CI, 0.45 - 0.81; p=0.00081), with minimal heterogeneity (I=14%, p=0.31) but low certainty. Subgroup analysis showed that only prophylaxis with antithrombin supplementation significantly decreased the VTE rate in adult patients with moderate certainty. In pediatric patients, one nonrandomized prospective study showed that LMWH combined with antithrombin has a better thromboprophylaxis effect than antithrombin alone. In the PREVAPIX-ALL trial, prophylaxis with direct factor Xa inhibitor Apixaban did not benefit children younger than 18 years except for cases of obesity. We concluded that thromboprophylaxis with antithrombin is effective in ALL patients older than 18 years during the early phase of therapy, and LMWH combined with antithrombin supplementation might be effective for pediatric patients with ALL. Apixaban is effective in pediatric ALL patients with obesity and needs further study in other high-risk patients.
Topics: Humans; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Asparaginase; Venous Thromboembolism; Anticoagulants; Heparin, Low-Molecular-Weight; Antithrombins
PubMed: 38583546
DOI: 10.1016/j.critrevonc.2024.104347 -
Journal of Hematology Oct 2023Treatment with non-anthracycline (ANT)-based chemotherapy has increased survival in patients with extranodal natural killer/T-cell lymphoma (ENKTCL). However, the...
BACKGROUND
Treatment with non-anthracycline (ANT)-based chemotherapy has increased survival in patients with extranodal natural killer/T-cell lymphoma (ENKTCL). However, the relative efficacy of various drug combinations has been contentious. We aimed to identify the most effective chemotherapy regimens for newly diagnosed ENKTCL.
METHODS
A network meta-analysis was performed to evaluate the differences in survival and treatment responses across various regimens. The primary objective was overall survival (OS), while secondary outcomes included progression-free survival (PFS), objective response rate (ORR), and complete response (CR). We utilized a Bayesian framework to perform the network meta-analysis. Rank probabilities were assessed by the surface under the cumulative ranking curve (SUCRA). Node-splitting method was used to assess the inconsistency.
RESULTS
A total of 1,113 patients were enrolled across 10 studies. Chemotherapy regimens were grouped into five modalities, for which six types of direct comparisons were available. We identified the asparaginase (ASP)/gemcitabine (GEM)-based regimens superiority over ANT-based, non-ASP/ANT-based and ASP/methotrexate (MTX)-based regimens on OS. Although no significant differences were observed compared with ASP/not otherwise specified-based, ASP/GEM-based regimens were still the best option chemotherapy for OS. Moreover, the ASP/GEM-based regimens demonstrated advantages in PFS, ORR and CR.
CONCLUSIONS
According to our network meta-analysis, it appears that ASP/GEM-based regimens could potentially serve as the most effective frontline chemotherapy option for ENKTCL.
PubMed: 37936976
DOI: 10.14740/jh1169 -
Future Microbiology Jan 2024To review the available literature about heterologous expression of fungal L-asparaginase (L-ASNase). A search was conducted across PubMed, Science Direct, Scopus and... (Review)
Review
To review the available literature about heterologous expression of fungal L-asparaginase (L-ASNase). A search was conducted across PubMed, Science Direct, Scopus and Web of Science databases; 4172 citations were identified and seven articles were selected. The results showed that heterologous expression of fungal L-ASNase was performed mostly in bacterial expression systems, except for a study that expressed L-ASNase in a yeast system. Only three publications reported the purification and characterization of the enzyme. The information reported in this systematic review can contribute significantly to the recognition of the importance of biotechnological techniques for L-ASNase production.
Topics: Humans; Asparaginase; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Bacteria; Antineoplastic Agents
PubMed: 37882841
DOI: 10.2217/fmb-2023-0131 -
Pediatric Blood & Cancer Dec 2023The established association between acute lymphoblastic leukemia (ALL) and hyperlipidemia has, in some studies, been linked to toxicities such as pancreatitis,... (Review)
Review
BACKGROUND
The established association between acute lymphoblastic leukemia (ALL) and hyperlipidemia has, in some studies, been linked to toxicities such as pancreatitis, thrombosis, and osteonecrosis. However, a systematic review investigating the incidence, management, and clinical implications of hyperlipidemia during childhood ALL treatment is lacking.
OBJECTIVES
Systematically assess the incidence of hyperlipidemia during ALL treatment, explore associations with risk factors and severe toxicities (osteonecrosis, thrombosis, and pancreatitis), and review prevalent management strategies.
METHODS
A systematic review was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Data synthesis was descriptive, and a meta-analysis of hypertriglyceridemia and risk of severe toxicities was performed.
RESULTS
We included 13 studies with 3,425 patients. Hyperlipidemia incidence varied widely (6.7%-85%) but with inconsistent definitions and screening strategies across studies. Evidence regarding risk factors was conflicting, but age (> 10 years) and treatment with asparaginase and glucocorticosteroids seem to be associated with hyperlipidemia. Hypertriglyceridemia (grade 3/4) increased the risk for osteonecrosis (odds ratio (OR): 4.27, 95% confidence interval (CI): 2.77-6.61). No association could be established for pancreatitis (OR: 1.60, 95% CI: 0.53-4.82) or thrombosis (OR: 2.45, 95% CI: 0.86-7.01), but larger studies are needed to confirm this.
CONCLUSION
The overall evidence of this systematic review is limited by the small number of studies and risk of bias. Our review suggests that hypertriglyceridemia increases the risk for osteonecrosis. However, larger studies are needed to explore the clinical implications of hyperlipidemia and randomized trials investigating hyperlipidemia management and its impact on severe toxicities.
PubMed: 37776083
DOI: 10.1002/pbc.30683 -
The Cochrane Database of Systematic... May 2023Asparaginase has played a crucial role in the improvement of survival in children with acute lymphoblastic leukaemia (ALL), which is the commonest cancer among children.... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Asparaginase has played a crucial role in the improvement of survival in children with acute lymphoblastic leukaemia (ALL), which is the commonest cancer among children. Survival rates have steadily increased over decades since the introduction of asparaginase to ALL therapy, and overall survival rates reach 90% with the best contemporary protocols. Currently, polyethylene glycolated native Escherichia coli-derived L-asparaginase (PEG-asparaginase) is the preferred first-line asparaginase preparation. Besides its clinical benefits, PEG-asparaginase is well known for severe toxicities. Agreement on the optimal dose, treatment duration, and frequency of administration has never been reached among clinicians.
OBJECTIVES
Primary objective To assess the effect of the number of PEG-asparaginase doses on survival and relapse in children and adolescents with ALL. Secondary objectives To assess the association between the number of doses of PEG-asparaginase and asparaginase-associated toxicities (e.g. hypersensitivity, thromboembolism, pancreatitis and osteonecrosis). To undertake a network meta-analysis at dose-level in order to generate rankings of the number of doses of PEG-asparaginase used in the treatment for ALL, according to their benefits (survival and relapse) and harms (toxicity).
SEARCH METHODS
We searched CENTRAL, PubMed, Embase, Web of Science databases and three trials registers in November 2021, together with reference checking, citation searching and contact with study authors to identify additional studies.
SELECTION CRITERIA
We included randomised controlled trials (RCTs) comparing different PEG-asparaginase treatment regimens in children and adolescents (< 18 years of age) with first-line ALL treated with multiagent chemotherapy including PEG-asparaginase.
DATA COLLECTION AND ANALYSIS
Using a standardised data collection form, two review authors independently screened and selected studies, extracted data, assessed risk of bias for each outcome using a standardised tool (RoB 2.0) and assessed the certainty of evidence for each outcome using the GRADE approach. Primary outcomes included overall survival, event-free survival and leukaemic relapse. Secondary outcomes included asparaginase-associated toxicities (hypersensitivity, thromboembolism, pancreatitis, sinusoidal obstruction syndrome and osteonecrosis as well as overall asparaginase-associated toxicity). We conducted the review and performed the analyses in accordance with the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions.
MAIN RESULTS
We included three RCTs in the review, and identified an additional four ongoing studies. We judged outcomes of two RCTs to be at low risk of bias in all the Cochrane risk of bias (RoB 2) domains. We rated the remaining study as having some concerns regarding bias. Due to concerns about imprecision, we rated all outcomes as having low- to moderate-certainty evidence. One study compared intermittent PEG-asparaginase treatment (eight doses of PEG-asparaginase, 1000 IU/m, intramuscular (IM) administration) versus continuous PEG-asparaginase treatment (15 doses of PEG-asparaginase, 1000 IU/m, IM) in 625 participants with non-high risk ALL aged 1.0 to 17.9 years. We found that treatment with eight doses probably results in little to no difference in event-free survival compared to treatment with 15 doses (RR 1.01, 95% CI 0.97 to 1.06; moderate-certainty evidence). Compared to treatment with 15 doses, treatment with eight doses may result in either no difference or a slight reduction in hypersensitivity (RR 0.64, 95% CI 0.21 to 1.93; low-certainty evidence), thromboembolism (RR 0.55, 95% CI 0.22 to 1.36; low-certainty evidence) or osteonecrosis (RR 0.68, 95% CI 0.35 to 1.32; low-certainty evidence). Furthermore, we found that treatment with eight doses probably reduces pancreatitis (RR 0.31, 95% CI 0.12 to 0.75; moderate-certainty evidence) and asparaginase-associated toxicity (RR 0.53, 95% CI 0.35 to 0.78; moderate-certainty evidence) compared to treatment with 15 doses. One study compared low-risk standard treatment with additional PEG-asparaginase (six doses, 2500 IU/m, IM) versus low-risk standard treatment (two doses, 2500 IU/m, IM) in 1857 participants aged one to nine years old with standard low-risk ALL. We found that, compared to treatment with two doses, treatment with six doses probably results in little to no difference in overall survival (RR 0.99, 95% CI 0.98 to 1.00; moderate-certainty evidence) and event-free survival (RR 1.01, 95% CI 0.99 to 1.04; moderate-certainty evidence), and may result in either no difference or a slight increase in osteonecrosis (RR 1.65, 95% CI 0.91 to 3.00; low-certainty evidence). Furthermore, we found that treatment with six doses probably increases hypersensitivity (RR 12.05, 95% CI 5.27 to 27.58; moderate-certainty evidence), pancreatitis (RR 4.84, 95% CI 2.15 to 10.85; moderate-certainty evidence) and asparaginase-associated toxicity (RR 4.49, 95% CI 3.05 to 6.59; moderate-certainty evidence) compared to treatment with two doses. One trial compared calaspargase (11 doses, 2500 IU/m, intravenous (IV)) versus PEG-asparaginase (16 doses, 2500 IU/m, IV) in 239 participants aged one to 21 years with standard- and high-risk ALL and lymphoblastic lymphoma. We found that treatment with 11 doses of calaspargase probably results in little to no difference in event-free survival compared to treatment with 16 doses of PEG-asparaginase (RR 1.06, 95% CI 0.97 to 1.16; moderate-certainty evidence). However, treatment with 11 doses of calaspargase probably reduces leukaemic relapse compared to treatment with 16 doses of PEG-asparaginase (RR 0.32, 95% CI 0.12 to 0.83; moderate-certainty evidence). Furthermore, we found that treatment with 11 doses of calaspargase results in either no difference or a slight reduction in hypersensitivity (RR 1.17, 95% CI 0.64 to 2.13; low-certainty evidence), pancreatitis (RR 0.85, 95% CI 0.47 to 1.52; low-certainty evidence), thromboembolism (RR 0.83, 95% CI 0.48 to 1.42; low-certainty evidence), osteonecrosis (RR 0.63, 95% CI 0.15 to 2.56; low-certainty evidence) and asparaginase-associated toxicity (RR 1.00, 95% CI 0.71 to 1.40; low-certainty evidence) compared to treatment with 16 doses of PEG-asparaginase.
AUTHORS' CONCLUSIONS
We were not able to conduct a network meta-analysis, and could not draw clear conclusions because it was not possible to rank the interventions. Overall, we found that different numbers of doses of PEG-asparaginase probably result in little to no difference in event-free survival across all studies. In two studies, we found that a higher number of PEG-asparaginase doses probably increases pancreatitis and asparaginase-associated toxicities.
Topics: Adolescent; Child; Child, Preschool; Humans; Infant; Asparaginase; Neoplasm Recurrence, Local; Network Meta-Analysis; Pancreatitis; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Systematic Reviews as Topic; Thromboembolism; Recurrence
PubMed: 37260073
DOI: 10.1002/14651858.CD014570.pub2 -
Critical Reviews in Food Science and... 2024Acrylamide (AA) is a toxic substance formed in many carbohydrate-rich food products, whose formation can be reduced by adding some additives. Furthermore, the type of...
Acrylamide (AA) is a toxic substance formed in many carbohydrate-rich food products, whose formation can be reduced by adding some additives. Furthermore, the type of food consumed determines the AA intake. According to the compiled information, the first route causing AA formation is the Maillard reaction. Some interventions, such as reducing AA precursors in raw materials, (i.e., asparagine), reducing sugars, or decreasing temperature and processing time can be applied to limit AA formation in food products. The L-asparaginase is more widely used in potato products. Also, coatings loaded with proteins, enzymes, and phenolic compounds are new techniques for reducing AA content. Enzymes have a reducing effect on AA formation by acting on asparagine; proteins by competing with amino acids to participate in Maillard, and phenolic compounds through their radical scavenging activity. On the other hand, some synthetic and natural additives increase the formation of AA. Due to the high exposure to AA and its toxic effects, it is essential to recognize suitable food additives to reduce the health risks for consumers. In this sense, this study focuses on different additives that are proven to be effective in the reduction or formation of AA in food products.
Topics: Asparagine; Acrylamide; Hot Temperature; Carbohydrates; Asparaginase; Maillard Reaction
PubMed: 36194060
DOI: 10.1080/10408398.2022.2126428 -
Molecular Biology Reports Dec 2022L-asparaginases are mostly obtained from bacterial sources for their application in the therapy and food industry. Bacterial L-asparaginases are employed in the...
L-asparaginases are mostly obtained from bacterial sources for their application in the therapy and food industry. Bacterial L-asparaginases are employed in the treatment of Acute Lymphoblastic Leukemia (ALL) and its subtypes, a type of blood and bone marrow cancer that results in the overproduction of immature blood cells. It also plays a role in the food industry in reducing the acrylamide formed during baking, roasting, and frying starchy foods. This importance of the enzyme makes it to be of constant interest to the researchers to isolate novel sources. Presently L-asparaginases from E. coli native and PEGylated form, Dickeya chrysanthemi (Erwinia chrysanthemi) are in the treatment regime. In therapy, the intrinsic glutaminase activity of the enzyme is a major drawback as the patients in treatment experience side effects like fever, skin rashes, anaphylaxis, pancreatitis, steatosis in the liver, and many complications. Its significance in the food industry in mitigating acrylamide is also a major reason. Acrylamide, a potent carcinogen was formed when treating starchy foods at higher temperatures. Acrylamide content in food was analyzed and pre-treatment was considered a valuable option. Immobilization of the enzyme is an advancing and promising technique in the effective delivery of the enzyme than in free form. The concept of machine learning by employing the Artificial Network and Genetic Algorithm has paved the way to optimize the production of L-asparaginase from its sources. Gene-editing tools are gaining momentum in the study of several diseases and this review focuses on the CRISPR-Cas9 gene-editing tool in ALL.
Topics: Humans; Acrylamide; Asparaginase; Dickeya chrysanthemi; Escherichia coli; Precursor Cell Lymphoblastic Leukemia-Lymphoma
PubMed: 35816224
DOI: 10.1007/s11033-022-07688-4 -
Seminars in Thrombosis and Hemostasis Jun 2022Venous thromboembolism (VTE) in children is a rare but serious event. Current guidance on pharmacological thromboprophylaxis in children is mostly based on adult studies...
Venous thromboembolism (VTE) in children is a rare but serious event. Current guidance on pharmacological thromboprophylaxis in children is mostly based on adult studies and expert opinions. The aim of this systematic review was to examine under which conditions children (age ≤ 18 years) would benefit from pharmacological thromboprophylaxis with low molecular weight heparin or unfractionated heparin. Eligible studies included children, who did not receive pharmacological thromboprophylaxis as comparator, and VTE events were radiologically verified. MEDLINE and Embase were searched up to October 3, 2021. Ten studies were included presenting data for 976 children receiving pharmacological thromboprophylaxis. We divided the studies into three categories based on the population studied: children in the intensive care unit ( = 2), children with fractures and/or undergoing surgery ( = 5), and children with systemic disease ( = 3). A lower incidence of VTE was found when pharmacological thromboprophylaxis was used compared with no prophylaxis in children in intensive care unit with central venous catheter and mechanical ventilation (7/27 vs. 13/24), children in the intensive care unit admitted after trauma with a very high risk of VTE based on several risk factors (0/21 vs. 13/96), and children with acute lymphoblastic leukemia treated with L-asparaginase concomitant with steroid and presence of central venous catheter (0/82 vs. 8/121). Pharmacological thromboprophylaxis was not associated with an increased bleeding risk. In conclusion, pharmacological thromboprophylaxis in children is sparsely investigated. Only children with several risk factors for VTE are likely to benefit from pharmacological thromboprophylaxis.
Topics: Adolescent; Adult; Anticoagulants; Child; Hemorrhage; Heparin; Heparin, Low-Molecular-Weight; Humans; Venous Thromboembolism
PubMed: 35772401
DOI: 10.1055/s-0042-1748151 -
European Journal of Cancer (Oxford,... Nov 2021This review focuses on asparaginase, a key component of childhood acute lymphoblastic leukaemia (ALL) treatment since the 1970s. This review evaluates how much...
This review focuses on asparaginase, a key component of childhood acute lymphoblastic leukaemia (ALL) treatment since the 1970s. This review evaluates how much asparaginase is needed for optimal outcome in childhood ALL. We provide an overview of asparaginase dose intensity, i.e. duration of total cumulative exposure in weeks and level of exposure reflected by dose and/or asparaginase activity level, and the corresponding outcome. We systematically searched papers published between January 1990 and March 2021 in the PubMed and MEDLINE databases and included 20 papers. The level and duration of exposure were based on the pharmacokinetic profile of the drug and the assumption that trough asparaginase activity levels of ≥100 IU/L should be achieved for complete l-asparagine depletion. The statistical meta-analysis of outcomes was not performed because different outcome measures were used. The level of exposure was not associated with the outcome as long as therapeutic asparaginase activity levels of ≥100 IU/L were reached. Conflicting results were found in the randomised controlled trials, but all truncation studies showed that the duration of exposure (expressed as weeks of l-asparagine depletion) does affect the outcome; however, no clear cutoff for optimal exposure duration was determined. Optimal exposure duration will also depend on immunophenotype, (cyto)genetic subgroups, risk group stratification and backbone therapy.
Topics: Antineoplastic Agents; Asparaginase; Child; Disease-Free Survival; Dose-Response Relationship, Drug; Drug Administration Schedule; Humans; Neoplasm Recurrence, Local; Polyethylene Glycols; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Progression-Free Survival; Randomized Controlled Trials as Topic; Time Factors
PubMed: 34536947
DOI: 10.1016/j.ejca.2021.08.025