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L. Fan - One of the best experts on this subject based on the ideXlab platform.

Paul S. Gaynon - One of the best experts on this subject based on the ideXlab platform.

  • A randomized comparison of native Escherichia coli asparaginase and polyethylene glycol conjugated asparaginase for treatment of children with newly diagnosed standard-risk acute lymphoblastic leukemia: a children's Cancer Group Study
    Blood, 2002
    Co-Authors: Vassilios I. Avramis, Bruce Bostrom, Susan Sencer, Antonia P. Periclou, Harland N. Sather, Lewis J. Cohen, Alice G. Ettinger, Lawrence J. Ettinger, Janet Franklin, Paul S. Gaynon
    Abstract:

    For this study, 118 children with standard-risk acute lymphoblastic leukemia (ALL) were given randomized assignments to receive native or pegylated Escherichia coli asparaginase as part of induction and 2 delayed intensification phases. Patients treated with Pegaspargase had more rapid clearance of lymphoblasts from day 7 and day 14 bone marrow aspirates and more prolonged asparaginase activity than those treated with native asparaginase. In the first delayed intensification phase, 26% of native asparaginase patients had high-titer antibodies, whereas 2% of Pegaspargase patients had those levels. High-titer antibodies were associated with low asparaginase activity in the native arm, but not in the Pegaspargase arm. Adverse events, infections, and hospitalization were similar between arms. Event-free survival at 3 years was 82%. A population pharmacodynamic model using the nonlinear mixed effects model (NONMEM) program was developed that closely fit the measured enzyme activity and asparagine concentrations. Half-lives of asparaginase were 5.5 days and 26 hours for Pegaspargase and native asparaginase, respectively. There was correlation between asparaginase enzymatic activity and depletion of asparagine or glutamine in serum. In cerebrospinal fluid asparagine, depletion was similar with both enzyme preparations. Intensive Pegaspargase for newly diagnosed ALL should be tested further in a larger population.

  • A pharmacoeconomic analysis of Pegaspargase versus native Escherichia coli L-asparaginase for the treatment of children with standard-risk, acute lymphoblastic leukemia: the Children's Cancer Group study (CCG-1962).
    Journal of pediatric hematology oncology, 2002
    Co-Authors: Helen A Kurre, Susan Sencer, Alice G. Ettinger, Janet Franklin, Paul S. Gaynon, David L Veenstra, Gregory H. Reaman, Beverly J. Lange, John S. Holcenberg
    Abstract:

    Purpose The purpose of this pharmacoeconomic analysis was to compare Pegaspargase. a newer chemotherapeutic agent used for treating acute lymphoblastic leukemia, with native Escherichia coli L-asparaginase in induction, delayed intensification 1 and delayed intensification 2. Materials and methods A subset of patients with newly diagnosed, standard-risk, acute lymphoblastic leukemia enrolled in the Children's Cancer Group (CCG) study CCG-1962 at seven participating institutions gave consent and was enrolled in our pharmacoeconomic analysis study. Societal (transportation, lodging, missed workdays, food, babysitter) and payer (frequency of encounters) cost data were collected from diaries (n = 27). Additional payer costs, such as drug costs, cost per clinic visit, and cost per inpatient day stay were collected from patients in CCG-1962 and participating institutions. We considered costs of therapy, including higher Pegaspargase costs when comparing regimens of Pegaspargase versus native E. coli L-asparaginase in induction, delayed intensification 1, and delayed intensification 2. Results Our results showed that the costs of the two therapies were similar from the payer perspective, with Pegaspargase costing 1.8% more than E. coli L-asparaginase. The difference between groups also was small ( Conclusion We recommend that Pegaspargase not be withheld from treatment protocols solely because of its higher pharmacy costs.

  • acute lymphoblastic leukaemia a guide to asparaginase and Pegaspargase therapy
    BioDrugs, 1997
    Co-Authors: Lawrence J. Ettinger, Vassilios I. Avramis, Alice G. Ettinger, Paul S. Gaynon
    Abstract:

    The cure rate for children with acute lymphoblastic leukaemia (ALL) has increased to approximately 70%, in part related to the use of the protein synthesis inhibitor drug asparaginase in multiagent chemotherapy regimens. Its lack of haematological toxicity allows its incorporation into phases of therapy in which myelosuppression would be expected either from the disease itself (induction therapy) or secondary to other chemotherapeutic agents (consolidation, intensification or reinduction phases of therapy). Its antileukaemic effect is related to the degree and duration of asparagine depletion. The 2 native forms of L-asparaginase are derived from Escherichia coli and Ewinia chrysantherni. The half-lives (t½) of these forms are approximately 1.2 and 0.6 days, respectively. In order to increase the biological t½, Pegaspargase was synthesised by the covalent attachment of monomethoxypolyethylene glycol (PEG) to native E. coli L-asparaginase: it has a t½, of approximately 5.7 days. The duration of asparagine depletion, the substrate amino acid of the drug, is directly related to asparaginase t½. Asparaginase is associated with several unique toxicities, including hyperglycaemia, hypolipoproteinaemia, hypoalbuminaemia, coagulation factor deficiencies, hepatotoxicity and pancreatitis. Since asparaginase is a protein, it may induce hypersensitivity reactions. The incidence of these reactions increases with use. In addition, silent hypersensitivity, i.e. the development of IgG antibodies without clinical reactions, results in a decreased t½ of asparaginase, shortened duration of asparagine depletion, and probably decreased efficacy. The use of Pegaspargase allows continued treatment with asparaginase in patients with clinical hypersensitivity reactions. In addition, its use in patients with silent hypersensitivity may maintain the efficacy of asparaginase. So far, the optimal use of the 3 forms of asparaginase has not been determined in children with ALL, partly due to the lack of appropriate pharmacokinetic monitoring methods. As the technology has become available, it has been demonstrated that there is little rationale for the dosage and administration schedules presently in use. Studies are required to determine appropriate dosages and administration methods (intravenous or intramuscular) and schedules for each form of asparaginase, based upon pharmacokinetic parameters. The incidence and time to onset of hypersensitivity (clinical or silent) reactions and the appropriate means of continuing asparaginase therapy with therapeutic effect needs to be evaluated. Pharmacokinetic studies are now available as a research tool. These will allow further investigation to determine if failure to maintain asparagine depletion is a remediable cause of treatment failure.

  • Acute Lymphoblastic Leukaemia
    BioDrugs, 1997
    Co-Authors: Lawrence J. Ettinger, Alice G. Ettinger, Wassilios I. Avramis, Paul S. Gaynon
    Abstract:

    The cure rate for children with acute lymphoblastic leukaemia (ALL) has increased to approximately 70%, in part related to the use of the protein synthesis inhibitor drug asparaginase in multiagent chemotherapy regimens. Its lack of haematological toxicity allows its incorporation into phases of therapy in which myelosuppression would be expected either from the disease itself (induction therapy) or secondary to other chemotherapeutic agents (consolidation, intensification or reinduction phases of therapy). Its antileukaemic effect is related to the degree and duration of asparagine depletion. The 2 native forms of L-asparaginase are derived from Escherichia coli and Ewinia chrysantherni . The half-lives (t_½) of these forms are approximately 1.2 and 0.6 days, respectively. In order to increase the biological t_½, Pegaspargase was synthesised by the covalent attachment of monomethoxypolyethylene glycol (PEG) to native E. coli L-asparaginase: it has a t_½, of approximately 5.7 days. The duration of asparagine depletion, the substrate amino acid of the drug, is directly related to asparaginase t_½. Asparaginase is associated with several unique toxicities, including hyperglycaemia, hypolipoproteinaemia, hypoalbuminaemia, coagulation factor deficiencies, hepatotoxicity and pancreatitis. Since asparaginase is a protein, it may induce hypersensitivity reactions. The incidence of these reactions increases with use. In addition, silent hypersensitivity, i.e. the development of IgG antibodies without clinical reactions, results in a decreased t_½ of asparaginase, shortened duration of asparagine depletion, and probably decreased efficacy. The use of Pegaspargase allows continued treatment with asparaginase in patients with clinical hypersensitivity reactions. In addition, its use in patients with silent hypersensitivity may maintain the efficacy of asparaginase. So far, the optimal use of the 3 forms of asparaginase has not been determined in children with ALL, partly due to the lack of appropriate pharmacokinetic monitoring methods. As the technology has become available, it has been demonstrated that there is little rationale for the dosage and administration schedules presently in use. Studies are required to determine appropriate dosages and administration methods (intravenous or intramuscular) and schedules for each form of asparaginase, based upon pharmacokinetic parameters. The incidence and time to onset of hypersensitivity (clinical or silent) reactions and the appropriate means of continuing asparaginase therapy with therapeutic effect needs to be evaluated. Pharmacokinetic studies are now available as a research tool. These will allow further investigation to determine if failure to maintain asparagine depletion is a remediable cause of treatment failure.

J-h Liang - One of the best experts on this subject based on the ideXlab platform.

L. Lee Dupuis - One of the best experts on this subject based on the ideXlab platform.

  • Allergic Reactions Associated with Intravenous Versus Intramuscular Pegaspargase: A Retrospective Chart Review
    Pediatric Drugs, 2015
    Co-Authors: Lesleigh S. Abbott, Maria Zakova, Furqan Shaikh, Nisha Shewaramani, Angela Punnett, L. Lee Dupuis
    Abstract:

    Background Pegaspargase (PEG-ASP) is essential chemotherapy for acute lymphoblastic leukemia (ALL). Since changing to intravenous (IV) administration from intramuscular (IM), an increased number of allergic reactions have been anecdotally noted at our institution. This study compares the rate and severity of allergic reactions in children receiving IM or IV PEG-ASP. Methods We performed a retrospective chart review of patients treated with IV or IM PEG-ASP at The Hospital for Sick Children, Toronto, Canada, from March 1, 2010 to January 1, 2012. The incidence and severity of allergic reactions attributed to PEG-ASP were documented. Patient age, sex, route of PEG-ASP administration, disease (risk group and lineage) and mean time interval between PEG-ASP doses were evaluated as possible risk factors for allergic reaction. Results A total of 109 patients were included. There were 14 (35 %) allergic reactions among 40 patients who received IV, compared with eight (12 %) of the 69 who received IM [odds ratio (OR) 4.11, 95 % confidence interval (CI) 1.54–10.97, p  = 0.005]. In multivariable logistic regression adjusting for disease risk group, route (IV vs. IM) remained independently significant ( p  = 0.011). Patients with standard-risk ALL had a lower risk of experiencing an allergic reaction associated with PEG-ASP compared with patients in high-risk disease risk groups (collectively referred to as “other”; 11 vs. 31 %, OR 3.36, 95 % CI 1.16–9.72, p  = 0.025). Conclusions IV PEG-ASP is associated with a significantly higher rate of allergic reactions than IM. The clinical preference for IV PEG-ASP may warrant re-evaluation.

  • Allergic Reactions Associated with Intravenous Versus Intramuscular Pegaspargase: A Retrospective Chart Review
    Pediatric Drugs, 2015
    Co-Authors: Lesleigh S. Abbott, Maria Zakova, Furqan Shaikh, Nisha Shewaramani, Angela Punnett, L. Lee Dupuis
    Abstract:

    Background Pegaspargase (PEG-ASP) is essential chemotherapy for acute lymphoblastic leukemia (ALL). Since changing to intravenous (IV) administration from intramuscular (IM), an increased number of allergic reactions have been anecdotally noted at our institution. This study compares the rate and severity of allergic reactions in children receiving IM or IV PEG-ASP. Methods We performed a retrospective chart review of patients treated with IV or IM PEG-ASP at The Hospital for Sick Children, Toronto, Canada, from March 1, 2010 to January 1, 2012. The incidence and severity of allergic reactions attributed to PEG-ASP were documented. Patient age, sex, route of PEG-ASP administration, disease (risk group and lineage) and mean time interval between PEG-ASP doses were evaluated as possible risk factors for allergic reaction. Results A total of 109 patients were included. There were 14 (35 %) allergic reactions among 40 patients who received IV, compared with eight (12 %) of the 69 who received IM [odds ratio (OR) 4.11, 95 % confidence interval (CI) 1.54–10.97, p  = 0.005]. In multivariable logistic regression adjusting for disease risk group, route (IV vs. IM) remained independently significant ( p  = 0.011). Patients with standard-risk ALL had a lower risk of experiencing an allergic reaction associated with PEG-ASP compared with patients in high-risk disease risk groups (collectively referred to as “other”; 11 vs. 31 %, OR 3.36, 95 % CI 1.16–9.72, p  = 0.025). Conclusions IV PEG-ASP is associated with a significantly higher rate of allergic reactions than IM. The clinical preference for IV PEG-ASP may warrant re-evaluation.

  • Allergic Reactions Associated with Intravenous Versus Intramuscular Pegaspargase: A Retrospective Chart Review
    Paediatric drugs, 2015
    Co-Authors: Lesleigh S. Abbott, Maria Zakova, Furqan Shaikh, Nisha Shewaramani, Angela Punnett, L. Lee Dupuis
    Abstract:

    Background Pegaspargase (PEG-ASP) is essential chemotherapy for acute lymphoblastic leukemia (ALL). Since changing to intravenous (IV) administration from intramuscular (IM), an increased number of allergic reactions have been anecdotally noted at our institution. This study compares the rate and severity of allergic reactions in children receiving IM or IV PEG-ASP.

Archie Bleyer - One of the best experts on this subject based on the ideXlab platform.

  • Pegaspargase hypersensitivity reactions intravenous infusion versus intramuscular injection a review
    Leukemia & Lymphoma, 2017
    Co-Authors: Lynda K. Beaupin, Matthew J. Barth, Irene Franklin, Raven Jaeger, Priyanka Kamath, Brian Schreiber, Bruce C Bostrom, Archie Bleyer
    Abstract:

    Pegaspargase is a mainstay in the treatment of acute lymphoblastic leukemia. When intravenous (IV) infusion replaced intramuscular (IM) injection as the standard route of administration, there were early reports suggested an increased hypersensitivity reactions (HSRs) rate with IV administration. There have since been eight published reports comparing the incidence of HSRs occurring with IV versus IM Pegaspargase. This review analyzes the reports and summarizes their consistent findings where feasible. For grade 3-4 HSRs, the rates are comparable with IV and IM administration. Grade 2 HSRs appear to be more likely with IV than IM administration but the validity of the difference is uncertain. Multiple factors confound the analyses, including the historically controlled nature of the comparisons and the increased likelihood of reporting adverse reactions with IV administration. In summary, the reports do not support the conclusion that Pegaspargase-induced HSR rate is more frequent with IV administration.

  • Pegaspargase hypersensitivity reactions: intravenous infusion versus intramuscular injection – a review
    Leukemia & lymphoma, 2016
    Co-Authors: Lynda K. Beaupin, Bruce Bostrom, Matthew J. Barth, Irene Franklin, Raven Jaeger, Priyanka Kamath, Brian Schreiber, Archie Bleyer
    Abstract:

    Pegaspargase is a mainstay in the treatment of acute lymphoblastic leukemia. When intravenous (IV) infusion replaced intramuscular (IM) injection as the standard route of administration, there were early reports suggested an increased hypersensitivity reactions (HSRs) rate with IV administration. There have since been eight published reports comparing the incidence of HSRs occurring with IV versus IM Pegaspargase. This review analyzes the reports and summarizes their consistent findings where feasible. For grade 3-4 HSRs, the rates are comparable with IV and IM administration. Grade 2 HSRs appear to be more likely with IV than IM administration but the validity of the difference is uncertain. Multiple factors confound the analyses, including the historically controlled nature of the comparisons and the increased likelihood of reporting adverse reactions with IV administration. In summary, the reports do not support the conclusion that Pegaspargase-induced HSR rate is more frequent with IV administration.

  • Plasma asparaginase activity and asparagine depletion in patients with acute lymphoblastic leukemia (ALL) treated with Pegaspargase (SS-PEG E. coli L-asparaginase): Results from Children’s Oncology Group (COG) study AALL07P4.
    Journal of Clinical Oncology, 2016
    Co-Authors: Reuven J Schore, Meenakshi Devidas, Elizabeth A Raetz, Archie Bleyer, Naomi J. Winick, William L. Carroll, Mignon L. Loh, Stephen P. Hunger, Gregory Reaman, Anne L Angiolillo
    Abstract:

    10508Background: The effectiveness of asparaginase in the treatment of ALL is dependent on depletion of plasma asparagine, an essential amino acid for leukemic lymphoblasts. Previous reports have concluded that the threshold level of plasma asparaginase activity necessary to achieve plasma asparagine depletion is between 0.1 and 0.4 IU/mL. Methods: COG AALL07P4, a limited-institution, closely-supervised sentinel trial for planned FDA submission, examined the pharmacokinetics (PK) and pharmacodynamics (PD) of Pegaspargase during induction and consolidation therapy. A major objective was to determine the optimal level of plasma asparaginase required for asparagine depletion when given as part of an augmented BFM chemotherapy regimen for the treatment of newly-diagnosed, NCI high-risk, B-precursor ALL. Plasma asparaginase activity was determined by a validated enzymatic-coupled assay with a lower limit of detection of 0.013 IU/mL. Plasma asparagine was determined using validated reverse-phase high-performanc...

  • Clinical application of asparaginase activity levels following treatment with Pegaspargase.
    Pediatric blood & cancer, 2014
    Co-Authors: Archie Bleyer, Barbara L Asselin, Susannah E. Koontz, Stephen P. Hunger
    Abstract:

    Asparaginase, an enzyme used to treat acute lymphoblastic leukemia and related forms of nonHodgkin lymphoma, depletes asparagine, which leads to lymphoblast cell death. Unlike most chemotherapeutic agents, asparaginase is a foreign protein that can result in clinical allergy and/or silent hypersensitivity with production of neutralizing antibodies that inactivate asparaginase. In North America, asparaginase activity levels can now be obtained via a commercially available assay, for therapeutic drug monitoring and investigation of potential allergic reactions. Herein, we provide recommendations and a corresponding algorithm for the clinical application of this assay after treatment with Pegaspargase to evaluate suspected hypersensitivity reactions and/or silent inactivation.