Pharmacokinetics of PEGasparaginase in Infants with Acute Lymphoblastic Leukemia.

BACKGROUND: PEGasparaginase is known to be a critical drug for treating pediatric acute lymphoblastic leukemia (ALL), however, there is insufficient evidence to determine the optimal dose for infants who are less than one year of age at diagnosis. This international study was conducted to identify the pharmacokinetics of PEGasparaginase in infants with newly diagnosed ALL and gather insight into the clearance and dosing of this population. METHODS: Infants with ALL who received treatment with PEGasparaginase were included in our population pharmacokinetic assessment employing non-linear mixed effects modelling (NONMEM). RESULTS: 68 infants with ALL, with a total of 388 asparaginase activity samples, were included. PEGasparaginase doses ranging from 400 to 3,663 IU/m2 were administered either intravenously or intramuscularly. A one-compartment model with time-dependent clearance, modeled using a transit model, provided the best fit to the data. Body weight was significantly correlated with clearance and volume of distribution. The final model estimated a half-life of 11.7 days just after administration, which decreased to 1.8 days 14 days after administration. Clearance was 19.5% lower during the post-induction treatment phase compared to induction. CONCLUSION: The pharmacokinetics of PEGasparaginase in infants diagnosed under one year of age with ALL is comparable to that of older children (1-18 years). We recommend a PEGasparaginase dosing at 1,500 IU/m2 for infants without dose adaptations according to age, and implementing therapeutic drug monitoring as standard practice.

Continuous PEGasparaginase Dosing Reduces Hypersensitivity Reactions in Pediatric ALL: A Dutch Childhood Oncology Group ALL11 Randomized Trial.

PURPOSE: The primary objective of this randomized study was to determine whether a continuous dosing schedule (without the asparaginase-free interval) would result in less hypersensitivity reactions to PEGasparaginase (PEGasp) compared with the standard noncontinuous dosing schedule. METHODS: Eight hundred eighteen patients (age 1-18 years) with ALL were enrolled in the Dutch Childhood Oncology Group-ALL11 protocol and received PEGasp. Three hundred twelve patients stratified in the medium-risk arm were randomly assigned to receive 14 individualized PEGasp doses once every two weeks in either a noncontinuous or continuous schedule after the first three doses in induction (EudraCT: 2012-000067-25). Hypersensitivity reactions were defined as allergies, allergic-like reactions, and silent inactivation. Secondary end points were other asparaginase-related toxicities, asparaginase activity and antibody levels, and outcome. RESULTS: During induction, 27 of 818 patients (3.3%) experienced hypersensitivity reactions. After random assignment, 4 of 155 (2.6%) in the continuous treatment arm versus 17 of 157 (10.8%) patients in the noncontinuous treatment arm had hypersensitivity reactions (P < .01), of which two (1.3%) versus 13 (8.3%) were inactivating reactions (P < .01). The occurrence of inactivating hypersensitivity reactions was seven times lower in the continuous arm (odds ratio, 0.15 [0.032-0.653]). In addition, antibody levels were significantly lower in the continuous arm (P < .01). With exception of a lower incidence of increased amylase in the continuous arm, there were no significant differences in total number of asparaginase-associated toxicities between arms. However, the timing of the toxicities was associated with the timing of the asparaginase administrations. No difference in 5-year cumulative incidence of relapse, death, or disease-free survival was found between both treatment arms. CONCLUSION: A continuous dosing schedule of PEGasp is an effective approach to prevent antibody formation and inactivating hypersensitivity reactions. The continuous PEGasp schedule did not increase toxicity and did not affect the efficacy of the therapy.

Safety of mRNA-based COVID-19 vaccination in paediatric patients with a PEG-asparaginase allergy.

Background: Children treated for a malignancy are at risk to develop serious illness from a COVID-19 infection. Pegylated E. coli asparaginase (PEG-asparaginase) is used in the treatment of acute lymphoblastic leukemia. Allergy to this drug is common and both asparaginase and polyethylene glycol (PEG) are identified as possible antigens. The mRNA-based vaccines against COVID-19 contain PEG as a stabilizing component. Methods: We developed a protocol to be able to safely vaccinate children with a PEG-asparaginase allergy. All patients with a history of allergy to PEG-asparaginase have been included and skin prick testing for various PEGs was performed before vaccination with the mRNA Pfizer-BioNTech COVID-19 vaccine. Results: Twelve children between six and 16 years old were vaccinated, without allergic reaction. None of them got a positive skin prick test for PEG. Ten patients had pre-existing IgG or IgM antibodies against PEG. Conclusion: Children with a PEG-asparaginase allergy can be safely vaccinated against COVID-19 with mRNA vaccines containing PEG irrespective of IgG/IgM antibodies to PEG-asparaginase. Routine skin prick testing in patients with PEG-asparaginase allergy does not seem to be of added value.

Depletion of d- and l-asparagine in cerebrospinal fluid in acute lymphoblastic leukemia during PEGasparaginase therapy.

BACKGROUND: l-Asparaginase hydrolyzes l-asparagine and not its enantiomer d-asparagine. Unlike l-asparagine, d-asparagine is nonessential for the survival of acute lymphoblastic leukemia (ALL) cells. Studies showed that serum asparagine is depleted below 0.5 µM in ≥96% of the patients during pegylated Escherichia coli l-asparaginase (PEGasparaginase) treatment; however, cerebrospinal fluid (CSF) asparagine levels are depleted in only 20%-30% of the patients. Thus far, studies only reported the total CSF asparagine (sum of d- and l-asparagine) concentrations. Data on the pharmacological goal, which is l-asparagine depletion, are lacking. METHOD: Therefore, we studied this in 30 patients (95 samples) with newly diagnosed ALL. They received two doses of PEGasparaginase on day 4 and 18 in induction. RESULTS: Median age at diagnosis was 5.7 years (range 1.5-17.1 years). d-Asparagine and l-asparagine concentrations (median (range)) before PEGasparaginase treatment were 0.038 (0.0-0.103) µM and 6.1 (1.82-11.5) µM, respectively. CSF l-asparagine concentrations were reduced by 85% (76%-100%) and approximately one-third of the patients (32%) had CSF l-asparagine depletion below 0.5 µM 11 days after the second PEGasparaginase dose administration. CSF d-asparagine and l-glutamine levels remained stable before and after administration of PEGasparaginase. The percentage of d-asparagine as a fraction of total asparagine (sum of d- and l-asparagine) was 0.62% before and 4.5% after PEGasparaginase treatment. No correlation was found between higher serum PEGasparaginase activity and CSF l-asparagine concentration. CONCLUSION: l-Asparagine is not a better parameter than total asparagine in CSF due to the negligible amount of d-asparagine in the CSF before and after PEGasparaginase treatment.

Hypersensitivity to Pegylated E.coli asparaginase as first-line treatment in contemporary paediatric acute lymphoblastic leukaemia protocols: a meta-analysis of the Ponte di Legno Toxicity working group.

BACKGROUND: Hypersensitivity reactions to asparaginase challenge its use and occur frequently (30-75%) after native Escherichia Coli (E.coli) asparaginase. Comparison of incidence of allergic reactions to pegylated E.coli asparaginase (PEGasparaginase) across contemporary paediatric acute lymphoblastic leukaemia (ALL) protocols is lacking. METHOD AND PATIENTS: Questionnaires were sent to all members of the international ALL Ponte di Legno Toxicity Working Group. Meta-analyses were conducted to estimate the incidence of three types of hypersensitivity (allergy, allergic-like reaction and silent inactivation). Information on protocol level regarding PEGasparaginase dosing regimen, administration route and use of therapeutic drug monitoring was collected for risk analysis. RESULTS: Newly diagnosed patients with ALL (n = 5880), aged 1-24 years old, were enrolled in seven different upfront ALL protocols using PEGasparaginase as first-line treatment. The incidence of allergic reactions (sum of allergies and allergic-like reactions) [95% confidence interval] was 2% [1%; 3%] during induction and 8% [5%; 11%] during postinduction. Route of administration, number of doses, dosage and number of PEGasparaginase-free weeks did not significantly influence risk of hypersensitivity. Multivariate meta-regression analysis suggests that initiation of PEGasparaginase in postinduction and higher number of PEGasparaginase-free intervals increased the risk for allergic reactions. 9-16% and 23-29% of all hypersensitivities were allergic-like reactions and silent inactivation, respectively. CONCLUSION: The incidence of allergic reactions is lower in protocols using PEGasparaginase as first-line treatment compared with that reported for E.coli asparaginase or PEGasparaginase after E.coli asparaginase. Postinduction phase, a higher number of PEGasparaginase-free intervals, and initiation of PEGasparaginase in postinduction phase are risk factors for allergic reactions. These results are important for planning of PEGasparaginase administrations in future frontline therapy.

How much asparaginase is needed for optimal outcome in childhood acute lymphoblastic leukaemia? A systematic review.

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.