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Research Article

Retrospective cohort study monitoring PEG-asparaginase activity in acute lymphoblastic leukemia patients with and without premedication

[version 1; peer review: 3 approved with reservations]
PUBLISHED 04 Jul 2019
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Abstract

Background: PEG-L-asparaginase (pegaspargase) is a critical component of therapy for children and adults with acute lymphoblastic leukemia (ALL). Allergic reactions, which may occur in up to one third of patients, are the major cause for discontinuation. One study reported lower rates of allergic reactions with premedication. Besides allergy, an unknown number of patients develop silent neutralizing antibodies not associated with allergic reactions. The purpose of this retrospective cohort study was to determine the incidence of silent inactivation of pegasparaginase and compare incidence of allergic reactions with and without premedication.
Methods: Using a commercial assay, asparaginase activity was monitored following pegaspargase (2500 units/m2) in newly diagnosed children and young adults with B- and T-cell ALL from February 2013 to May 2017. The incidence of allergic reactions before and after initiation of premedication in May 2015 was compared.
Results: One patient out of 59 (1.7%) had silent inactivation after the second dose. No patient had silent inactivation after the first pegaspargase dose and no standard risk B-cell ALL patients, who received only two pegaspargase doses in combination with oral dexamethasone, had silent inactivation. The incidence of grade 3 or 4 allergic reactions was 3.7% per dose with premedication (methylprednisolone, acetaminophen and diphenhydramine) versus 5.2% without.  The incidence per patient with premedication given for most of the doses was 8.3% versus 17% without. These values are not statistically significant. Premedication did not affect pegaspargase activity.
Conclusions: Due to the low incidence of silent inactivation with intravenous pegaspargase and the unlikely event patients receiving only two doses of pegasparaginase would receive erwinase for this possible transient silent inactivation, we recommend routine monitoring of pegaspargase activity only in patients scheduled to receive more than two doses.

Keywords

Pegasparginase Activity, Premedication, Silent Inactivation, Allergy, Anaphylaxis

Introduction

PEG-L-asparaginase (pegaspargase) is a critical component of therapy for children and adults with acute lymphoblastic leukemia (ALL). Its use is hampered by many issues including allergic reactions, silent inactivation, thrombosis, hyperbilirubinemia and pancreatitis1. Other common toxicities, such as hyperglycemia and hypertriglyceridemia, may be mitigated with the use of metformin and omega-3, respectively2,3. There is also ongoing interest in the use of carnitine to treat, and possibly prevent, hepatic toxicity, manifested by a severe increase in direct bilirubin, among other findings4.

The optimal dose, dose interval and target asparaginase level for pegaspargase is not completely established5. In pediatrics, a dose of 2500 units/m2 is the norm, whereas for adult patients, doses are often reduced due to increased toxicity at the pediatric dose. Some investigators have suggested using a pharmacokinetic driven model to individualize pegaspargase dosing6.

The use of premedication (acetaminophen, diphenhydramine and a corticosteroid) has been suggested as a possible means of reducing allergic reactions. In a multi-center study testing the use of pediatric-based regimens in young adults, the rate of grade 3 or 4 allergic reactions was reduced from 10% to 4% after premedication was mandated7. A study in adults with ALL reported allergic reactions in 7.2% of patients when pegaspargase was given concurrently with, or followed by, one week of prednisone8. Using a novel mouse model of asparaginase hypersensitivity, pretreatment with seven days of oral dexamethasone was the only agent capable of mitigating the severity of hypersensitivity and partially restoring asparaginase activity9. Dexamethasone given at the time of, or for one week following, asparaginase was not as effective.

The presence of antibodies against asparaginase may be found, from as early as the end of induction therapy10,11. The presence of asparaginase antibodies is a highly specific finding that is predictive of future allergic reactions but does not have the sensitivity to suggest modifications to therapy should be made10. The presence of asparaginase antibodies at end of induction did not appear to alter prognosis in a large multi-center study11. This suggests that measuring asparaginase activity is more useful than looking for the presence of antibodies.

Silent inactivation of pegaspargase activity by anti-asparaginase antibodies or other immune-mediated mechanisms are potentially of greater concern than allergic reactions, as patients with allergic reactions to pegaspargase will be switched to erwinase, which theoretically will improve outcome. The true incidence of silent inactivation is unknown, as there are no reports of a comprehensive screening program for silent inactivation in a large multi-institutional trial. The largest published study found silent inactivation in 7/89 (8%) of patients12. However, these patients received induction with native Escherichia coli asparaginase before switching to pegaspargase, which is not current practice. The authors also report in the same group of patients that silent antibodies may spontaneously resolve with continued pegaspargase13. Prudence suggests that patients who receive premedications should have pegaspargase activity monitored after every dose, due to the possible but unproven concern that premedication will mask allergic reactions and silent inactivation. In fact, a consensus panel of experts recommends screening for silent inactivation in all patients undergoing therapy for ALL with asparaginase14.

Methods

Ethical statement

As the use of premedications and measurement of pegaspargase activity was considered by the leukemia provider group at Children’s Minnesota to be necessary for optimal care, no informed consent was obtained. Parents/adult patients were not informed of results unless intervention was indicated, which did not occur. This retrospective review study was approved by the institutional review board of Children’s Minnesota (IRB# 1606-062).

Patients

This retrospective study occurred in a large pediatric oncology center that diagnoses and treats approximately 40 new cases of ALL yearly in children and young adults up to age 30. If there are open studies, the patients are enrolled on Children’s Oncology Group protocols. Otherwise, patients are treated according to the most recent risk adapted protocols for standard risk B, high risk B and T-ALL. In order to reduce acquisition bias, charts of every patient who received pegasparaginase from December 2013 to September 2016 were abstracted (N=99). As this was a pilot study and the expected reduction of grade 3 or 4 allergic reactions with premedications was unknown at the time, sample sizes calculations could not be calculated. Data from all 99 patients were used to estimate the incidence of grade 3 or 4 allergic reactions by patient and by dose. For the detailed pharmacokinetic analysis, we used a subgroup of all patients from May 2014 to September 2016 (N=46) who had pegaspargase levels drawn. This number was sufficient to define the confidence intervals of the pegasparaginase activity.

Pegaspargase administration

A total of 112 blood samples from these 46 patients were collected from a central venous portacath in conjunction with scheduled clinical visits from 3 to 12 days following pegaspargase administration at the standard dose of 2500 mg/m2. Pegaspargase was given by intramuscular injection or intravenously per Children’s Oncology Group protocols on an intermittent schedule starting with induction and completed prior to starting maintenance therapy. Because the distribution of the collection days clustered in ranges from day 3–5, 6–8 and 10–12, for analyses, pegaspargase activity was grouped in these categories. To better estimate the incidence of silent inactivation, pegaspargase levels lower than 0.01 units/ml were looked for in the data from an additional 13 patients, making a total of 59 evaluated. No evidence of silent inactivation was found in these 13 patients.

These patients were all treated according to Children’s Oncology Group protocols, using either intramuscular or intravenous pegaspargase as the only form of asparaginase. Intramuscular asparaginase was the standard of care until 2010 when intravenous administration became the new standard of care based on the Children’s Oncology Group AALL0932 protocol15. A comprehensive review of published studies concluded that the risk of grade 3 or 4 allergic reactions is independent of the pegaspargase route of administration15.

Premedication administration

We became aware of an abstract showing a decrease in grade 3 or 4 allergic reactions in a multi-institutional study employing pegaspargase in young adults with ALL16. This prompted us to institute in May 2015 premedication with acetaminophen (10–15 mg/kg orally), diphenhydramine (1 mg/kg orally or intravenously), and methylprednisolone (1 mg/kg intravenously), within the hour prior to administering pegasparaginase. Every subsequent patient was to receive with all three of the premedication drugs without exception. The numbers with and without premedication are listed in Table 2 (per pegaspargase dose) and Table 3 (per patient).

Assessment of allergic reactions

Allergic reactions to were graded per CTC 4.0 toxicity scales. We compared the incidence of grade 3 or 4 allergic reaction in patients with and without premedication, both per pegaspargase dose and per patient.

Pharmacokinetic analysis

Routine monitoring of pegaspargase activity in patients with ALL was initiated in 2013 after the ‘asparaginase activity analysis’ test approved by Clinical Laboratory Improvement Amendments was introduced by AIBioTech, Richmond, VA 23225 US. Subsequent to the introduction in 2015 of a quantitatively identical test by Next Molecular Analytics, Chester, VA, samples were exclusively sent there.

Statistical analyses

SPSS version 23 was used for graphing and analyses. Grouped data were displayed with box graphs depicting the 1st, 25th, 50th (median), 75th and 99th percentiles. The comparison of pegaspargase activity with and without premedication was done by independent sample t-test. The comparison of grade 3 or 4 allergic reactions by patient and pegaspargase dose with and without the use of premedication was done by Chi-squared analysis. As some premedication doses were missed due to omission by the treating physician, an additional analysis of the incidences of those who received premedication after every dose or most doses were compared to those who received no premedication before any dose. Missed pegaspargase activity samples were omitted from analysis (Table I).

Table 1. Percent of pegaspargase activity specimens collected following doses one to nine.

OneTwoThreeFourFiveSixSevenEightNineTotal
Collected8331819186721112
Missed381216107633196
Total4645342925121052208
% Collected17%73%53%66%72%50%70%40%50%54%

Table 2. Grade 3-4 allergic reactions by use of premedication per dose of pegaspargase.

Grade 3-4 allergic reactionsNoneTotal
No premedication7 (17%)35 (83%)42
Some premedication4 (6%)58 (94%)62
Every dose premedication4 (12%)30 (88%)34

Table 3. Grade 3-4 allergic reactions by use of premedication per patient.

Grade 3-4 allergic reactionsNoneTotal
No premedication7 (17%)35 (83%)42
Some premedication4 (6%)58 (94%)62
Every dose premedication4 (12%)30 (88%)34

Results

Pharmacokinetic analyses were done on 112 specimens from 46 patients17. The 46 patients included 12 standard risk B-cell patients, 21 high risk B-cell ALL patients, and 13 T-cell ALL patients. There were 25 males and 21 females. The ages ranged from one to 29 years with a median of 8.3 years. The number of specimens and missed specimens per pegaspargase dose number are shown in Table 1. First dose specimens were frequently missed, whereas specimens on doses two to seven were collected at least half the time.

Figure 1 is a box and whisker graph of pegaspargase activity on days 3–5, 6–8 and 10–12. The mean, standard error of the mean and standard deviation are: 1.37, 0.21 and 0.76 units/mL, respectively, for day 3–5; 0.89, 0.05 and 0.42 units/mL for day 6–8; and 0.89, 0.06 and 0.28 units/mL for day 10–12. These values are similar to those previously reported in pediatric patients with ALL18,19.

7417ff3b-711f-475f-9888-049d53f1ec05_figure1.gif

Figure 1. Box plot of pegaspargase (PEG) activity following 2500 units/m2 on day 3-5, 6-8 and 10-12.

Data points outside of the whiskers of the 1st and 99th percentiles are represented by a circle (outlier more than 1.5 times the interquartile range) or star (extreme outlier more than three times the interquartile range). The attached number is a data point and not a value.

Figure 2 is box and whisker graph of the pegaspargase activity on day 6–8, following doses with or without premedication. This time ranged was used for the comparison as it is the most common time for checking asparaginase activity. The mean and standard deviation for the no premedication group is 0.79 and 0.34 units/mL (N=14 samples), respectively, and for the premedication group is 0.92 and 0.41 units/mL (N=52 samples). These were not found to be significantly different by the independent sample t-test.

7417ff3b-711f-475f-9888-049d53f1ec05_figure2.gif

Figure 2. Box plot of pegaspargase activity day 6-8 after 2500 units/m2 with and without premedication.

There was no significant difference in the activity with or without of premedication. Data points outside of the whiskers of the 1st and 99th percentiles are represented by a circle (outlier more than 1.5 times the interquartile range) or star (extreme outlier more than 3 times the interquartile range). The attached number is a data point and not a value.

Only one patient had silent inactivation with the following activity levels by dose number and day following pegaspargase activity was checked: dose 1, day 24 - 0.11 units/mL; dose 2, day 8 - 0.05 units/mL; dose 3 day 6 - 0.01 units/mL; dose 4 day 8 - 0.33 units/mL; dose 5, day 8 - 0.82 units/mL; and dose 6, day 10 - 0.62 units/mL. The low values after doses 2 and 3 were not reviewed due to a clerical error until after dose 4, which showed adequate activity, so pegaspargase was continued until the end of treatment.

For the analysis of the role of premedication in preventing grade 3-4 allergic reactions, the data was analyzed per pegaspargase dose and per patient. In the analysis per pegaspargase dose, premedication did not significantly reduce grade 3-4 allergic reactions. With premedication, 7/185 (3.7%) had grade 3-4 allergic reactions compared to 8/155 (5.2%) without premedication, p=0.5 (Table 2).

Table 3 shows the incidence of grade 3-4 allergic reactions per patient. Without premedication, 7/42 (17%) had grade 3-4 allergic reactions. When premedication was given most of the time (usually the first dose was missed), 4/62 (6%) had grade 3-4 allergic reactions. When premedication was given for every dose, 4/32 (12%) had allergic reactions. There was no significant effect of premedication on grade 3-4 allergic reactions by dose when the premedication group (8/96; 8.3%) was compared to the no premedication group (7/42; 17%) (chi square = 2.09; p = 0.15) (Table 3). There was no difference in the distribution of patients who did or did not receive premedication by risk group.

Discussion

Compared with historical controls that received similar therapy, premedication did not significantly reduce the incidence of grade 3 or 4 allergic reactions when measured per patient or per dose of pegaspargase. However, there was a downward trend in the incidence per patient when any use of premedication was compared to no premedication. As premedication does not negatively affect pegaspargase activity levels, and other studies using historical comparisons have suggested premedication may reduce allergic reactions, we are continuing the practice7,8.

The interesting observation by Tong et al. that asparaginase antibodies generated after native E. coli asparaginase may resolve while on pegaspargase continuation therapy needs to be confirmed in patients who receive only pegaspargase during induction and beyond15. We noted a transient decrease in pegaspargase activity, likely due to silent inactivating antibodies in 1/59 patients (1.7%). This decrease of pegaspargase activity occurred after the second dose in a high-risk B-cell ALL patient and resolved with continuation of pegaspargase dosing. No decrease in pegaspargase activity was seen in standard risk patients who received only two doses of pegaspargase in combination with oral dexamethasone.

Limitations of the study include multiple missed activity levels that may have found addition patients with silent inactivation. The sample size also makes it difficult to estimate the true incidence of silent inactivation and if premedication reduces the incidence of grade 3 or 4 allergic reactions. Additional studies are needed to clarify this.

Contrary to the findings of a large multi-institutional trial, where the introduction of premedication significantly reduced the incidence of high-grade allergic reactions, our study did not show a statistically significant reduction with the use of premedication7. Despite this, we continue to use premedication in all patients receiving pegasparaginase. Due to the low incidence of silent inactivation we are only monitor asparaginase activity in patients who are planned to receive more than two doses of pegaspargase during their entire course of treatment (T-cell ALL and high-risk B-cell ALL).

Addendum

A recent publication by the pediatric oncology group at Johns Hopkins also reported significant reduction of infusion reactions and need for erwinase using premedication of H1 and H2 histamine antagonists. They also found a low incidence of silent inactivation with intravenous pegaspargase in one of 68 patients (1.5%), similar to our finding of one in 59 patients (1.7%)20.

Data availability

Underlying data

Figshare: Data Set for Retrospective cohort study monitoring Pegaspargase activity in acute lymphoblastic leukemia patients with and without premedication Lossaso M, Messinger Y, Bostrom B. https://doi.org/10.6084/m9.figshare.8281826.v117

This project contains the following underlying data:

  • - PEG Data De-identifyed.xlsx (demographic, medical and treatment information for each patient)

Data are available under the terms of the Creative Commons Zero "No rights reserved" data waiver (CC0 1.0 Public domain dedication).

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Losasso M, Bostrom B and Messinger Y. Retrospective cohort study monitoring PEG-asparaginase activity in acute lymphoblastic leukemia patients with and without premedication [version 1; peer review: 3 approved with reservations]. F1000Research 2019, 8:1007 (https://doi.org/10.12688/f1000research.19298.1)
NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article.
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ApprovedThe paper is scientifically sound in its current form and only minor, if any, improvements are suggested
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Not approvedFundamental flaws in the paper seriously undermine the findings and conclusions
Version 1
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PUBLISHED 04 Jul 2019
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Reviewer Report 01 Oct 2019
David J. Young, Translational Stem Cell Biology Branch of the National Heart, Lung, and Blood Institute, National Institutes of Health (NIH), Bethesda, MD, USA 
Approved with Reservations
VIEWS 12
This report by Losasso, Bostrom and Messinger expand upon our growing understanding of the appropriate treatment with and management of asparaginase-based therapies in lymphoblastic leukemia. In this retrospective study, the authors have reviewed the single center experience of therapeutic drug ... Continue reading
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HOW TO CITE THIS REPORT
Young DJ. Reviewer Report For: Retrospective cohort study monitoring PEG-asparaginase activity in acute lymphoblastic leukemia patients with and without premedication [version 1; peer review: 3 approved with reservations]. F1000Research 2019, 8:1007 (https://doi.org/10.5256/f1000research.21156.r53445)
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
  • Author Response 17 Jan 2020
    Bruce Bostrom, Cancer and Blood Disorders, Children's Minnesota, 2525 Chicago Avenue South, Minneapolis, 55404, USA
    17 Jan 2020
    Author Response
    David Young Reviewer 3
    This report by Losasso, Bostrom and Messinger expand upon our growing understanding of the appropriate treatment with and management of asparaginase-based therapies in lymphoblastic leukemia. In this ... Continue reading
COMMENTS ON THIS REPORT
  • Author Response 17 Jan 2020
    Bruce Bostrom, Cancer and Blood Disorders, Children's Minnesota, 2525 Chicago Avenue South, Minneapolis, 55404, USA
    17 Jan 2020
    Author Response
    David Young Reviewer 3
    This report by Losasso, Bostrom and Messinger expand upon our growing understanding of the appropriate treatment with and management of asparaginase-based therapies in lymphoblastic leukemia. In this ... Continue reading
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13
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Reviewer Report 30 Sep 2019
Vinod Pullarkat, Department of Hematology and Hematopoietic Cell Transplantation, Gehr Family Center for Leukemia Research, City of Hope Medical Center, Duarte, CA, USA 
Approved with Reservations
VIEWS 13
In this manuscript the authors have retrospectively examined the incidence of allergic reactions in a cohort of patients with ALL receiving multiple doses of PEGylated aspraginase. They show that premedication did not have an impact on allergic reactions. The study ... Continue reading
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HOW TO CITE THIS REPORT
Pullarkat V. Reviewer Report For: Retrospective cohort study monitoring PEG-asparaginase activity in acute lymphoblastic leukemia patients with and without premedication [version 1; peer review: 3 approved with reservations]. F1000Research 2019, 8:1007 (https://doi.org/10.5256/f1000research.21156.r53513)
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
  • Author Response 17 Jan 2020
    Bruce Bostrom, Cancer and Blood Disorders, Children's Minnesota, 2525 Chicago Avenue South, Minneapolis, 55404, USA
    17 Jan 2020
    Author Response
    Vinod Pullarkat: Department of Hematology and Hematopoietic Cell Transplantation, Gehr Family Center for Leukemia Research, City of Hope Medical Center, Duarte, CA, USA 
     
    In this manuscript the authors have retrospectively examined ... Continue reading
COMMENTS ON THIS REPORT
  • Author Response 17 Jan 2020
    Bruce Bostrom, Cancer and Blood Disorders, Children's Minnesota, 2525 Chicago Avenue South, Minneapolis, 55404, USA
    17 Jan 2020
    Author Response
    Vinod Pullarkat: Department of Hematology and Hematopoietic Cell Transplantation, Gehr Family Center for Leukemia Research, City of Hope Medical Center, Duarte, CA, USA 
     
    In this manuscript the authors have retrospectively examined ... Continue reading
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Reviewer Report 26 Sep 2019
Bernard L. Marini, Department of Pharmacy Services and Clinical Sciences, Michigan Medicine, University of Michigan College of Pharmacy, Ann Arbor, MI, USA 
Approved with Reservations
VIEWS 16
Drs. Losasso, Bostrom, and Messinger should be applauded for their work in characterizing asparaginase activity levels in ALL patients. The results and research are clearly presented and accurately reported. The conclusions of the study are appropriate, and the limitations of this ... Continue reading
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HOW TO CITE THIS REPORT
Marini BL. Reviewer Report For: Retrospective cohort study monitoring PEG-asparaginase activity in acute lymphoblastic leukemia patients with and without premedication [version 1; peer review: 3 approved with reservations]. F1000Research 2019, 8:1007 (https://doi.org/10.5256/f1000research.21156.r53512)
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
  • Author Response 17 Jan 2020
    Bruce Bostrom, Cancer and Blood Disorders, Children's Minnesota, 2525 Chicago Avenue South, Minneapolis, 55404, USA
    17 Jan 2020
    Author Response
    Bernard L. Marini, Department of Pharmacy Services and Clinical Sciences, Michigan Medicine, University of Michigan College of Pharmacy, Ann Arbor, MI, USA 
     
    Drs. Losasso, Bostrom, and Messinger should be applauded for their ... Continue reading
COMMENTS ON THIS REPORT
  • Author Response 17 Jan 2020
    Bruce Bostrom, Cancer and Blood Disorders, Children's Minnesota, 2525 Chicago Avenue South, Minneapolis, 55404, USA
    17 Jan 2020
    Author Response
    Bernard L. Marini, Department of Pharmacy Services and Clinical Sciences, Michigan Medicine, University of Michigan College of Pharmacy, Ann Arbor, MI, USA 
     
    Drs. Losasso, Bostrom, and Messinger should be applauded for their ... Continue reading

Comments on this article Comments (0)

Version 2
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Alongside their report, reviewers assign a status to the article:
Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested
Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.
Not approved - fundamental flaws in the paper seriously undermine the findings and conclusions
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