ABSTRACT
Background: Multi-agent
chemotherapy is the primary treatment for acute lymphoblastic leukemia
(ALL), of which the asparaginase including Escherichia coli
L-asparaginase (E. coli L-Asp) and Pegylated-asparaginase
(PEG-Asp) is a cornerstone component. The study aimed to conduct a
meta-analysis to compare the efficacy and safety of PEG-Asp withE. coli L-Asp in Chinese
children with ALL.
Methods :A systematic literature search was conducted to collect randomized
controlled trials (RCTs) on PEG-Asp versus E. coli L-Asp in Chinese
children with ALL. Two reviewers independently selected articles and
extracted data. Risk-of-bias assessment used the Cochrane recommendation
tool. Pooled estimates and risk
ratios with 95% confidence intervals (CIs) for all outcomes in Review
Manager 5.3.
Result s: 15 studies of a total of 470 publications were
included, involving 1 194 patients.
Pooled estimates showed that there
were no significant differences in CR, ORR,
gastrointestinal symptoms, and
coagulation abnormalities rate between the PEG-Asp and E. coliL-Asp group (all P>0.05). Hypersensitivity (RR=0.63; 95%CI
0.40-1.01; Ρ=0.05) and hepatic
injury rate (RR=0.45; 95%CI 0.27-0.75; Ρ=0.002) were lower in
the
PEG-Asp group. The frequency of
administration and length of hospital stay of patients in the PEG-Asp
group was less than that in the E. coli L-Asp group (both
Ρ<0.0001).
Conclusion s: Current
evidence pointed out a similarity efficacy in the two groups. While the
PEG-Asp group had a lower hypersensitivity and hepatic injury rate.
Besides, using PEG-Asp decreased
the frequency of administration and the length of hospital stay, which,
to some extent, might reduce patients’ burden caused by medical
resources consumption.
Key words: PEG-asparaginase; E. coliL-asparaginase; childhood acute lymphoblastic leukemia;
Meta-analysis
1 INTRODUCTION
Acute lymphoblastic
leukemia (ALL) is the most common
subtype of leukemia in children and
adolescents, characterized by the
proliferation of immature lymphoid cells in the bone marrow, peripheral
blood, and other organs.1 In China, the prevalence
rate of leukemia was about 4/100000 under 15 years of age which was
reported in 2019 in published literature.2 The number
of ALL cases account for 81.75% in 2018 of total childhood malignant
tumor in the same period, up from 34.78% in 2008.2
The multi-agent chemotherapy used in the treatment of children with ALL
already achieved good efficacy, 5-year overall survival (OS) in children
with ALL is 86–89%.1 3Escherichia
coli L-asparaginase
(E.coliL-Asp) is an enzyme as the cornerstone component in multi-agent
chemotherapy, has been an important part of regimens in ALL. However,
the delivery of asparaginase can be highly immunogenic, as it is derived
from bacteria.4 5 Which may cause adverse events
including hypersensitivity, thromboembolic events, and
hepatotoxicity.6Pegylated-asparaginase
(PEG-Asp) is an inert compound, an enzyme-conjugated to polyethylene
glycol (PEG) molecules. PEG-Asp greatly diminishes the immunogenicity
while maintaining the biological activity of
asparaginase.7 And the half-life period of PEG-Asp
(7±2d) is significantly longer than E.coli L-Asp (20h), which
indicated PEG-Asp can reduce the frequency of
administration.8
PEG-Asp is recommended as the
first line of treatment by
theChinese Guideline for the Diagnosis and Management of
Children with ALL (2018) and was
admitted into the
national
reimbursement drug list (NRDL) through national drug price negotiation
in 2018. The agreement is valid
until the end of 2020. Whether it will belong to NRDL drugs in the
future still needs to be negotiated, While E. coli L-Asp has
always been in the NRDL. In fact, there was no clear evidence to prove
that PEG-Asp and E.coli L-Asp have a significant difference in
efficacy and safety among the published research.8-13And there is no meta-analysis targeted at china’s pediatric ALL
patients. Therefore, the objective of this study was to conduct a
meta-analysis to compare the efficacy and safety of PEG-Asp and E.
coli L-Asp in Chinese children with acute lymphoblastic leukemia, with
the aim of providing evidence support for clinical medication and future
negotiation of the NRDL adjustment.
2 MATERIALS AND METHODS
2.1 Data Sources and Search Strategy.
The meta-analysis was conducted according to the Cochrane Collaboration
recommendations. We searched PubMed, Cochrane Library, China National
Knowledge Infrastructure (CNKI), WanFang Data, and VIP Chinese
periodical service platform,
from
inception to December 2019. Medical Subject Heading (MesH) and text
words
included
polyethylene glycol conjugated asparaginase, pegaspargase, PEG-Asp,Escherichia coli L-Asparaginase, E. coli L-Asp, childhood
acute lymphoblastic leukemia, and ALL. References of included studies
were traced to dig out more relevant studies.
2.2 Inclusion and Exclusion Criteria.
The PICO strategy recommended by
Cochrane14 was used to define the eligibility
criteria. RCTs, containing a control group and an intervention group,
which fulfill the following criteria were eligible for inclusion: (1)
study population consisted of Chinese patients aged 0-18 years with ALL;
(2)
PEG-Asp
as a component of multi-agent chemotherapy was the experimental group
(PEG-Asp group), and E.coli L-Asp included in multi-agent
chemotherapy was used for the control group (E.coli L-Asp group).
Other
drugs involved in multi-agent chemotherapy for two groups are consistent
basically, including Vincristine or Vindesine, Daunorubicin or
Pirarubicin, and Prednisone or Prednisolone or Dexamethasone; (3)
Efficacy outcomes included
complete responses (CR) and
overall response rate (ORR). Safety outcomes included
hypersensitivity rate, hepatic injury
rate, gastrointestinal symptoms, and
coagulation abnormalities. Each
Study should report at least one outcome of those; (4) published in full
manuscript form; (5) published in Chinese or English.
Studies were excluded if they were (1) study population with severe
complications (such as pulmonary infection) or other diseases (such as
diabetes); and (2) duplicate publications.
2.3 Data Extraction and Risk-of-Bias Assessment.
Two authors (ZD and YH) extracted data independently and disagreements
were resolved by consensus. For each eligible study, the following
information was extracted: (1) basic information (e.g. first author,
year of publication, sample size); (2) intervention and study
population’s baseline characteristics; (3) efficacy and safety outcomes
as mentioned in inclusion criteria. The quality of included studies was
assessed using the Cochrane risk-of-bias tool.14Assessment items include selection bias, performance bias, detection
bias, attrition bias, reporting bias, and other biases. Publication bias
assessment was performed in Stata/MP version 13.0 (StataCorp LLC, Texas,
USA), using the Egger’s test.15 If publication bias
existed, the trim and fill approach was implemented to generate an
estimated pooled RR that accounts for unpublished negative
findings.16
2.4 Statistical Analysis.
The meta-analysis was undertaken in Review Manager version 5.3 (Cochrane
Collaboration, Copenhagen, Denmark). The risk ratio (RR)
with
95% CI was generated to evaluate dichotomous outcomes. The mean
difference (MD) with 95%CI was generated to evaluate continuous
outcomes. Heterogeneity was assessed using the I2estimate and the P-value of 𝜒2-test. If the
P-value > 0.10 and
I2 < 50%, homogeneity was assumed and the
fixed-effects model (FE) was used to analyze. Otherwise, heterogeneity
was assumed and the source of
heterogeneity should be further
determined by subgroup analysis or meta-regression. In the absence of
clear clinical and methodological heterogeneity, the random-effects
model (RE) was used to analyze the outcomes.
3 RESULTS
3.1 Included studies.
Our search identified 470 publications through database searching. After
screening titles and abstracts, 32 studies were considered potentially
eligible and were retrieved for full-text review.15
studies17-31 of these were finally included in this
meta-analysis. All included studies were in Chinese. The search
procedure and exclusion reasons can be found in the flowchart (Figure
1).
3.2 Study Characteristics.
The characteristics of the included studies were summarized in Table 1.
A total of 1 194
patients
were involved, of which 594 were treated with PEG-Asp, and 600 were
treated with E. coli L-Asp.
3.3 Risk-of-Bias Assessment.
The category “Random sequence generation” exhibited a high risk of
bias in three of fifteen studies. The methods taken to generate random
sequence and arrange groups in these three studies did not accord with
the randomization standard. Six17-19, 21, 24, 31studies described the methods of randomization in detail. Only one
study18 illustrated the allocation concealment.
Blinding was not mentioned in any of the included studies. One
study23 did not completely report the pre-specified
outcomes and was assessed as high risk. No subjects withdrew from the
studies. The category “other bias” exhibited an unclear risk of bias
associated with a lack of information. Details were shown in Figure 2.
3.4 Meta-Analysis Results
After summarizing the
characteristics of the included studies, we found that the dosage of the
PEG-Asp group was similar while there was some difference in theE. coli L-Asp group. Therefore, we conducted a subgroup analysis
based on the dosage of the E. coli L-Asp group reported in the
included studies. Subgroups were divided into (1) E. coli L-Asp:
≤ 6000 U/m2 once, 6-10 times, (2) E. coliL-Asp: 6000-10000 U/m2 once, 6-10 times, (3) E.
coli L-Asp: 700U/m2 once, 7 times, and (4) E.
coli L-Asp: 200U/kg once, 8 times.
3.4.1 CR. All fifteen studies reported CR, 1 194
patients were involved. The pooled analysis demonstrated that there was
no significant difference in CR under the fixed-effects model between
the PEG-Asp group and the E. coli L-Asp group (RR=1.01; 95%CI
0.96-1.08; Ρ=0.64; Figure 3).
No
heterogeneity between studies was noted in each subgroup
(I2=0%, P=0.86 in the subgroup with E. coliL-Asp: ≤ 6000 U/m2 once, 6-10 times; and
I2=26%, P=0.25 in the subgroup with E. coliL-Asp: 6000-10000 U/m2 once, 6-10 times ).
3.4.2 ORR. Thirteen studies reported ORR, 1 099
patients were involved. Homogeneity was assumed as P-value
> 0.10 and I2 < 50% in each
subgroup and the pooled estimates. The fixed-effects model was applied
and pooled
estimates
showed there was no significant difference in ORR between the PEG-Asp
group and the E. coli L-Asp group (RR=1.03; 95%CI 1.00-1.06;
Ρ=0.06; Figure 4).
3.4.3Adverse
events. Eight studies (715 patients) reported hypersensitivity rate and
four studies (239 patients) reported hepatic injury rate. Homogeneity
was assumed as the I2 was 0%. The fixed-effects model
was applied and the results showed that there was a lower
hypersensitivity rate (RR=0.63;
95%CI 0.40-1.01; Ρ=0.05) and a lower hepatic injury rate
(RR=0.45; 95%CI 0.27-0.75;
Ρ=0.002) in the PEG-Asp group compared with the E.coli L-Asp
group. In terms of gastrointestinal symptoms and coagulation
abnormalities reported by ten and nine studies respectively, the
differences between the PEG-Asp group and the E.coli L-Asp group
were not significant(Ρ>0.05). Details were shown in
Figure 5.
3.4.4 Frequency of administration and length of
hospital stay. Besides the efficacy and adverse events, we considered
some relevant resources used during the treatment, such as the
administration and hospital stay. Five studies (407 patients) of the
included studies reported the frequency of administration and the length
of hospital stay. The analysis was conducted under the fixed-effects
model as I2 was 0%. The frequency of administration
and length of hospital stay of patients in the PEG-Asp groups both
significantly less than that of patients in theE.coli L-Asp
groups(MD=-5.58, 95%CI -5.92 to -5.24; MD=-7.04, 95%CI -8.06 to
-6.02; both Ρ<0.00001; Figure
6).
3.5 Publication bias
The P-value of 0.031 (95% CI 0.82–1.44) was calculated by Egger’s
test, indicating the presence of publication bias. The trim and fill
approach was applied to generate an estimated pooled fixed effects RR of
-0.010 (95% CI -0.053-0.033), four study were filled. The initial
estimated pooled fixed effects RR was -0.002 (95% CI -0.046-0.041),
which changed clearly.
4 DISSCUSSION
This meta-analysis focused on the efficacy and safety of
PEG-asparaginase versus E. coli L-asparaginase in Chinese
children with acute lymphoblastic leukemia. Fifteen studies,1 194
patients, were involved. The dosage of the PEG-Asp group was similar,
often be 2500U/m2 once and a total of twice. While
there was some apparent difference in the dosage of the E. coliL-Asp group, a subgroup analysis was conducted according to the dosage
difference. The result showed that there was no significant difference
between the two groups in each subgroup in terms of CR and ORR. Which
seemed that the difference of E. coli L-Asp dosage would not
impact on the pooled result. Further, we removed the two extreme dosage
subgroups (E. coli L-Asp: 700U/m2 once, 7
times, and E. coli L-Asp: 200U/kg once, 8 times), the pooled
estimates results did not change.
Our study didn’t conduct quantitative analysis on long-term efficacy,
because only one included study22 provided the
predicted progression-free survival (PFS) and
overall survival (OS) by using
Kaplan-Meier analysis. They predicted that a 5-year PFS of 63.5%±12.5%
for the PEG-Asp group and 77.8%±9.8% for the E.coli L-Asp
group; a 5-year OS of 68.9%±11.8% for the PEG-Asp group and
82.1%±9.5% for the E.coli L-Asp group. The difference was not
significant between groups.
This
is consistent with the systematic evaluation result of scholar
Medawar32, which was performed based on the population
of the USA, Puerto Rico and Canada. And researches from the United
States and India with evaluation on the local patients also proved that
there were no significant differences between the two groups in terms of
event-free survival and overall survival.10, 11, 14
As for safety, our meta-analysis showed that PEG-Asp group had lower
hypersensitivity rate and hepatic injury rate, but with no significant
differences in gastrointestinal symptoms rate and coagulation
abnormalities rate. One thing worth noting in this meta-analysis is that
all included studies administered PEG-Asp intramuscularly, which is the
recommended administration in the Chinese Guideline for the
Diagnosis and Management of Children with ALL (2018) . However, due to
patients’ anxiety and pain, intravenous delivery is also available in
practice. And as for the hypersensitivity rate between intramuscular and
intravenous administration, one meta-analysis reported it was not
statistically significant.33 In addition, our results
showed that the frequency of
administration and length of hospital stay of patients in PEG-Asp group
both were significantly less than that of patients in E.coliL-Asp group, which indicated that
using PEG-Asp in the treatment could reduce the economic burden caused
by less used medical resources including administration and hospital
stay.
In total, this study examined 1 194 patients, which allows for
substantially more statistical power and precision. However, there were
several limitations to this meta-analysis. Firstly,
all the included studies were
published in Chinese, study populations were all small-scale. And the
results of Egger’s test and trim and fill approach indicated the
presence of publication bias. Secondly, the result of the risk-of-bias
assessment presented a large proportion of uncertain risks associated
with insufficient information in the trial methods. Thirdly, our study
lacked an analysis of long-term outcomes. Only one included
study22 provided long-term outcomes, which cannot
carry out a quantitative synthesis. Thus, more studies relevant to
long-term outcomes of PEG-Asp in treatment with Chinese children with
ALL are needed in the future to confirm the long-term efficacy and
safety of PEG-Asp.
5 CONCLUSIONS
In summary, current evidence shows that the use of PEG-Asp as a core
component
in multi-agent chemotherapy was not superior to E. coli L-Asp in
terms of efficacy in the treatment of Chinese children with ALL. More
trials with adequate methods and longer follow-up are necessary to
classify their efficacy. However, the assessment of the data collected
showed that patients in the PEG-Asp groups had a lower hypersensitivity
rate and hepatic injury rate. The use of PEG-Asp reduced the frequency
of administration and shorten the length of hospital stay, which
indicates that using PEG-Asp in the pharmacotherapy could reduce the
economic burden caused by used medical resources.
Although there were some limitations to this study we discussed earlier,
this study complements special evidence based on the Chinese population
by conducting a meta-analysis to analyze the efficacy and safety of
PEG-Asp in the treatment of Chinese children with ALL. The results are
more macroscopic, representative. Which could help reduce the
possibility of experts misled by differences between individual RCTs,
and can provide data support for clinical medication and future
negotiation of the NRDL adjustment.
Data availability statement All data relevant to the study
are included in the article or can be found from references. No
additional data are
available.
References
- National
Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in
Oncology (NCCN Guidelines): pediatric acute lymphoblastic leukemia
(version 2.2020).https://www.nccn.org/professionals/physician_gls/pdf/ped_all.pdf.
Accessed 20 May 2020.
- Gong
A, Di Y, Wang X, et al. Epidemiological Data Analysis of Childhood
Acute Lymphoblastic Leukemia. Chinese Medical Record.2019;20(10):59-62. (in Chinese)
- Kako S, Akahoshi Y, Harada N, et
al. Meta-analysis and meta-regression analysis to compare the outcomes
of chemotherapy for T-and B-lineage acute lymphoblastic leukemia
(ALL): the use of dexamethasone, E.coli L-Asparaginase, and/or
methotrexate may improve the outcome of T-lineage ALL. Annals of
hematology . 2016;95(1): 87-92.
- Peterson RG, Handschumacher RE,
Mitchell MS. Immunological responses to E.coli L-Asparaginase.
Journal of Clinical Investigation 1971;50(5):1080–1090.
- Raetz EA, Salzer WL.
Tolerability and efficacy of E.coli L-Asparaginase therapy in
pediatric patients with acute lymphoblastic leukemia. Journal of
pediatric hematology/oncology. 2010;32(7):554–563.
- Kurre, H.A., et al., A
pharmacoeconomic analysis of pegaspargase versus native Escherichia
coli E.coli L-Asparaginase for the treatment of children with
standard-risk, acute lymphoblastic leukemia: the Children’s Cancer
Group study (CCG-1962). J Pediatr Hematol Oncol . 2002;24(3): p.
175-81.
- Sun
X, Xu Q, Ao G, et al. Antitumor agents: multidrug resistance and
enhanced permeability and retention. Chinese Journal of New
Drugs . 2007(01):16-20. (in Chinese)
- Hao
Q, He Z. Safety of E.coli L-Asp and Peg-asp in Treatment of
Children with Newly Diagnosed Acute Lymphoblastic Leukemia.Genomics and Applied Biology. 2018;37(11):5006-5011. (in
Chinese)
- Avramis V I, Sencer S, Periclou
A P, et al. 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,
The Journal of the American Society of Hematology . 2002;99(6):
1986-1994.
- Place A E, Stevenson K E,
Vrooman L M, et al. Intravenous pegylated asparaginase versus
intramuscular native Escherichia coli E.coli L-Asparaginase in
newly diagnosed childhood acute lymphoblastic leukemia (DFCI 05-001):
a randomized, open-label phase 3 trial. The lancet oncology .
2015;16(16): 1677-1690.
- Kurtzberg J, Asselin B,
Bernstein M, et al. Polyethylene glycol-conjugated E.coliL-Asparaginase versus native E.coli L-Asparaginase in
combination with standard agents for children with acute lymphoblastic
leukemia in second bone marrow relapse: A Children’s Oncology Group
Study (POG 8866). Journal of pediatric hematology/oncology.2011; 33(8): 610.
- Vyas C, Jain S, Kapoor G, et al.
Experience with generic pegylated E.coli L-Asparaginase in
children with acute lymphoblastic leukemia and monitoring of serum
asparaginase activity. Pediatric hematology and oncology .
2018;35(5-6): 331-340.
- Liang
Y. A randomized controlled study of pegaspargase and E.coliL-Asparaginase in the treatment of children with acute lymphoblastic
leukemia. Practical Clinical Journal of Integrated Traditional
Chinese and Western Medicine . 2017;17(11):117-119. (in Chinese)
- Higgins J P T, Wells G A.
Cochrane handbook for systematic reviews of interventions. 2011.
- Sedgwick
P, Marston L. How to read a funnel plot in a meta-analysis.BMJ . 2015;351:h4718.
- Dreyer NA, Velentgas P, Westrich
K, Dubois R. The GRACE checklist for rating the quality of
observational studies of comparative effectiveness: a tale of hope and
caution. J Manag Care Spec Pharm. 2014;20(3):301-308.
- Cheng X. Comparison of Efficacy
and Adverse Reactions of E.coli L-Asparaginase and Pegaspargase
in Treatment of Children with Acute Lymphoblastic Leukemia.Evaluation and analysis of drug-use in hospitals of China .
2015;15(08):1009-1011. (in Chinese)
- The
Cooperation Group of Phase II Clinical Trial of PEG-Asp. Comparison of
polyethylene glycol conjugated asparaginase and E.coliL-Asparaginase for treatment of childhood acute lymphoblastic
leukemia. Chinese Journal of Hematology . 2008;29(1):29-33. (in
Chinese)
- Feng
J. An efficacy observation of
domestic pegaspargase in the treatment of children with initial acute
lymphoblastic leukemia. China Medical Engineering . 2015;23(7):
86-87. (in Chinese)
- Jin
Y. Adverse reactions of pegaspargase in the treatment of children with
acute lymphoblastic leukemia and its prevention treatment. For
all Health . 2014;8(15):99-100. (in Chinese)
- Li
F, Zhou P. Clinical comparison of permenthase and E.coliL-Asparaginase in the treatment of acute lymphoblastic leukemia in
children. Chinese Journal of Convalescent Medicine.2019;28(10):1028-1030. (in Chinese)
- Liu
F, Zou Y, Zhang L, et al. Long-term efficacy of polyethylene glycol
conjugated asparaginase (PEG-Asp) in newly diagnosed childhood acute
lymphoblastic leukemia (ALL). Journal of China Pediatric Blood
and Cancer . 2010;15(06):254-257. (in Chinese)
- Liu
Z.
Clinical observation of pegaspargase in the treatment of children with
acute lymphoblastic leukemia. Chinese Community Doctors .
2019;35(05):51-52. (in Chinese)
- Shi
L, Huang S and Liu W. Comparison of efficacy of pegaspargase andE.coli L-Asparaginase in the treatment of children with acute
lymphoblastic leukemia . Clinical Research . 2019;27(06):58-59.
(in Chinese)
- Tang
Y, He Z, Jin J, et al. Comparison of Efficacy of Pegaspargase andE.coli L-Asparaginase in the Treatment of Children with
Leukemia. Laboratory Medicine and Clinic. 2016;13(z1):233-234.
(in Chinese)
- Wu
H. Curative effect comparison and safety evaluation of pegaspargase
and E.coli L-Asparaginase in the treatment of children with
acute lymphoblastic leukemia. Chinese Community Doctors .
2016;32(36):38-39. (in Chinese)
- Xia
L. The curative effects and safety of pegaspargase-asparaginase on
acute lymphoblastic leukemia in childre. Journal of North
Sichuan Medical College . 2016;31(05):644-647. (in Chinese)
- Xie
S, Liang C, and Zhong X. The side effects and clinical efficacy of
pegaspargase and E.coli L-Asparaginase in the treatment of
childhood acute lymphoblastic leukemia. National Medical
Frontiers of China . 2013;8(15):60-61. (in Chinese)
- Zhang
H, Li H, and Li Y. Observation on Clinical Effect of Pegaspargase in
Treating Acute Lymphoblastic Leukemia of Childhood. Chinese
Journal of Rational Drug Use . 2018;15(04):16-19. (in Chinese)
- Zhang
S. Clinical analysis of pegaspargase on early onset of acute
lymphoblastic leukemia in children. Chinese Journal of Trauma
and Disability Medicine . 2015;(4):32-33. (in Chinese)
- Zhang
S,Liu L, Yang Y, et al. Analysis of toxicity and efficacy of
chemotherapy pegaspargase and E.coli L-Asparaginase acute
lymphoblastic leukemia. Journal of Hunan Normal University
(Medical Sciences) . 2015;12(01):95-97. (in Chinese)
- Medawar C V, Mosegui G B G, de
Mello Viana C M, et al. PEG-asparaginase and native Escherichia coliE.coli L-Asparaginase in acute lymphoblastic leukemia in
children and adolescents: a systematic review. Hematology,
transfusion and cell therapy . 2019;42(1):54-61.
- Hasan H, Shaikh OM, Rassekh SR,
et al. Comparison of hypersensitivity rates to intravenous and
intramuscular PEG-asparaginase in children with acute lymphoblastic
leukemia: A meta-analysis and systematic review. Pediatr Blood
Cancer . 2017;64(1):81-88.