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Clinical efficacy and safety of 6-thioguanine in the
treatment of childhood acute lymphoblastic
leukemia
A protocol for systematic review and meta-analysis
Liang Chen, MD, Huai-Xiu Yan, MD, Xiao-Wei Liu, MD, Wen-Xin Chen, PhD
∗
Abstract
Background: To systematic review the efficacy and safety of 6-thioguanine (6-TG) in the substitute of 6-mercaptopurine (6-MP) in
the treatment for patients with childhood acute lymphoblastic leukemia (ALL) in the maintenance phase, and to explore its clinical
application value. It provides theoretical guidance for the maintenance treatment of ALL in children from the perspective of evidence-
based medicine.
Methods: By means of computer retrieval, Chinese databases were searched: Chinese Biomedical Database (CBM), China
national knowledge internet (CNKI), Chongqing Weipu Database (VIP), and Wanfang Database; Foreign databases: PubMed, The
Cochrane Library, Embase, and Web of Science were applied to find out randomized controlled trial (RCT) for 6-TG in childhood
acute lymphoblastic leukemia. By manual retrieval, documents without electronic edition and related conference papers were
retrieved. The retrieval time ranges from the beginning of the establishment of the databases to September 1st, 2019. According to
the inclusion, and exclusion criteria by 3 researchers, the literature screening, data extraction, and research methodological quality
evaluation were completed. RevMan 5.3 software was applied to evaluate the quality of the included literature, and Stata 12.0
software was used to conduct meta-analysis of the outcome indicators of the included literature.
Results: This study systematically evaluated the efficacy and safety of 6-TG in the substitute of 6-MP as a maintenance drug for
childhood acute lymphoblastic leukemia. Through the key outcome indicators, this study is expected to draw a scientific, practical
conclusion for 6-TG in the treatment of childhood acute lymphoblastic leukemia. This conclusion will provide evidence-based medical
direction for clinical treatment.
Conclusion: The efficacy and safety of 6-TG in the substitute of 6-MP in the maintenance treatment of childhood acute
lymphoblastic leukemia will be confirmed through this study. The conclusions will be published in relevant academic journals.
Registration: PROSPERO (registration number is CRD42020150466).
Abbreviations: 6-MP =6-mercaptopurine, 6-TG =6-thioguanine, ALL =acute lymphoblastic leukemia, ALT =alanine
aminotransferase, AML =acute myelogenous leukemia, AST =aspartate aminotransferase, CALL =childhood acute lymphoblastic
leukemia, CBM =Chinese Biomedical Database, CI =confidence interval, CNKI =China national knowledge internet, FUT4 =
fucosyltransferase-4, GGT =gglutamyl transferase, Hb =hemoglobin, ICNS =isolated central nervous system, IL =interleukin,
PGE-2 =prostaglandin E2, PICOS =patient, intervention, contrast, outcome, study, PLT =platelet, RCT =randomized control trial,
RR =relative risk, SMD =standardized mean difference, SMMP =serum matrix metalloproteinase, SOCS-3 =Suppressor of
Cytokine Signaling-3, TIMP-2 =tissue-specific inhibitor-2, VIP =Chongqing Weipu Database, WanFang =Wanfang Database, WBC
=leukocyte.
Keywords: 6-mercaptopurine, 6-thioguanine, childhood acute lymphoblastic leukemia, clinical efficacy, meta-analysis,
randomized controlled trials, safety
This study is supported by Inner Mongolia Medical University Talent Team Project (NYTD-2018026).
The authors have no conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. The datasets generated
during and/or analyzed during the current study are publicly available.
Department of Hematology, Inner Mongolia Baogang Hospital (The Third Affiliated Hospital of Inner Mongolia Medical University), No. 20 Shaoxian Road, Kundulun
District, Baotou, Inner Mongolia Autonomous Region, 014010, China.
∗
Correspondence: Wen-Xin Chen, Department of Hematology, Inner Mongolia Baogang Hospital (The Third Affiliated Hospital of Inner Mongolia Medical University), No.
20 Shaoxian Road, Kundulun District, Baotou, Inner Mongolia Autonomous Region, 014010, China (e-mail: chenwenxin_work@sina.com).
Copyright ©2020 the Author(s). Published by Wolters Kluwer Health, Inc.
This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
How to cite this article: Chen L, Yan HX, Liu XW, Chen WX. Clinical efficacy and safety of 6-thioguanine in the treatment of childhood acute lymphoblastic leukemia: A
protocol for systematic review and meta-analysis. Medicine 2020;99:18(e20082).
Received: 31 March 2020 / Accepted: 1 April 2020
http://dx.doi.org/10.1097/MD.0000000000020082
Study Protocol Systematic Review Medicine®
OPEN
1
1. Introduction
Leukemia is a group of malignant clonal diseases, which is a
malignant tumor of hematopoietic system caused by mutation of
the hematopoietic stem cells or hematopoietic progenitor cells. As
leukemia cells self-renewal enhances, proliferation is out of
control, differentiation is disordered, apoptosis is blocked, and
stagnating at different stages of cell development. Abnormal
primitive and immature cells (leukemia cells) in bone marrow can
proliferate and inhibit normal hematopoiesis. They can infiltrate
various organs such as liver, spleen, and lymph nodes. Their
clinical manifestations are anemia, bleeding, infection, infiltra-
tion, etc.
[1–3]
At present, the etiology is not completely clear,
which may be related to viral infection, physical, and chemical
factors, genetic quality, and so on. Its pathogenesis includes the
transformation of the proto-oncogene, the aberration of anti-
oncogene, inhibition of apoptosis, etc.
[4,5]
ALL can be divided
into acute lymphoblastic leukemia (ALL) and acute myelogenous
leukemia (AML) based on the primary cell series involved.
Among them, ALL is the most commonly seen malignant disease
in childhood, accounting for 30% of children’s tumors.
[6,7]
More
than 50 years ago, the survival rate of leukemia was meagre, and
leukemia was considered to be a refractory disease. However, the
cure rate of ALL in children (defined as disease-free survival for
more than 10 years) can reach as high as 80%, which is related to
stratified therapy based on the risk of relapse, and biological
characteristics of leukemia cells, increasingly excellent supportive
treatment and communication, and the optimization of treatment
regimens by cooperative research at home and abroad.
[8,9]
Among them, according to morphology, immunology, cytoge-
netics, molecular biology, early treatment response, and other
risk factors, the risk classification of ALL children with
corresponding stratified chemotherapy provided have got more
importance, and attention from clinicians increasingly.
[10]
ALL in children is the most common malignant hematological
neoplasm. The key to its treatment is to kill tumor cells and keep
the children in remission effectively. Although the cure rate of
ALL in children is over 90%, the prognosis of ALL in children is
not ideal, and they even face a recurrence risk of up to 20%.
[11]
Mercaptopurine drugs as part of the continuous treatment of
ALL have been the key to prevent its recurrence for a long time.
Among them, 6-mercaptopurine (6-MP) is used in the period of
maintenance therapy, while 6-thioguanine (6-TG) is only used in
the period of intensive treatment. Generally speaking, there is no
optimal drug regimen in the treatment process.
[12,13]
For more
than 60 years, 6-MP has been used to treat ALL in children. Its
mechanism has not been fully elucidated. The treatment-related
hepatotoxicity and bone marrow suppression are still significant
challenges for clinicians. Due to the lack of direct parameters to
inspect the efficacy of patients, it is difficult to grasp the intensity
of treatment. Clinicians still need to further adjust the treatment
regimen to reduce the resistance to mercaptopurine drugs.
[14]
Since 1980, pharmacokinetic studies have found that 6-TG has a
more direct intracellular activation pathway, shorter cytotoxicity
time, and stronger effect than 6-MP, which clarify why 6-TG is
more potentially useful theoretically. Since 1990, clinical studies
have been conducted to compare the efficacy of the 2 drugs. Some
experimental animal data also preliminarily show that 6-TG may
be more effective than 6-Mp.
[15]
Therefore, we use a systematic
review method to study the efficacy, and safety of 6-TG as an
alternative to 6-MP in the maintenance phase of childhood acute
lymphoblastic leukemia for the clinical treatment of childhood
acute lymphoblastic leukemia, which provides a scientific basis
for clinical treatment of childhood acute lymphoblastic leukemia.
2. Methods
2.1. Study registration
PROSPERO (registration number is CRD42020150466). The
registered website for this protocol is https://www.crd.york.ac.
uk/PROSPERO/.
2.2. Document inclusion and exclusion criteria
2.2.1. Types of research. Randomized controlled trial of 6-TG
in the treatment of childhood acute lymphoblastic leukemia.
Whether or not the blind method and distribution concealment
are mentioned, there is no restriction on the language of
literature.
2.2.2. Research object. Inclusion criteria:
(1) Literature published at home and abroad on 6-TG in the
substitute of 6-MP for treating ALL in children.
(2) The subjects of study were children with acute lymphoblastic
leukemia (from 1 to 18 years old), excluding patients with
acute biphenotypic leukemia, severe complications, or
complications with no limitation of race and nationality.
(3) Intervening measures were suffered children who were given
6-TG or 6-MP at the end of induction remission.
Exclusion criteria:
(1) Non-RCT research literature.
(2) Duplicated published and reported literature.
(3) Only abstracts, missing raw data, or the valid unattained data
even contacting the author.
(4) Documents that interfere with the drug in this study before
the diagnosis of acute lymphoblastic leukemia in children.
(5) Animal experiments.
(6) Review literature.
(7) Repeated literature.
2.2.3. Intervening measures. The experimental group (6-TG
group) was treated with chemotherapeutic drugs and supportive
therapy based on 6-TG. The control group (6-MP group) was
treated with chemotherapeutic drugs and supportive therapy
based on 6-MP. The included drug dosage and mode of use of
each study may vary.
2.2.4. Outcome indicator. Main outcome indicators
(1) Overall efficiency;
(2) The recurrence rate of the isolated central nervous system
(ICNS);
(3) The recurrence rate of non-ICNS (the recurrence rate of bone
marrow, testis, and other parts, the multi-site recurrence
exclusion);
(4) Overall recurrence rate;
(5) Incidence of secondary malignant tumors;
(6) Incidence of adverse events;
Secondary outcome indicators
(1) Incidence of hepatic venous occlusion;
(2) Ki-67;
(3) Fucosyltransferase-4 (FUT4);
Chen et al. Medicine (2020) 99:18 Medicine
2
(4) Suppressor of Cytokine Signaling-3 (SOCS-3);
(5) Serum matrix metalloproteinase (SMMP), interleukin (IL),
tissue-specific inhibitor-2 (TIMP-2), and prostaglandin E2
(PGE-2);
(6) Hospitalization days;
(7) The levels of leukocyte (WBC), platelet (PLT), and
hemoglobin (Hb);
(8) Liver function (alanine aminotransferase, aspartate amino-
transferase, gglutamyl transferase);
(9) Lymphocyte subpopulation (CD3, CD4, CD8, CD4/CD8,
CD19);
(10) Coagulation function.
2.2.5. Data extraction. Literature screening: Firstly, we led the
retrieved titles into NoteExpress 2.0 software, which is document
management software, and set up a catalog database. Secondly,
the software was used to classify and sort out the initial
documents, and duplicated documents were removed by using
the function of automatic searching for duplicated documents by
software. Thirdly, 2 researchers screened the literature indepen-
dently. By reading the topics and abstracts of each study, the
literature that did not meet the inclusion criteria was excluded.
Fourthly, the full texts of the corresponding the literature of the
remaining titles were downloaded. The full text was read with the
combination of the inclusion, and the criteria were excluded from
determining whether the selected literature can be included.
Documents with incomplete information can be obtained by
contacting the original author through e-mail. All excluded
documents should record the reasons for the exclusion. Fifthly,
the results of literature screening were cross-checked by 2
researchers. If there are differences, they will consult with the
third party; if it cannot be solved after discussion, it will be dealt
with in consultation with the third party.
2.3. Search strategy
Computer Search Chinese Database: CMB, China national
knowledge internet (CNKI), Chongqing Weipu Database (VIP),
and Wanfang Database; Foreign Database: PubMed, The
Cochrane Library, EMbase, and Web of Science. The random-
ized controlled trial (RCT) study of 6-TG in the treatment of
children’s ALL and the included references, academic conferences
and network resources, etc in the literature were inquired at the
same time to find out the research that may meet the inclusion
criteria. The retrieval time is from the establishment of databases
to September 1, 2019.
Firstly, the clinical problems were refined by the principle
patient, intervention, contrast, outcome, study (PICOS)
[16]
:
P: children with acute lymphoblastic leukemia;
I: chemotherapy;
C: 6-thioguanine vs 6-mercaptopurine;
O: effectiveness and safety;
S: RCTs.
Chinese search terms include (Chinese pinyin): “Ertong”,
“Xiaohai”,“Ji-xing-lin-ba-xi-bao-xing-bai-xue-bing”,“6-liu-
niaopiaoling”,“2-anjipiaoling-6(1H)-liutong”,“6-qiupiaoling”,
“6-qiujipiaoling”,“Lejining”, and “Sui-ji-dui-zhao-shi-yan”.
English search terms include: “child”,“children”,“precursor
cell lymphoblastic leukemia–lymphoma”,“acute lymphoid
leukemia”,“6-thioguanine”,“thioguanin”,“6-mercaptopu-
rine”,“mercaptopurine”,“randomized trial”,“RCT”. Finally,
the method of combining keywords and free words is used for
further supplementary retrieval. The retrieval strategy takes the
PubMed database as an example, as shown in Table 1.
2.4. Data extraction
Firstly, data extraction tables are designed according to research
purposes and requirements. The contents of data extraction
tables include:
(1) Basic information: the title, publication time, publishing
magazines, publishing languages, authors, research sites, etc
of the included literature.
(2) The characteristics of the study included: demographic
characteristics, pathological types, stages, intervention mea-
sures of treatment group and control group, etc.
(3) Inclusion of information related to literature bias risk
assessment.
(4) Extraction of relevant data of outcome indicators.
Secondly, to ensure the accuracy of data extraction, 2
researchers independently extract relevant data based on the
data extraction table with the cross-check to make statistical
analysis after making it accurate and unambiguous. In case of
contradictory opinions, they can be settled through consultation
with the third party. When coming across the data missing, the
author of the relevant literature was contacted through e-mail to
obtain the relevant original data. For the duplicate publications
of the same study, the most comprehensive one was selected for
data entry. The literature screening process is shown in Figure 1.
2.5. Quality assessment
According to the “Bias Risk Assessment”tool recommended by
Cochrane Collaboration Network (Version 5.1.0), the 6 aspects
of selective bias (random sequence generation and allocation
concealment), implementation bias (blind method for subjects
and experimenters), measurement bias (blind method for
outcome assessors), follow-up bias (incomplete outcome data),
reporting bias (selective reporting of results), and other bias were
used respectively to make the evaluation for the quality of
evidence for inclusion in research.
[17]
According to the criteria in
Cochrane Handbook 5.1.0, “High Risk”,“Low Risk”,“Un-
clear”were used to express the evaluation results. When
evaluating the quality of evidence, the 2 researchers indepen-
dently review the evaluation results. If there is any difference of
opinion, it should be settled through consultation with the third
party. RevMan 5.3 software was used to draw the bias risk
pictures.
2.6. Statistical method
2.6.1. Statistical analysis. The software of Review Manager 5.3
and STATA12.0 provided by Cochrane was applied to make
statistical analysis for the included literature, and forest maps,
and funnel maps were made from the results. Relative risk (RR)
and standardized mean difference (SMD) were applied as the
effect combination indicator. Various effect quantities were
expressed by 95% confidence interval (CI), and there was the
significant difference between the results of P<.05.
2.6.2. Heterogeneity test. Before the meta-analysis of the
literature that meets the inclusion requirements, the heterogeneity
of the literature was tested by statistics at first. In recent years, Ka
Chen et al. Medicine (2020) 99:18 www.md-journal.com
3
Fang test has been widely used with the application of an I
2
index
to make the heterogeneity testing of included literature
research.
[18]
The size of heterogeneity among the studies is
measured by the percentage of I
2
. If the value of I
2
is less than
25%, it shows that the heterogeneity among the studies is small,
while if the value of I
2
is between 25% and 50%, it indicates that
there is moderate heterogeneity among the studies. Fixed effect
model can be used to merge the research data. If the value of I
2
is
more than 50%, it is considered that there is a high degree of
heterogeneity among the studies. Sensitivity analysis or subgroup
analysis is needed to identify the sources of heterogeneity among
the literature. In this paper, the combination of research data
adopts the way of stochastic effect model.
2.7. Sensitivity analysis
Sensitivity analysis refers to the important factors that influence
the results of the study, such as, inclusion criteria, randomized
grouping, loss or withdrawal of the study subjects, different
statistical methods, criteria for evaluating efficacy and selection
of efficacy (e.g., ratio or relative risk), etc to observe the
homogeneity between the studies, or whether the final results of
the synthesis can be changed so as to determine whether the
results of the study are stable. If the results of sensitivity analysis
are the same or similar to those of this meta-analysis, it shows that
the results of the study are reliable. If the results of sensitivity
analysis are quite different from those of meta-analysis in this
paper, it shows that the results of meta-analysis have potential
factors that influence the effectiveness of interventions. There-
fore, it is necessary to draw cautious conclusions or only make a
descriptive analysis.
2.8. Subgroup analysis
This study will apply the subgroup analysis method to find out
the causes of heterogeneity. Subgroup analysis will be applied
from the following aspects, including, dosage, dosage form,
frequency of drug use, duration of drug use, ethnic differences,
and so on.
2.9. Publication bias
Bias refers to the difference between inferred results, and true
values, which can be drawn from various stages of clinical trials,
Table 1
Search strategy for the PubMed database.
Number Search terms
#1 Search “Child”[Mesh]
#2 Search (Child[Title/Abstract]) OR children[Title/Abstract]
#3 Search “Precursor Cell Lymphoblastic Leukemia–Lymphoma”[Mesh]
#4 Search (((((((((((Precursor Cell Lymphoblastic Leukemia–Lymphoma[Title/Abstract] OR Precursor Cell Lymphoblastic Leukemia Lymphoma
[Title/Abstract])) OR (Leukemia, Acute Lymphoblastic[Title/Abstract] OR Acute Lymphoblastic Leukemia[Title/Abstract] OR Leukemia,
Lymphoblastic[Title/Abstract])) OR (Leukemia, Lymphoblastic, Acute[Title/Abstract] OR Leukemia, Lymphocytic, Acute[Title/Abstract] OR
Lymphoblastic Leukemia[Title/Abstract])) OR (Lymphoblastic Leukemia, Acute[Title/Abstract] OR Lymphoblastic Lymphoma[Title/Abstract]
OR Lymphocytic Leukemia, Acute[Title/Abstract])) OR (Acute Lymphocytic Leukemia[Title/Abstract] OR Leukemia, Acute Lymphocytic
[Title/Abstract] OR Lymphoma, Lymphoblastic[Title/Abstract])) OR (Acute Lymphoid Leukemia[Title/Abstract] OR Leukemia, Acute
Lymphoid[Title/Abstract] OR Lymphoid Leukemia, Acute[Title/Abstract])) OR (Leukemia, Lymphoid, Acute[Title/Abstract] OR Leukemia,
Lymphocytic, Acute, L1[Title/Abstract] OR Lymphocytic Leukemia, L1[Title/Abstract])) OR (L1 Lymphocytic Leukemia[Title/Abstract] OR
Leukemia, L1 Lymphocytic[Title/Abstract] OR Lymphoblastic Leukemia, Acute, Childhood[Title/Abstract])) OR (Lymphoblastic Leukemia,
Acute, L1[Title/Abstract] OR ALL, Childhood[Title/Abstract] OR Childhood ALL[Title/Abstract] OR Leukemia, Lymphoblastic, Acute, L1
[Title/Abstract] OR Leukemia, Lymphocytic, Acute, L2[Title/Abstract])) OR (Lymphocytic Leukemia, L2[Title/Abstract] OR L2 Lymphocytic
Leukemia[Title/Abstract] OR Leukemia, L2 Lymphocytic[Title/Abstract] OR Lymphoblastic Leukemia, Acute, Adult[Title/Abstract])) OR
(Lymphoblastic Leukemia, Acute, L2[Title/Abstract] OR Leukemia, Lymphoblastic, Acute, L2[Title/Abstract] OR Leukemia,
Lymphoblastic, Acute, Philadelphia-Positive[Title/Abstract])
#5 Search “Thioguanine”[Mesh]
#6 Search ((((Thioguanine[Title/Abstract] OR 2-Amino-6-Purinethiol[Title/Abstract] OR 2 Amino 6 Purinethiol[Title/Abstract] OR Tioguanine
[Title/Abstract])) OR (6-Thioguanine[Title/Abstract] OR 6 Thioguanine[Title/Abstract] OR Tabloid[Title/Abstract] OR Thioguanine Tabloid
[Title/Abstract] OR Thioguanin-GSK[Title/Abstract])) OR (Thioguanin GSK[Title/Abstract] OR ThioguaninGSK[Title/Abstract] OR Tioguanina
Wellcome[Title/Abstract] OR Thioguanine Hemihydrate[Title/Abstract])) OR (Thioguanine Monosodium Salt[Title/Abstract] OR Lanvis[Title/
Abstract] OR Thioguanine Anhydrous[Title/Abstract] OR Anhydrous, Thioguanine[Title/Abstract])
#7 Search “Mercaptopurine”[Mesh]
#8 Search (((((Mercaptopurine[Title/Abstract] OR 6H-Purine-6-thione, 1,7-dihydro-[Title/Abstract] OR 6-Mercaptopurine Monohydrate[Title/
Abstract])) OR (6 Mercaptopurine Monohydrate[Title/Abstract] OR 6-Thiopurine[Title/Abstract] OR 6 Thiopurine[Title/Abstract] OR 1,7-
Dihydro-6H-purine-6-thione[Title/Abstract])) OR (6-Mercaptopurine[Title/Abstract] OR 6 Mercaptopurine[Title/Abstract] OR 6-
Thiohypoxanthine[Title/Abstract] OR 6 Thiohypoxanthine[Title/Abstract])) OR (Purinethol[Title/Abstract] OR Puri-Nethol[Title/Abstract] OR
Mercaptopurina Wellcome[Title/Abstract])) OR (Leupurin[Title/Abstract] OR BW 57-323H[Title/Abstract] OR BW 57 323H[Title/Abstract]
OR BW 57323H[Title/Abstract] OR Purimethol[Title/Abstract] OR Mecaptopurine Anhydrous[Title/Abstract])
#9 Search “Randomized Controlled Trial”[Publication Type]
#10 #1 OR #2
#11 #3 OR #4
#12 #5 OR #6
#13 #7 OR #8
#14 #10 AND #11 AND #12 AND #13 AND #9
Chen et al. Medicine (2020) 99:18 Medicine
4
including selective bias, implementation bias, measurement bias,
follow-up bias, and reporting bias. The first 4 biases can be
reduced by controlling the quality of the included literature;
however, reporting bias is mainly assessed by assessing
publication bias. According to the number of studies included,
when the number of studies exceeds 10 items, the funnel plot
method will be used to evaluate the bias qualitatively.
[19]
When
the number of studies is less than 10 items, the quantitative
Figure 1. Flowchart of literature selection.
Chen et al. Medicine (2020) 99:18 www.md-journal.com
5
evaluation is carried out by using the Egger linear regression
method with STATA 12.0 software. It defines that when P<.05,
there is publication bias.
2.10. Ethics and dissemination
The ethical approval of clinical research is not suitable for this
study.
3. Discussion
ALL is a malignant disease originating from abnormal
proliferation of B and T cells in the bone marrow. The
lymphocyte proliferation of ALL is uncontrolled, and cannot
differentiate, mature, and function. Tumor cells infiltrate into
bone marrow and other hematopoietic tissues and organs, and
inhibit the normal hematopoietic function of bone marrow,
resulting in related clinical symptoms. ALL can occur in all age
groups, mainly seen in children, and adolescents. It ranks first in
the incidence of malignant tumors in children. ALL belongs to a
highly heterogeneous disease. Different clonal subtypes have
different biological characteristics, and the clinical efficacy, and
prognosis are different as well.
[20]
In recent years, with the development of immunology,
cytogenetics, molecular biology, and other disciplines, more in-
depth understanding of the pathogenesis and clinical character-
istics of ALL has been achieved, and its treatment strategies have
made new progress as well. In addition to the main treatment of
chemotherapy, hematopoietic stem cell transplantation and
targeted therapy have been applied as well.
[21]
However, for
children with ALL, the status of chemotherapy is not question-
able. The prognosis of children with ALL has been greatly
improved thanks to the treatment strategy guided by risk
classification, and optimized combination of chemotherapeutic
drugs.
Clinical use of thioguanine drugs in children with ALL is
complicated in dose, course of treatment, drug selection, and
remedy of toxic and side effects. The therapeutic effect of ALL
was also linked to the disease grade, gender, and age of the
patients. All the included studies were based on the risk
classification of children with intrathecal injection of chemother-
apeutic drugs in the prophylactic treatment of isolated central
nervous system leukemia. Currently, there is no evidence proving
that 6-TG is better than 6-MP in terms of improving the quality of
life, prolonging the survival time, and reducing the mortality of
ALL children. This study provides some important clues for the
drug selection of thioguanine drugs during maintenance therapy
of ALL in children.
[22]
There is no definite clinical effect of 6-TG
in the substitute of 6-MP in the treatment of ALL in children
during maintenance therapy. Further studies are needed to
provide evidence-based evidence for the clinical treatment of 6-
TG. Therefore, it is suggested that the monitoring of active
metabolite concentration and side effects in blood should be
strengthened in the treatment of 6-TG. Anti-infection, liver
protection, jaundice alleviation, and low molecular weight
heparin can be offered to improve the prognosis of children.
[23]
In terms of preventing the recurrence of ALL in children, 6-TG
may be more effective than 6-MP, but 6-TG has strong
hepatotoxicity, which should be avoided to use for in the long
run. Ongoing pharmacogenetic studies can establish models
to explore whether children with specific type can benefit from
6-TG.
The efficacy and safety of 6-TG in the substitute of 6-MP in the
maintenance phase of childhood acute lymphoblastic leukemia
(CALL) are controversial due to the lack of high-quality clinical
studies. Therefore, there are some controversies about the
effectiveness and safety of 6-TG at present. As a result, this
study evaluates the efficacy and safety of 6-TG in the substitute of
6-MP as a maintenance drug to treat childhood acute
lymphoblastic leukemia through a comprehensive search of
related studies. This study will draw a scientific and practical
conclusion through a systematic review.
Author contributions
Conceptualization: Liang Chen, Wen-Xin Chen.
Data curation: Huai-Xiu Yan, Xiao-Wei Liu.
Formal analysis: Liang Chen, Huai-Xiu Yan.
Funding acquisition: Wen-Xin Chen.
Methodology: Liang Chen, Huai-Xiu Yan.
Software: Huai-Xiu Yan, Xiao-Wei Liu.
Writing –original draft: Liang Chen, Huai-Xiu Yan, Xiao-Wei
Liu.
Writing –review & editing: Wen-Xin Chen.
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