Efficacy and association analysis of high‑dose methotrexate in the treatment of children with acute lymphoblastic leukemia
- Authors:
- Published online on: March 8, 2019 https://doi.org/10.3892/ol.2019.10128
- Pages: 4423-4428
Abstract
Introduction
Acute lymphoblastic leukemia (ALL) has an extremely rapid progression and is more common in children aged 3–7 years (1). According to statistics, ALL accounts for ~80% of leukemia, and this number is rising year by year (2). Data show that, in 2016, the number of new ALL patients in the world exceeded 2.1 million, and the cumulative number of patients reached >300 million (3,4). Because of the rapid progression of ALL, there is a high probability of death caused by the absence of effective treatment within 5–10 days after its onset (5). As there are no obvious special symptoms in the early stages of ALL, many patients often miss the best treatment period because of limited medical general knowledge or because they are misdiagnosed, which is also one of the key problems that lead to poor long-term prognosis in ALL (6). It has been reported that the 5-year survival rate of the prognosis of ALL patients corresponds to only 20–40% (7). Because of its high incidence and high risk, ALL has been included in the key research of disease, but its pathogenesis has not yet obtained breakthrough research results. In clinic, methotrexate (MTX) is the most common drug in the treatment of leukemia, lymphadenoma, osteosarcoma and other autoimmune diseases (8).
MTX, an oncology drug of antifolate metabolism, that has a similar chemical structure to folic acid and can inhibit DNA synthesis by inhibiting the activity of dihydrofolate reductase in cells, has been proven to have a high application value in ALL (9–11). With the deepening of research, an increasing number of scholars worldwide consider that the efficacy of high-dose MTX in the treatment of ALL is more significant (12–14). However, most of the current studies are limited to the wide application of MTX, and there is little research on the exact effect of MTX in the treatment of ALL patients with different subtypes and different disease courses. Since 2014, the People's Hospital of Pingyi County (Linyi, China) has begun to promote the use of MTX in clinical practice as the first choice for the treatment of ALL, and has accumulated a large number of sample cases. Therefore, by comparing efficacy differences of high-dose MTX in ALL patients with different subtypes and disease courses, the efficacy of high-dose MTX in the treatment of ALL was studied in depth to provide reference and guidance for clinical practice.
Patients and methods
Patients
A retrospective analysis of 207 children with ALL, treated with high-dose MTX in The People's Hospital of Pingyi County from March 2014 to June 2017, was carried out, including 124 males and 83 females, with an age range of 3–11 years and an average age of 6.13±3.27 years. Inclusion criteria: children conforming to the clinical manifestations of ALL (15) and diagnosed with ALL in the People's Hospital of Pingyi County; children with complete data; children not receiving related medical treatment in other hospitals. Exclusion criteria: children unwilling to receive relevant medical treatment; children allergic to drugs; children with other serious cardiovascular diseases or tumors; children with severe liver and renal insufficiency; children with communication or cognitive impairment. This study was approved by the Ethics Committee of the People's Hospital of Pingyi County. Guardians of the patients signed informed consent and agreed that the tissue of the patient could be used in this study, and cooperated with the medical staff to complete the diagnosis and treatment.
Main reagents
MTX was purchased from Beijing Baiaolaibo Technology Co., Ltd., Beijing, China (cat. no. QN0838-IKA). Dexamethasone was purchased from Hubei Yuancheng Saichuang Technology Co., Ltd., Wuhan, China (cat. no. 50-02-2). Cytosine arabinoside was purchased from Shanghai Baoman Biotechnology Co., Ltd., Shanghai, China (cat. no. N0072). Calcium formyltetrahydrofolate (CF) was purchased from Shanghai Yijing industrial Co., Ltd., Shanghai, China (cat. no. 151533-22-1).
Methods
All patients received chemotherapy according to the 2013 Leukemia Diagnosis and Treatment Guidelines (16). Intravenous infusion of 1/6 of the total amount of MTX (≤500 mg each time) was performed within 30 min, and the remaining 5/6 was administered within 24 h. A triple sheath injection was performed 1 h after the infusion of the first 1/6 MTX (including MTX 12.5 mg, dexamethasone 5 mg, cytosine arabinoside 35 mg). CF rescue (15 mg/m2) was performed after 12 h of complete infusion of MTX, and in the case of delayed excretion, the number and dose of CF rescue were increased. Sufficient hydration (3 l/m2) and urine alkalization (pH >8) were conducted on the same day and 3 days after administration. The changes of the vital signs in children were monitored during chemotherapy. Venous blood (2 ml) was drawn in the anticoagulant tube on an empty stomach at 12 h (T1), 48 h (T2), 72 h (T3) after infusion, and separated by centrifuging at 2,500 × g for 15 min at 4°C to collect serum. The concentration of MTX in the serum of children and the adverse reactions were determined by Siemens Viva-E automatic drug concentration monitoring system (Siemens AG, Munich, Germany), including bone marrow suppression, gastrointestinal reaction and liver function injury.
Statistical analysis
SPSS 24.0 software (Beijing Strong Vinda Information Technology Co., Ltd., Beijing, China) was used for statistical analysis. The clinical enumeration data of children with different subtype of ALL and different course of disease were expressed as percentage [n (%)] and analyzed using χ2 test. The measurement data were expressed as mean ± standard deviation and t-test was used for their comparison. F analysis was used to compare the differences between multiple groups. LSD test was used as a post hoc test. P<0.05 was considered to indicate a statistically significant difference.
Results
Comparison of clinical data of ALL children with different subtypes
Of the 207 children, there were 128 cases of B-lineage (B-lineage group) and 79 cases of T-lineage (T-lineage group). There was no significant difference between the two groups of patients regarding the clinical data of age, body weight, living environment, whether he/she was the only child, whether there was a family history of hereditary disease, and whether it was the first onset (P>0.05), proving that the two groups of patients were comparable (Table I).
Comparison of plasma concentration and CF rescue times in ALL children with different subtypes
There was no significant difference in plasma concentration between the two groups at T1 (P>0.05). The plasma concentration in B-lineage group (1.86±2.17 µmol/l) was significantly higher than that in T-lineage group (1.12±2.18 µmol/l) at T2 (P<0.05). The plasma concentration in B-lineage group (0.83±1.57 µmol/l) was also significantly higher than that in T-lineage group (0.62±1.24 µmol/l) at T3 (P<0.05). The plasma concentration at T2 was significantly lower than that at T1, and at T3 was lower than that at T2 in both groups (P<0.05). There was no significant difference in CF rescue times between B-lineage group (8.17±4.58 times) and T-lineage group (8.26±5.03 times) (P>0.05) (Figs. 1 and 2).
Comparison of adverse reactions in ALL children with different subtypes
The incidence of adverse reactions in children with ALL in B-lineage group was significantly higher than that in the T-lineage group, and the difference was statistically significant (P<0.05) (Table II).
Comparison of clinical data of children with different disease courses
According to the disease course, the children were divided into three groups. High-risk group: disease course >15 days (n=67); moderate-risk group: disease course >8 and <15 days (n=58); low-risk group: disease course <8 days (n=82). There was no significant difference between the three groups in the clinical data of age, body weight, living environment, whether he/she was the only child, whether there was a family history of hereditary disease, and whether it was the first onset (P>0.05), confirming that the three groups of patients were comparable (Table III).
Comparison of plasma concentration and CF rescue times in children with different disease courses
There was no significant difference in plasma concentration at T1, T2 and T3 between the three groups (P>0.05). The plasma concentration at T2 was lower than that at T1, and at T3 was lower than that at T2 in the three groups, and the differences were statistically significant (P<0.05). The CF rescue times in high-risk group (9.57±5.16 times) were more than that in moderate-risk group (7.63±4.66 times) and low-risk group (6.37±3.58 times), and the differences were statistically significant (P<0.05) (Figs. 3 and 4).
Comparison of adverse reactions in children with different disease courses
The incidence of a gastrointestinal reaction, skin allergic reaction and respiratory tract reaction, as well as the adverse reaction rate in the high- and moderate-risk groups were significantly higher than that in the low-risk group (P<0.05). Also, the adverse reactions rate in the high-risk group was significantly higher than that in the low-risk group (P<0.05) (Table IV).
Discussion
As an antifolate metabolite, MTX combined with dihydrofolate reductase can inhibit the conversion of dihydrofolic acid to tetrahydrofolic acid, block the synthesis of pyrimidine and purine, inhibit the synthesis of DNA, thus achieving an antitumor effect (17). MTX is usually not able to penetrate the blood-brain barrier and is difficult to be detected in cerebrospinal fluid during tumor therapy (18). To achieve the goal of treating leukocyte, the concentration of MTX in cerebrospinal fluid needs to be >107 µmol/l, at which time the inhibitory effect on the synthesis of DNA in leukemic cells could be completed (19). Therefore, the dosage of MTX needs to be increased. When MTX is highly concentrated and continuously injected into the patient's body, it can enter the cells through the reductive folate carrier on the cell membrane, thus affecting leukemic cells (20). MTX can affect leukemic cells, but also produce toxicity to normal cells of patients, so it is necessary to carry out CF rescue in the treatment of MTX (21), which can reduce the toxicity of MTX and increase the effectiveness of the treatment by providing tetrahydrofolate coenzyme to the normal cells of the patient (22).
In the present study, the analysis on the efficacy differences of high-dose MTX in ALL patients with different subtypes and disease courses showed that the plasma concentration of B-lineage ALL children with different subtypes is significantly higher than that of T-lineage ALL children after 48 h of MTX infusion, and the incidence of adverse reactions of B-lineage ALL children is significantly higher than that of T-lineage ALL children, which indicates that MTX is less toxic and more suitable for T-lineage ALL children. The reason is presumed to be that methylene tetrahydrofolate reductase and γ-glutamyl transferase are very important metabolites during the treatment of MTX, and the higher their expression, the better metabolic circulation conditions of MTX in children (23). B-lineage ALL originates from B-lineage lymphocytes that are mainly distributed in human plasma, and belong to the first line of defense (24). The onset of B lymphoid causes the patient's plasma antibody ability to be in an extremely poor condition, and then the toxicity caused by the injection of MTX begins to invade the patient's blood, but the blood tissues cannot resist the toxicity of MTX and could only be counteracted by the injection of CF. Therefore, the toxic effect of MTX in vivo is greater than its metabolic effect, which results in higher plasma concentration in patients with B-lineage ALL. T-lineage ALL originates from T-lineage lymphocytes that are mainly distributed in the cell membrane and play a role in immune metabolism through surface antigen and surface receptor (25). Therefore, the immune metabolic function of B cells in patients can form the first filter device after the MTX injection, and the toxicity of MTX can be eliminated completely after CF injection, which indicates that MTX can directly undergo metabolic reactions for effective treatment after entering the cells of the patient. The results of Conter et al (26) in the study of high-dose MTX in ALL patients are consistent with this experiment. Among patients with different disease courses, we found that there is no significant difference in plasma concentration among the three groups at different time-points. Also, the adverse reaction rate in the high-risk group was found to be significantly higher than that in moderate- and low-risk groups, and in the moderate-risk group was significantly higher than that in the low-risk group. Moreover, the CF rescue times in high-risk group were found to be more than that in the other two groups, which suggested that high-dose MTX is more toxic to children with more severe disease. The cause may be that the disease course in the high-risk group is significantly higher than that in the other two groups, and the internal environment of children is severely damaged by leukemic cells, and is totally unable to resist the incidental toxicity of MTX injected into the body, and only continuous CF rescue can neutralize the efficacy of MTX. Therefore, more attention should be paid to children with serious ALL in clinic. The vital signs of children should be paid close attention in order to prevent the toxic effect of MTX treatment from being greater than its efficacy and having a negative effect on the children.
The purpose of this study was to analyze the efficacy differences of high-dose MTX in ALL children with different subtypes and disease courses. However, because of the limited experimental conditions, there are still some shortcomings, such as the small base of the study subjects for statistical analysis. Also there may be differences in the results among different ethnic and age groups. Thus, further studies are still needed.
In conclusion, compared with T-lineage ALL children, high-dose MTX caused more toxic injury to B-lineage ALL children. During clinical application of MTX in the treatment of ALL, close attention should be paid to the changes of vital signs of patients, and timely CF rescue should be performed.
Acknowledgements
Not applicable.
Funding
No funding was received.
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Authors' contributions
FG and QM were responsible for the treatment of the patients. CL and YZ analyzed the patient data and revised the manuscript. FG drafted the manuscript. All authors read and approved the final manuscript.
Ethics approval and consent to participate
This study was approved by the Ethics Committee of the People's Hospital of Pingyi County (Linyi, China). Signed informed consents were obtained from the guardians of the patients.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
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