| Objective:The purpose of this study was to analyze the gene polymorphisms related to methotrexate(MTX)metabolism in children with acute lymphoblastic leukemia(ALL).To study the correlation between MTX and adverse reactions in different periods of MTX treatment in children with ALL,and to analyze the differences of adverse reactions in the maintenance period of MTX therapy in different ways.To guide the clinical medication of MTX in children with ALL,so as to reduce the adverse reactions and guide the individualized treatment.Methods:A total of 86 children diagnosed with ALL in the Pediatric Hematologic Oncology Department of Qingdao University Affiliated Hospital from September 2020 to September 2022 and treated according to the CCCG-ALL2020 protocol of China Pediatric Cancer Cooperative Group were selected as the study subjects.The general data of ALL children were collected,and the polymorphism of ATP-binding box transporter B1(ABCB1)and methylenetetrahydrofolate reductase(MTHFR)gene were detected by fluorescence quantitative PCR,and the adverse reactions of ALL children in different periods,namely,high-dose MTX(HD-MTX),maintenance treatment period,and different medication modes(oral administration group and intramural injection group)after MTX were recorded and graded.SPSS 26.0 statistical software was used to analyze the correlation between different genotypes and adverse reactions by Chi-square test.The adverse reactions and prognosis of different medication methods during the maintenance treatment period were compared.Results:1.General conditions: There were 50 males(58.1%)and 36 females(41.9%),with an average age of(8.43±1.49)years and an average body surface area(BSA)of(1.17±0.32)㎡.83 cases(96.5%)were B-ALL and 3 cases(3.5%)were T-ALL.There were 46 cases(53.5%)of low risk and 40 cases(46.5%)of medium and high risk.2.Polymorphisms of ABCB1 and MTFHR genes: ABCB1 C3435 T heterozygous mutant CT was the most common,accounting for 45.3%,CC wild type and TT mutant accounted for 38.4% and 16.3%,respectively.MTHFR C677 T heterozygous mutation CT was the most common,accounting for 51.2%,wild type CC and mutant TT accounted for23.3% and 25.5%,respectively.MTHFR A1298 C wild type AA was the most common,accounting for 73.3%,and the mutant AC and CC accounted for 22.1% and 4.6%,respectively.3.MTX-related adverse reactions: A total of 344 high-dose methotrexate(HD-MTX)were administered in 86 children,including 211(61.34%)drops in WBC,220(64%)drops in neutrophil,11(3.2%)drops in platelet,244(70.9%)drops in hemoglobin,137(39.8%)increases in alanine transaminase,102(29.7%)increases in aspartate transaminase,6(1.74%)increases in creatinine,22(6.4%)oral mucositis,and 159(46.2%)vomiting.One patient developed reversible posterior leukoencephalopathy,which was relieved after treatment.There was no death due to serious adverse events.A total of 1032 MTX treatments were observed in 86 children during the maintenance treatment period,including 201 times of leucopenia(19.47%),255 times of neutrophil reduction(24.71%),159 times of hemoglobin reduction(15.41%),18 times of platelet reduction(0.09%),and420 times of alanine aminotransferase increase(40.69%).There were 431(41.76%)cases of elevated aspartate aminotransferase,11(1.06%)cases of oral mucositis,and 216(20.93%)cases of vomiting.4.Relationship between gene polymorphism and adverse reactions: During HD-MTX,there were 48 times of mild neutropenia and 32 times of severe neutropenia in wild CC genotype of ABCB1 C3435 T,57 times of mild neutropenia and 83 times of severe neutropenia in CT+TT genotype.The risk of severe neutropenia in CT and TT genotypes was higher than that in wild type(P < 0.05).In MTHFR C677 T,the children with CT and TT genotypes had a significantly higher risk of severe leukopenia and neutropenia than those with CC genotype(P < 0.05).There was no significant difference in adverse reactions among MTHFR A1298 C genotypes(P > 0.05).The higher the number of gene mutations,the higher the risk of severe leukopenia.There was no significant difference between the three gene polymorphisms and adverse reactions during the maintenance period.5.The relationship between gene polymorphism and delayed MTX metabolism:MTX C44 h had 97 metabolic delays,among which CC and CT+TT genotypes in ABCB1C3435 T had 32 and 65 metabolic delays,respectively.There were 27 CC and 70 CT+TT genotypes in MTHFR C677 T.There were 67 AA and 30 AC+CC genotypes in MTHFR A1298 C.MTX C68 h had 137 metabolic delays,among which the CC and CT+TT genotypes of ABCB1 C3435 T had 57 and 80,respectively.There were 28 CC and 109CT+TT genotypes in MTHFR C677 T.There were 104 AA and 33 AC+CC genotypes in MTHFR A1298 C.There was no significant difference in metabolic delay between C44 h and C68 h genotypes(P > 0.05).6.The difference of MTX administration methods: In the maintenance treatment of MTX,there were 293 cases of mild alanine aminotransferase and 31 cases of severe alanine aminotransferase in the oral group,and 93 cases of mild alanine aminotransferase and 3 cases of severe alanine aminotransferase in the intramuscular injection group,the difference was statistically significant(P < 0.05).There was no significant difference in bone marrow suppression and gastrointestinal injury between the two groups(P > 0.05).The weekly cost of oral group was higher than that of intramuscular group.In terms of medication acceptance,some children in the two groups had mild resistance,but the compliance was good,and there was no drug leakage due to resistance.The children in the two groups discontinued the drug because of low blood count,abnormal liver function and other reasons,and the difference was not statistically significant(P > 0.05).There was 1 case of bone marrow recurrence in the intramuscular injection group and no recurrence in the oral group.There was no significant difference in the prognosis between the two groups(P > 0.05).Conclusions:1.During HD-MTX,the T allele carriers of ABCB1 C3435 T and MTHFR C677 T were more likely to have severe neutropenia,and the latter were more likely to have severe leucopenia.2.During HD-MTX,children with more MTX metabolism-related gene mutations were more likely to have severe leukopenia.3.MTX metabolism-related gene polymorphisms were not associated with delayed HD-MTX metabolism.4.There was no significant correlation between ABCB1 C3435 T,MTHFR C677 T,A1298C gene polymorphisms and adverse reactions of low dose MTX in maintenance period.5.During the maintenance treatment period,intramuscular administration of MTX reduced the risk of severe elevation of alanine aminotransferase compared with oral administration,while there was no difference in the recurrence rate between the two administration methods. |
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