| Backgrounds:The incidence of acute lymphoblastic leukemia(ALL)ranks first in children's hematological malignancies.Methotrexate(MTX)is one of the main drugs for the treatment of children with ALL.Currently,high-dose methotrexate(HD-MTX)is the systemic consolidation treatment,prevention and treatment of extramedullary leukemia(central nervous system leukemia,Testicular leukemia).The occurrence of adverse reactions after the administration of HD-MTX is affected by a variety of factors.During the actual clinical treatment,there are large individual differences in the occurrence and extent of MTX adverse reactions.Serious adverse reactions may even suspend chemotherapy.Affecting the consistency of chemotherapy treatment may result in poor chemotherapy efficacy and increased risk of recurrence.Studies have shown that MTX-related drug metabolic enzyme gene polymorphism is closely related to the efficacy and adverse reactions of MTX.Therefore,the study of genes related to drug metabolic enzymes can reduce the adverse drug reactions while achieving the expected clinical efficacy,thereby better guiding clinical rational drug use.Objective:In this research,the genomic DNA of children was extracted to detect the genotypes of 68MTHFR,93MTHFR,62ABCB1 and other related genes.The adverse reactions after HD-MTX chemotherapy in ALL children were observed and the blood concentration of MTX was monitored.The correlation between gene polymorphism and MTX concentration and adverse reactions after chemotherapy was analyzed.In order to guide the individual treatment of MTX.Methods:1.Case data research object:a total of 100 children with ALL who were admitted to the Department of Hematology of Jiangxi Children's Hospital from January 2018 to December 2019(excluding recurrence)were selected.The inclusion criteria were set:all were examined by bone marrow cell morphology and Immunotyping and other tests confirmed that it was ALL,and the bone marrow showed complete remission after induction chemotherapy(VDLP+CAM),and there was no infection,gastrointestinal reaction,skin and mucous membrane damage in children before HD-MTX chemotherapy.Liver and kidney function examination showed no obvious abnormalities.2.Genotyping:peripheral blood was collected before the treatment with HD-MTX regimen,and the genotype distribution characteristics of the three sites MTHFR 677,MTHFR 1298 and ABCB1 3435 were statistically analyzed.3.Observation and analysis:the adverse reactions after HD-MTX chemotherapy in ALL children were observed and recorded,and the blood concentration of MTX was monitored and recorded at 44h;The correlation between each genotype and MTX side effect and MTX blood concentration was analyzed.Results:1.In the MTHFR gene locus,the C677T genotype detection results were dominated by mutated heterozygous CT.The A1298C genotypes in the MTHFR gene locus were detected with only two genotypes:AA homozygous(76 cases)and AC heterozygous(24 cases).In the ABCB1 gene locus,C3435T gene detection results were the most in the heterozygous CT.2.In the ALL children of this study,the adverse reactions after HD-MTX chemotherapy were mainly bone marrow suppression(100%),followed by gastrointestinal reactions(44%),liver toxicity(40%),skin and mucosa Damaged damage(28%),no renal toxicity;3.The differences of liver toxicity and mucosal damage in different MTX dose groups were statistically significant(P<0.001),and the liver toxicity and mucosal damage in the MTX dose group with 5g/m~2 were higher than those in the 3g/m~2 dose group.There was no statistical difference between the MTX dose groups in terms of kidney toxicity and gastrointestinal toxicity(P=1.000),and it was not considered that the kidney toxicity or gastrointestinal reaction rate of the MTX dose group with5g/m~2 was higher than that of the 3g/m~2 dose group.4.There are differences in liver toxicity and gastrointestinal reaction between different genotypes of MTHFR C677T gene locus.The risk of liver toxicity with MTHFR 677CC+CT genotype is significantly higher than TT.The hepatotoxicity risk of genotype CT is 5.490 times that of genotype TT(95%CI:1.398-21.563),and the hepatotoxicity risk of genotype CC is 3.215 times that of genotype TT(95%CI:1.009-10.247).,The gastrointestinal risk of genotype CT was 4.245 times that of genotype TT(95%CI:1.092-16.506).5.There was no statistically significant difference between MTHFR A1298C genotypes and liver toxicity,bone marrow suppression,gastrointestinal reaction and skin and mucosal damage(P>0.05).6.There are differences in skin and mucosal damage between different genotypes of the gene locus ABCB1 C3435T,and the risk of skin and mucosal damage with ABCB1 3435CC+CT genotype is significantly higher than TT.The risk of skin and mucosal damage in genotype CT is 5.919 times(95%CI:1.714-20.442)genotype TT,and 9.009 times(95%CI:2.500-32.465)genotype CC.;7.There was no statistical difference between the polymorphism of gene loci MTHFR C677T,MTHFR A1298C and ABCB1 C3435T and the concentration of MTX drug(umol/L)(?2=1.11,P=0.680),and it cannot be considered that there is a correlation between the polymorphism of each gene locus and the MTX drug concentration.Conclusions:1.The liver toxicity and skin and mucosal damage of the MTX dose group of5g/m~2 were higher than that of the MTX dose group of 3g/m~2.Therefore,for patients with a dose of 5g/m~2,clinical attention should be paid to monitoring liver function indicators and mucosal protection.2.MTHFR C677T polymorphism was correlated with MTX side effects,and there were differences in liver toxicity and gastrointestinal reactions.There was a correlation between ABCB1 C3435T polymorphism and MTX side effects,and there were differences in mucosal damage.It is suggested that the MTHFR C677T polymorphism and ABCB1 C3435T polymorphism may become the predictive indicators of clinical MTX dose and adverse reactions after treatment.3.There was no significant difference in the correlation between gene loci MTHFR C677T,MTHFR A1298C,ABCB1 C3435T and delayed drug excretion during hd-mtx treatment.It has no guiding significance for additional clinical rescue. |
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