Pharmacogenomic Study Of Adverse Reactions After High Dose Chemotherapy With Methotrexate

Purpose The aim of the present study was to investigate the risk factors of adverse reactions during high dose methotrexate(HD-MTX)chemotherapy in children with acute lymphoblastic leukemia(ALL),and to establish a predicted model of adverse reactions of HD-MTX in order to provide evidence for the precise treatment of methotrexate(MTX).Methods Children with ALL who received HD-MTX chemotherapy were included in the present study.Clinical data of the children were collected and 38 single nucleotide polymorphisms associated with MTX metabolism and transport were detected by sequenom Mass ARRAY SNP technique.The grade of adverse reactions was identified according to the National Cancer Institute common adverse reaction evaluation criteria Version 5.0.Firstly,the correlation between MTX adverse reactions and polymorphism was analyzed.Secondly,binomial logistics regression analysis was used to investigate the risk factors of MTX adverse reactions and establish risk prediction models.Results Among the enrolled 335 children with ALL,308 cases(91.94%)were lymphocyte type B and 27 cases(8.06%))were lymphocyte type T,while 51 cases(15.22%)of liver damage,5 cases(1.49%)of renal impairment,293 cases(87.46%)of myelosuppression,11 cases(3.28%)of mucositis,and 52 cases(15.52%)of gastrointestinal reaction.1.Plasma concentration at 44 and 68 hours after HD-MTX chemotherapy was correlated with the occurrence of renal impairment,myelosuppression and gastrointestinal reaction.2.Dihydrofolate reductase(DHFR)rs1650697 was associated with elimination delay of MTX at 44 h after HD-MTX chemotherapy.γ-glutamyl hydrolase(GGH)rs719235,DHFR rs1650697 and methionine synthase(MTR)rs1805087 were associated with elimination delay of MTX at 68 h after HD-MTX chemotherapy.3.Adenosine triphosphate-binding cassette transporters C2(ABCC2)rs2273697 and organic anion transporting polypeptides 1B1(SLCO1B1)rs2306283 were associated with liver damage after HD-MTX chemotherapy,while GGH rs11545078 and ITPA rs1127354 were associated with myelosuppression after HDMTX chemotherapy.4.The dose of MTX was an independent risk factor for liver and renal damage.The area under the receiver-operating characteristic curve(ROC)of the risk prediction model of liver and renal damage were 0.625(95% CI 0.545,0.705)and 0.932(95%CI 0.843,1.000),respectively.Risk grade of ALL,inosine triphosphate pyrophosphatase(ITPA)rs1127354 and methylenetetrahydrofolate dehydrogenase1(MTHFD1)rs2236225 were independent risk factors of myelosuppression.The area under the ROC of the risk prediction model containing these three influencing factors was 0.738(95% CI 0.657,0.818).Gender and 44-hour MTX plasma concentration were independent risk factors for gastrointestinal reactions,and the area under the ROC of the prediction model containing these two factors was 0.752(95% CI 0.683,0.821).No clinical and pharmacogenomic risk factors for mucositis were found in ALL children.Conclusion1.Routinely monitoring of 44-hour and 68-hour plasma concentrations of MTX in children with ALL is of great significance in predicting adverse reactions of MTX.2.DHFR rs1650697,GGH rs719235,DHFR rs1650697 and MTR rs1805087 can be used as predictors of MTX elimination delay.3.ABCC2 rs2273697 and SLCO1B1 rs2306283 can be used as predictors of liver damage in MTX,while GGH rs11545078 and ITPA rs1127354 can be used as predictors of myelosuppression in MTX.4.The dose of MTX was an independent risk factor for renal damage.Risk grade of ALL,ITPA rs1127354 and MTHFD1 rs2236225 were independent risk factors for myelosuppression.Gender and 44-hour MTX plasma concentration were independent risk factors for MTX gastrointestinal reactions.The prediction model of MTX renal damage,myelosuppression and gastrointestinal reactions including the above influencing factors has good predictive efficacy and can be used in clinical practice.