Monitoring of 6-mercaptopurine metabolites and drug adverse reactions in children with acute lymphoblastic leukemia

Guo Jia; Zhou Yan-sheng; Tian Yun-jiao; Li Pei-ling; Ma Yan-yan; Zhao Dong-ju

doi:10.3969/j.issn.1672-8157.2025.02.027

Abstract：Objective To analyze the adverse drug reactions(ADRs)of 6-mercaptopurine(6-MP)in children with acute lymphoblastic leukemia(ALL)and to explore the relationship between the concentration of 6-MP metabolites and ADRs.Methods A total of 76 children who received maintenance treatment for ALL and developed ADRs in the First Af-filiated Hospital of Xinxiang Medical College from April 2019 to February 2024 were selected using a retrospective study method.The concentration of 6-MP metabolites in the blood collected from the children was detected by liquid chroma-tography-tandem mass spectrometry(LC-MS/MS).The relationship between the concentration of 6-MP metabolites and ADRs was analyzed by assessing the adverse reactions of the children.Results Among the 76 children with ALL,the low-risk group accounted for the highest proportion(48.68%)and the high-risk group accounted for the lowest proportion(18.42%).Most children were treated with the CCLC-2018 regimen(92.11%),and only a few were treated with the CCCG-2015 regimen(7.89%).Among them,the number of male children(50 cases,65.79%)was greater than that of female chil-dren(26 cases,34.21%)(χ2=7.613,P<0.05).Among 76 children with ALL,the number of children aged 1 to 6 years(53 cases,69.74%)was greater than that of children aged 7 to 14 years(23 cases,30.26%).All 76 children completed at least 3 weeks of oral drug treatment,and 65 children(85.53%)received continuous medication for 2 or more courses;only 11 children(14.47%)received continuous medication for 1 course.In terms of dosage,42 patients(55.26%)took 50 mg·m-2 mercaptopurine tab-lets combined with 20 mg·m-2 methotrexate tablets.There were 34 cases(44.74%)who took 65 mg·m-2 mercaptopurine tablets combined with 20 mg·m-2 methotrexate tablets.52 cases(68.42%)stopped the drug briefly(≤3 days)due to ADR or blood pattern fluctuation(such as white blood cells<2.0×109/L),and then resumed the drug.24 cases(31.58%)of pediatric pa-tients reduced their dosage due to cytotoxicity.Among the 148 ADRs,77 were of grade Ⅰ adverse reactions(52.03%),45 of grade Ⅱ adverse reactions(30.41%),22 of grade Ⅲ adverse reactions(14.86%),and 4 of grade Ⅳ adverse reactions(2.70%).Most of the ADRs involved hematological system(35.81%)and skin(24.32%).The blood routine test and liver and kidney function test revealed that 22 cases(28.95%)had bone marrow suppression,13 cases(17.11%)had liver damage,and 2 cas-es(2.63%)had weakened renal excretion function.The concentrations of 6-thioguanine nucleotides(6-TGNs)and 6-methyl-mercaptopurine(6-MMP)metabolites of 6-MP were measured.The concentrations of 6-MP,6-TGNs,and 6-MMP before and after myelosuppression and liver damage(before and after myelosuppression(3.26±0.85)mg·L-1,(0.52±0.10)mg·L-1,(0.36±0.12)mg·L-1,(2.87±0.95)mg·L-1,(0.28±0.09)mg·L-1,(1.57±0.45)mg·L-1;before and after liver damage(3.15±0.87)mg·L-1,(1.02±0.21)mg·L-1,(0.42±0.14)mg·L-1,(1.31±0.45)mg·L-1,(0.31±0.10)mg·L-1,(2.03±0.25)mg·L-1)showed significant differences(t=15.016,-12.295,-13.185,8.581,-6.809,-23.032,all P<0.05).The metabolism of 6-MP in children with alopecia was normal,and there was no significant difference in the concentrations of the two metabolites(6-TGNs and 6-MMP)between the alopecia group and the non-alopecia group(t=-1.956,-1.467,both P>0.05).When renal excretion weakened,the metabolism of 6-MP in children was normal,and there was no significant difference in the concentrations of the two metabolites(6-TGNs and 6-MMP)between the re-nal impairment group and the non-impairment group(t=-1.961,-0.105,both P>0.05).Among the 76 children who developed ADRs,67(88.16%)improved after drug suspension or symptomatic treatment.The other 7 children recovered slowly and gradually im-proved after further treatment.Two children(2.63%)died due to severe decrease in white blood cell and neutrophil counts and sepsis.Conclusion Children with ALL in this study are mainly male and aged between 1 and 6 years old.Common ADRs include bone marrow suppression,alopecia,and liver damage.Concentrations of both metabolites are not associated with alopecia but the 6-TGNs concentration is related to bone marrow suppression and the 6-MMP concentration is related to liver damage.The impact on renal function is slight but should be paid close attention to.The drug monitoring can be closely followed in clinical practice.