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Genetic factors involved in delayed methotrexate elimination in children with acute lymphoblastic leukemia
Author(s) -
Cheng Yu,
Chen Maohua,
Zhuang Qian,
Lin Bijuan,
Chen Yingying,
Yang Ling,
Liu Maobai,
Que Wancai,
Qiu Hongqiang
Publication year - 2021
Publication title -
pediatric blood and cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.116
H-Index - 105
eISSN - 1545-5017
pISSN - 1545-5009
DOI - 10.1002/pbc.28858
Subject(s) - slco1b1 , medicine , methotrexate , excretion , odds ratio , mucositis , single nucleotide polymorphism , pharmacology , genotype , gastroenterology , oncology , toxicity , biology , genetics , gene
Background Delayed excretion of methotrexate can lead to life‐threatening toxicity that may result in treatment cessation, irreversible organ damage, and death. Various factors have been demonstrated to influence the pharmacokinetic process of methotrexate, including genetic and nongenetic factors. Methods We investigated the genetic factors primarily related to the metabolic pathway of methotrexate in children with acute lymphoblastic leukemia with delayed elimination, defined as C 44‐48h ≥ 1.0μmol/L in this study. A total of 196 patients (delayed excretion group: 98; normal excretion group: 98) who received CCCG‐ALL‐2015 protocol after propensity score‐matched analysis were included in the study. Twenty‐eight target single‐nucleotide polymorphisms (SNPs) were analyzed by multiplex polymerase chain reaction and sequencing, and 25 SNPs were finally included in the study. Results The genotype distribution of SLCO1B1 rs2306283 SNP was different between the delayed and normal excretion groups. SLCO1B1 rs2306283 AA carriers had a significantly lower methotrexate C 44‐48h /D ratio than GG carriers in both groups. Furthermore, compared with the normal excretion group, SLCO1B1 rs2306283 AG and GG were risk factors for developing oral mucositis (odds ratio [OR]: 2.13; 95% confidence interval [CI]: 1.11‐4.08; P < .001), hepatotoxicity (OR: 2.12; 95% CI: 1.26‐3.56; P < .001), and myelosuppression (OR: 1.21; 95% CI: 1.04‐1.41; P = .005) in delayed excretion group. Conclusions The results from this study indicate the potential role of SLCO1B1 rs2306283 as a pharmacogenomic marker to guide and optimize methotrexate treatment for delayed elimination in children with acute lymphoblastic leukemia.