A Risk Scoring Model for High-Dose Methotrexate-Induced Liver Injury in Children With Acute Lymphoblastic Leukemia Based on Gene Polymorphism Study

Abstract

A study on 70 acute lymphoblastic leukemia (ALL) children (age ≤16 years) treated with high-dose methotrexate (HD-MTX) in Sichuan Provincial People’s Hospital was conducted. The aim of the study was to establish a risk-scoring model to predict HD-MTX-induced liver injury, considering gene polymorphisms’ effects. Data screening was performed through t-test, chi-square test, and ridge regression, and six predictors were identified: age, MTRR_AA, MTRR_AG, SLCO1B1_11045879_CC, albumin_1 day before MTX administration, and IBIL_1 day before MTX administration (p < 0.1). Then, the risk-scoring model was established by ridge regression and evaluated the prediction performance. In a training cohort (n = 49), the area under the curve (AUC) was 0.76, and metrics including accuracy, precision, sensitivity, specificity, positive predictive value, and negative predictive value were promising (0.86, 0.81, 0.76, 0.91, 0.81, 0.88, respectively). In a test cohort (n = 21), the AUC was 0.62 and negative predictive value was 0.80; other evaluation metrics were not satisfactory, possibly due to the limited sample size. Ultimately, the risk scores were stratified into three groups based on their distributions: low- (≤48), medium- (49–89), and high-risk (>89) groups. This study could provide knowledge for the prediction of HD-MTX-induced liver injury and reference for the clinical medication.

Genetic basis of clinical variants of chemotherapy toxicity in children with acute lymphoblastic leukemia (literature review)

“…Детская онкологическая группа (COG) подтвердила результаты данного исследования на большей группе больных (2285 детей). Выявленный генетический вариант может объяснить возникновение стеатогепатита у детей, получающих лечение по поводу ОЛЛ, поскольку достоверно связан с биохимическими проявлениями гепатотоксичности [52,53].…”

“…В дополнение к ABCB1 генетический вариант в SLC19A1 был ассоциирован с гепатотоксичностью, обусловленной MTX. Например, исследование генов-кандидатов, проведенное в скандинавской группе детей, показало значительно более высокое повышение уровня АЛТ у пациентов, получавших терапию высокодозным MTX, с полиморфизмом SLC19A1 rs1051266 [23,52]. Хотя больные в этом исследовании получали разные химиотерапевтические препараты, гепатотоксичность была связана с MTX из-за известной значимой функции белка RFC при терапевтическом эффекте MTX.…”