Clinical and pharmacogenetics factors as therapeutic predictors in pediatric acute lymphoblastic leukemia

Background. Current protocols for pediatric acute lymphoblastic leukemia (ALL) are multicomponent, risk-adapted regimens in which high-dose (1–5 g / m2) methotrexate (MTX) is central. This drug has led to high long-term survival rates in children with ALL. Predicting the efficacy of the treatment given to further increase survival with minimization of toxic complications determines the relevance of pharmacogenetic studies to identify predictive biomarkers, implementing the personalized approach, which is essential for the development of modern practical medicine.
Aim. To identify predictors of ALL therapy outcomes using pharmacogenetic biomarkers and clinical data.
Materials and methods. A prospective analysis of pediatric ALL treatment outcomes was performed in a single-center observational (cohort) study. The analysis included 124 ALL patients who were treated according to the modern BFM (Berlin–Frankfurt–Munster) protocols with high-dose MTX. Treatment outcomes were compared with genetic polymorphisms of the ABCB1 gene, which is responsible for drug clearance (including MTX). Real-time polymerase chain reaction was used to study ABCB1 gene polymorphisms in peripheral blood. Statistical analysis of the influence of pharmacogenetic biomarkers was performed using SPSS Statistics 26.0 program (USA). To construct prognostic models, we used the method of logistic function construction by binary logistic regression with stepwise selection of factors and, if necessary, additional construction of ROC-curves with subsequent ROC-analysis. Differences were considered significant at p <0.05; at p ≥0.05, differences were considered unlikely and not statistically significant.
Results. According to the conducted complex analysis of high-dose MTX therapy efficacy and safety, 3 reliable (p <0.001) prognostic models with high sensitivity, specificity, and efficiency (>70 %) were developed, demonstrating interrelations of clinical and genetic factors influencing adverse outcomes of MTX therapy in children with ALL, which confirms the necessity of pharmacogenetic testing implementation in real clinical practice. Conclusion. Determination of polymorphisms of genes involved in transport and metabolism of cytostatic drugs should be introduced into clinical practice in order to further increase patient survival rates while reducing adverse effects of antitumor treatment.

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