The Role of Genetic Polymorphisms in High-Dose Methotrexate Toxicity and Response in Hematological Malignancies: A Systematic Review and Meta-Analysis.

High-dose methotrexate (HDMTX) is a mainstay therapeutic agent for the treatment of diverse hematological malignancies, and it plays a significant role in interindividual variability regarding the pharmacokinetics and toxicity. The genetic association of HDMTX has been widely investigated, but the conflicting results have complicated the clinical utility. Therefore, this systematic review aims to determine the role of gene variants within the HDMTX pathway and to fill the gap between knowledge and clinical practice. Databases including EMBASE, PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), and the Clinical Trials.gov were searched from inception to November 2020. We included twelve single-nucleotide polymorphisms (SNPs) within the HDMTX pathway, involving , , , , , , , , and . Meta-analysis was conducted by using Cochrane Collaboration Review Manager software 5.3. The odds ratios (ORs) or hazard ratios (HRs) with 95% confidence interval (95% CI) were analyzed to evaluate the associations between SNPs and clinical outcomes. This study was performed according to the PRISMA guideline. In total, 34 studies with 4102 subjects were identified for the association analysis. Nine SNPs involving , , , , , , and genes were investigated, while none of studies reported the polymorphisms of and yet. Two SNPs were statistically associated with the increased risk of HDMTX toxicity: and hepatotoxicity (dominant, OR=1.52, 95% CI=1.03-2.23; recessive, OR=1.68, 95% CI=1.10-2.55; allelic, OR=1.41, 95% CI=1.01-1.97), mucositis (dominant, OR=2.11, 95% CI=1.31-3.41; allelic, OR=1.91, 95% CI=1.28-2.85), and renal toxicity (recessive, OR=3.54, 95% CI=1.81-6.90; allelic, OR=1.89, 95% CI=1.18-3.02); and hepatotoxicity (dominant, OR=3.80, 95% CI=1.68-8.61), whereas a tendency toward the decreased risk of HDMTX toxicity was present in three SNPs: and mucositis (dominant, OR=0.66, 95% CI=0.47-0.94); and hepatotoxicity (recessive, OR=0.35, 95% CI=0.16-0.76); and and renal toxicity (allelic, OR=0.41, 95% CI=0.18-0.97). Since the data of prognosis outcomes was substantially lacking, current studies were underpowered to investigate the genetic association. We conclude that genotyping of and/or polymorphisms prior to treatment, particularly, is likely to be potentially useful with the aim of tailoring HDMTX therapy and thus reducing toxicity in patients with hematological malignancies.