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

Abstract

Objective: 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.Methods: 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 RFC1, SLCO1B1, ABCB1, FPGS, GGH, MTHFR, DHFR, TYMS, and ATIC. 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.Results: In total, 34 studies with 4102 subjects were identified for the association analysis. Nine SNPs involving MTHFR, RFC1, ABCB1, SLCO1B1, TYMS, FPGS, and ATIC genes were investigated, while none of studies reported the polymorphisms of GGH and DHFR yet. Two SNPs were statistically associated with the increased risk of HDMTX toxicity: MTHFR 677C>T 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); ABCB1 3435C>T 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: TYMS 2R>3R and mucositis (dominant, OR=0.66, 95% CI=0.47–0.94); RFC1 80A>G and hepatotoxicity (recessive, OR=0.35, 95% CI=0.16–0.76); and MTHFR 1298A>C 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.Conclusions: We conclude that genotyping of MTHFR and/or ABCB1 polymorphisms prior to treatment, MTHFR 677C>T particularly, is likely to be potentially useful with the aim of tailoring HDMTX therapy and thus reducing toxicity in patients with hematological malignancies.

Pharmacogenomic Profile of Amazonian Amerindians

“…The MTHFR gene has two main variants: the rs1801133 and rs1801131. A recent meta-analysis evaluating 34 studies showed that both variants are statistically associated with toxicities during high-dose methotrexate treatment; the rs1801133 was positively associated with increased risk of hepatotoxicity, mucositis, and renal toxicity, while the rs1801131 showed a decreased risk of renal toxicity during the therapy [ 45 ]. Concerning fluoropyrimidine-based treatments, results involving these variants are conflicting: while Campbell and colleagues found significant associations of rs1801133 and rs1801131 with a higher frequency of nonhematologic toxicity (nausea/vomiting), a protective effect for neutropenia, and global toxicity [ 46 ], Zhong and collaborators found no significant association between both polymorphisms and the clinical response to fluoropyrimidine-based chemotherapy under any of the three genetic models (allele model, dominant model, and recessive model) [ 47 ].…”

Genetic polymorphisms and clinical parameters associated with renal toxicity in Thai hematologic malignancy patients receiving high dose methotrexate

“…Forty-two polymorphisms of 25 genes were analyzed including ARID5B (rs10994982) , ADORA2A (rs5751876) , ADORA3 (rs1544223 , rs2298191, and rs3394), ADA (rs244076) , ATIC (rs12995526 , rs16853834, rs16853826, rs2372536, rs4673990, rs4673993, and rs7563206), BIRC5 (rs9904341) , C1orf167 (rs1801131), DDRGK1 (rs2295553) , DHFR (rs1643650 and rs7387), FPGS (rs1544105) , GSK3B (rs3732361) , GGH (rs11545078) , HLA-E (rs1264457) , IL12B (rs3212227) , ITPA (rs1127354) , KLRC1 (rs2734414 , rs2734440, and rs7301582), MIR5189 (rs56292801) , MROH2A (rs10929303) , MTHFD1 (rs2236225), MTHFR (rs1476413 and rs1801133) , MTR (rs1805087) , MTRR (rs162040 and rs1801394), NR1I2 (rs3814055 , rs6785049, and rs7643038), PTPRM (rs6506569) , and TYMS (rs2244500, rs2847153, and rs699517) by the MassARRAY ® system (Agena Bioscience, USA) at the Center of Excellence in Clinical Pharmacokinetics and Pharmacogenomics, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand. These genes were chosen from those that play important role in the MTX pathway and variants were found to pose some clinical significance 2 , 5 – 7 , 9 . The relationship between the MTX pathway and related pharmacogenomics is summarized in Fig.…”

“…Methotrexate (MTX) is an effective chemotherapy for the treatment of various hematologic malignancies, including primary central nervous system (CNS) lymphoma, diffuse large B-cell lymphoma, Burkitt lymphoma, extranodal NK/T-cell lymphoma, and acute lymphoblastic leukemia (ALL) 1 , 2 . As a folic acid antagonist, MTX inhibits the dihydrofolate reductase enzyme that catalyzes the conversion of dihydrofolate to tetrahydrofolate, an active form of folic acid that is crucial for the synthesis of deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), resulting in the cytotoxic effect.…”

“…Several previous studies focused on host genetic factors involved in the MTX metabolism pathway 5 . Example variants of MTHFR C677T (rs1801133), ABCB1 C3435T (rs1045642), and SLCO1B1 (rs11045879), and MTRR (rs1801394) were reported to be associated with MTX toxicity in hematologic malignancy conditions 2 , 6 , 7 . MTX is also used in autoimmune diseases.…”

Novel genomic variants influencing methotrexate delayed excretion in pediatric patients with acute lymphoblastic leukemia

“…Therefore, many studies have tried to explain the interindividual variability in the pharmacokinetics and pharmacogenomics of MTX [4,5]. However, most previous studies were conducted based on candidate gene panel analyses with a few genes or mutations related to the folate pathway or transporter genes.…”