Correlation between blood methotrexate concentrations at 24 hours after the initiation of high-dose methotrexate infusion and clinical outcomes in patients with hematologic neoplasms: a meta analysis

Objective To evaluate the association between blood methotrexate concentrations at 24 hours (C24 h) after the initiation of high-dose methotrexate (HDMTX) infusion and clinical outcomes in patients with hematologic neoplasm. Methods The literature on C24 h after the initiation of HDMTX treatment and clinical outcomes in MEDLINE (Ovid), EMBASE (Ovid), Clinical Trials. gov, CNKI, WanFang Data, and SinoMed databases up to March 2018 were retrieved (the outcome indicators mainly included safety indicators, such as adverse event incidence and effectiveness indicators, such as complete remission rate). The quality of the enrolled literature was evaluated by Newcastle-Ottawa Scale (NOS) and related outcome indicators were analyzed by meta-analysis or descriptive analysis. Results A total of 6 studies were enrolled, including 4 with high quality (NOS scores were 7-9) and 2 with medium quality (both of NOS scores were 6). All the subjects in the 6 studies were children with acute lymphoblastic leukemia (ALL), aged 0.4 to 17.0 years, and a total of 516 HDMTX treatments were given to them. Five studies reported the association between methotrexate C24 h and safety outcomes and 1 reported the association between methotrexate C24 h and effectiveness outcomes. For safety outcomes, compared with C24 h 10 μmol/L might increase the risk of hematological toxicity (OR=4.17, 95%CI: 1.17-14.90) rather than the risks of gastrointestinal toxicity (OR=2.22, 95%CI: 0.97-5.04), renal toxicity (P=0.130), oral mucositis (P=0.166), or dermal toxicity (P=0.227). Compared with C24 h 40 μmol/L might increase the risks of hepatotoxicity (OR=16.64, 95%CI: 6.35-43.64), oral mucositis (OR=31.73, 95%CI: 12.37-81.41), severe oral mucositis (P=0.002), and gastrointestinal toxicity (P=0.003). For effectiveness outcomes, the single study suggested that methotrexate C24 h>16 μmol/L could increase the complete and partial remission rates (P<0.05 for both) and decrease the 1.5 year-recurrence rate (P=0.006). Conclusions There was a significant association between methotrexate C24 h and clinical outcomes in children with ALL. Methotrexate C24 h>16 μmol/L was significantly associated with a favorable clinical outcome while C24 h>40 μmol/L was significantly associated with increased risks of hepatotoxicity, oral mucositis, and gastrointestinal toxicity. Key words: Methotrexate; Hematologic neoplasms; Drug monitoring; Drug toxicity; Treatment outcome; Meta-analysis; Blood drug concentration