Tsurusawa Masahito, Gosho Masahiko, Mori Tetsuya, Mitsui Tetsuo, Sunami Shosuke, Kobayashi Ryoji, Fukano Reiji, Tanaka Fumiko, Fujita Naoto, Inada Hiroko, Koh Katsuyoshi, Takimoto Tetsuya, Saito Akiko, Fujimoto Junichiro, Nakazawa Atsuko, Horibe Keizo
The Advanced Medical Research Center, Aichi Medical University, Aichi, Japan.
Division of Pediatric Oncology, National Center for Child Health and Development, Tokyo, Japan.
Pediatr Blood Cancer. 2015 Feb;62(2):279-284. doi: 10.1002/pbc.25305. Epub 2014 Oct 30.
Plasma monitoring of Methotrexate (MTX) levels is a standard approach to predict MTX-related toxicities in a high-dose (HD) MTX monotherapy for childhood acute lymphoblastic leukemia. However, it is uncertain whether plasma MTX levels can predict MTX-related toxicity in the HDMTX plus additional chemotherapy for childhood B-cell nonHodgkin lymphoma (B-NHL).
To statistically analyze the relationship between MTX pharmacokinetic parameters and MTX-related toxicities, we collected data from patients with delayed MTX elimination (≥1 µM at 48 hr and/or ≥0.5 µM at 72 hr) in the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) BNHL 03 study. Blood MTX levels were measured at 24, 48, and 72 hr after 3 or 5 g/m HD-MTX administration for 24 hr.
Three hundred and four patients received 2-4 courses of the HDMTX plus additional chemotherapy, and delayed MTX elimination was observed in 165 courses of 127 patients. In those, nephrotoxicity was significantly correlated with plasma MTX levels for each patient (P = 0.03), and also for each course (P = 0.009), but no other toxicities were correlated. Another analysis according to HDMTX courses showed no significant correlation between the first high plasma MTX levels and subsequent MTX levels in later course. It also showed that incidence of liver and gastrointestinal toxicities was most frequent in the first HDMTX course, and then sharply decreased in later courses (P < 0.001).
Our results suggest that plasma MTX level is not a reliable predictor for adverse events except for nephrotoxicity in multiple HDMTX therapy courses in childhood B-NHL. Pediatr Blood Cancer 2015;62:279-284. © 2014 Wiley Periodicals, Inc.
在儿童急性淋巴细胞白血病的大剂量甲氨蝶呤（MTX）单药治疗中，监测血浆MTX水平是预测MTX相关毒性的标准方法。然而，在儿童B细胞非霍奇金淋巴瘤（B-NHL）的大剂量MTX联合其他化疗方案中，血浆MTX水平能否预测MTX相关毒性尚不确定。
为了统计分析MTX药代动力学参数与MTX相关毒性之间的关系，我们收集了日本儿童白血病/淋巴瘤研究组（JPLSG）BNHL 03研究中MTX清除延迟（48小时时≥1μM和/或72小时时≥0.5μM）患者的数据。在给予3或5g/m²大剂量MTX持续24小时后，于24、48和72小时测量血MTX水平。
304例患者接受了2 - 4个疗程的大剂量MTX联合其他化疗，127例患者的165个疗程中观察到MTX清除延迟。在这些患者中，肾毒性与每位患者的血浆MTX水平显著相关（P = 0.03），与每个疗程的血浆MTX水平也显著相关（P = 0.009），但与其他毒性无关。根据大剂量MTX疗程进行的另一项分析显示，首个高血浆MTX水平与后续疗程中MTX水平之间无显著相关性。分析还显示，肝脏和胃肠道毒性的发生率在首个大剂量MTX疗程中最高，随后在后续疗程中急剧下降（P < 0.001）。
我们的结果表明，在儿童B-NHL的多个大剂量MTX治疗疗程中，除肾毒性外，血浆MTX水平并非不良事件的可靠预测指标。《儿科血液与癌症》2015年；62:279 - 284。©2014威利期刊公司。
