Division of Pediatric Hematology and Oncology, Department of Pediatrics, Baylor College of Medicine, 6701 Fannin Street, MWT Suite 1510.00, Houston, TX, 77030, USA.
Department of Pediatrics, University of North Carolina, Chapel Hill, NC, USA.
Cancer Chemother Pharmacol. 2019 Feb;83(2):349-360. doi: 10.1007/s00280-018-3733-2. Epub 2018 Nov 28.
High-dose methotrexate (HDMTX) is critical to the successful treatment of pediatric acute lymphoblastic leukemia (ALL) but can cause significant toxicities. This study prospectively evaluated the effectiveness of a fixed algorithm which requires no real-time pharmacokinetic modeling and no previous patient exposure to HDMTX, to individualize HDMTX dosing for at-risk patients with the aim of avoiding methotrexate-related toxicities.
We developed a simple algorithm to individualize HDMTX infusions with 0-2 rate adjustments based on methotrexate levels during the infusion. This was a prospective, open-label, study; eligible patients were identified and referred by their oncologist.
Fifty-four evaluable cycles of HDMTX (5 g/m over 24 h) were administered to 22 patients. Blood samples were obtained in 21 patients to examine single nucleotide polymorphisms (SNPs) related to methotrexate disposition. Twelve (54.5%) subjects had a history of previous HDMTX toxicities including seven (31.8%) who previously required glucarpidase rescue and seven (31.8%) with an entry glomerular filtration rate < 80 ml/min/1.73 m. 107/110 (97.2%) of methotrexate levels were drawn properly and 100% of algorithm dosing instructions were performed correctly at the bedside. Thirty-five (64.8%) of all cycles and 24 of 33 (72.7%) cycles that required a dose-adjustment had an end 24-h methotrexate level (Cp) within our goal range of 65 ± 15 µM with only 3 (5.6%) resulting in Cp higher than goal. Grade 3/4 toxicities were rare; no patients developed > Grade 1 acute kidney injury.
This algorithm is a simple, safe and effective method for individualizing HDMTX in pediatric patients with ALL. CLINICALTRIALS.
NCT02076997.
大剂量甲氨蝶呤（HDMTX）是成功治疗小儿急性淋巴细胞白血病（ALL）的关键，但会引起明显的毒性。本研究前瞻性评估了一种固定算法的有效性，该算法不需要实时药代动力学建模，也不需要患者以前接触过 HDMTX，目的是为有风险的患者个体化 HDMTX 剂量，以避免与甲氨蝶呤相关的毒性。
我们开发了一种简单的算法，根据输液过程中的甲氨蝶呤水平，对 0-2 次速率调整的 HDMTX 输液进行个体化。这是一项前瞻性、开放标签的研究；符合条件的患者由其肿瘤学家确定并转介。
22 名患者共接受了 54 个可评估的 HDMTX 周期（5g/m，持续 24 小时）。21 名患者采集血样检测与甲氨蝶呤处置相关的单核苷酸多态性（SNP）。12 名（54.5%）患者有既往 HDMTX 毒性史，其中 7 名（31.8%）此前需要使用葡萄糖醛酸酶解救，7 名（31.8%）入组时肾小球滤过率<80ml/min/1.73m。110 次甲氨蝶呤水平中有 107 次（97.2%）抽取正确，100%的床边算法剂量调整正确。35 个（64.8%）周期和 33 个（72.7%）需要剂量调整的周期的终末 24 小时甲氨蝶呤水平（Cp）在我们的 65±15μM 目标范围内，只有 3 个（5.6%）Cp 高于目标值。3/4 级毒性少见；无患者发生>1 级急性肾损伤。
该算法是一种简单、安全、有效的个体化治疗 ALL 患儿 HDMTX 的方法。临床试验。
NCT02076997。
