A prospective study of a simple algorithm to individually dose high-dose methotrexate for children with leukemia at risk for methotrexate toxicities

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/m2 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 Grade 1 acute kidney injury. This algorithm is a simple, safe and effective method for individualizing HDMTX in pediatric patients with ALL. NCT02076997.