Consensus on Managing Delayed Methotrexate Elimination in High-Dose Therapy: Insights from the Middle East

Mubarak Al Manasour^1*Ahmed Absi²Ahmad Alhuraiji³Muhammad Faisal Khanani⁴Kayane Mheidly⁵Mohamed Elsaid⁶Mohamed Waleed Ballora⁷Murtadha Al-Khabori⁸Naser Al Zain⁹Nisreen Khalifa¹⁰Rawad Rihani¹¹Shaker Abdallah¹²Yasser Wali¹³

• ¹National Guard, Jeddah, Saudi Arabia
• ²King Abdulaziz Medical City - Jeddah, Jeddah, Saudi Arabia
• ³Kuwait Cancer Control Center, Shuwaikh, Kuwait
• ⁴Tawam Hospital, Al Ain, United Arab Emirates
• ⁵Sheikh Shakhbout Medical City, Abu Dhabi, United Arab Emirates
• ⁶King Faisal Specialist Hospital & Research Centre - Madinah, Medina, Saudi Arabia
• ⁷King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
• ⁸Sultan Qaboos University, Seeb, Oman
• ⁹Mediclinic Middle East, Dubai, United Arab Emirates
• ¹⁰NBK Children's Hospital, Ministry of health, Kuwait city, Kuwait
• ¹¹King Hussein Cancer Center, Amman, Jordan
• ¹²King Faisal Specialized Hospital, Jeddah, Saudi Arabia
• ¹³Sultan Qaboos University College of Medicine and Health Sciences, Seeb, Oman

Introduction High-dose methotrexate (HDMTX) therapy is a cornerstone in treating pediatric and adult cancers, namely, acute lymphoblastic leukemia, non-Hodgkin lymphoma, and osteosarcoma, due to its capability to penetrate the blood–brain barrier. Despite its therapeutic benefits, HDMTX poses significant risks of delayed methotrexate elimination (DME) and associated toxicities such as acute kidney injury (AKI). These risks necessitate individualized dosing and preventive strategies, including hyperhydration, urine alkalinization, and leucovorin rescue. Methods To address these challenges, a modified Delphi method with two rounds was used to develop consensus statements to guide clinicians in mitigating HDMTX-associated toxicities and optimizing management strategies. A panel of 13 experts from Saudi Arabia, United Arab Emirates (UAE), Kuwait, Oman, Jordan, and Egypt formulated 54 initial statements focusing on HDMTX regimens, risk factors, preventive care, and monitoring strategies. Results Consensus (≥75%) was reached on 50 statements covering HDMTX regimens, preventive care, and toxicity management. Recommendations emphasized standardized methotrexate monitoring intervals, structured risk assessment for DME and AKI, supportive care measures (hyperhydration, urine alkalinization), pharmacokinetically adjusted leucovorin rescue, and the role of glucarpidase in severe toxicity or AKI. Conclusions This consensus provides concrete clinical strategies for the safe and effective use of HDMTX, including structured risk stratification for DME, standardized monitoring intervals, pharmacokinetically guided leucovorin adjustments, and early glucarpidase intervention in patients with AKI or severe toxicity. These recommendations are particularly relevant for optimizing HDMTX administration in regions with limited access to advanced interventions.