Monitoring Of High-Dose Methotrexate (Mtx)-Related Toxicity and Mtx Levels in Children with Acute Lymphoblastic Leukemia: A Pilot-Study in Indonesia

Sari, Nur Melani; Rakhmilla, Lulu E; Bashari, Muhammad Hasan; Zazuli, Zulfan; Suryawan, Nur; Susanah, Susi; Reniarti, Lelani; Raspati, Harry; Supriyadi, Eddy; Kaspers, Gertjan J L; Idjradinata, Ponpon

doi:10.31557/APJCP.2021.22.7.2025

Monitoring Of High-Dose Methotrexate (Mtx)-Related Toxicity and Mtx Levels in Children with Acute Lymphoblastic Leukemia: A Pilot-Study in Indonesia

Document Type : Research Articles

Authors

¹ Hematology Oncology Division, Department of Child Health Faculty of Medicine Universitas Padjadjaran/Dr. Hasan Sadikin General Hospital, Bandung, Indonesia.

² Department of Public Health, Division of Epidemiology and Biostatistics, Faculty of Medicine Universitas Padjadjaran, Bandung, Indonesia.

³ Department of Biomedical Sciences, Division of Pharmacology and Therapy, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia.

⁴ Department of Pharmacology-Clinical Pharmacy, School of Pharmacy, Bandung Institute Technology, Bandung, Indonesia.

⁵ Amsterdam UMC, location Academic Medical Center, Amsterdam, Netherlands.

⁶ Pediatric Hematology Oncology Division, Department of Pediatrics, Dr Sardjito Hospital-Faculty of Medicine Public Health and Nursing Universitas, Gajah Mada, Yogyakarta, Indonesia.

⁷ Princess Máxima Center for pediatric oncology, Utrecht, Netherlands.

⁸ Emma Children’s Hospital, Amsterdam UMC, Vrije Universiteit Amsterdam, Pediatric Oncology, Netherlands, Netherlands.

10.31557/APJCP.2021.22.7.2025

Abstract

The administration of high-dose methotrexate (HD-MTX) requires an accurate monitoring of blood MTX levels to determine the regimen of leucovorin rescue and urine alkalinization to prevent toxicity. However, it is technically and logistically challenging to screen patients routinely in limited-resource settings. This study aimed to evaluate blood MTX levels at 24- and 48-hours from start of infusion in relation to clinical toxicity in childhood ALL. Methods: A prospective cohort study was conducted on 32 consecutive children with acute lymphoblastic leukemia (ALL) who had received at least one cycle of 1 g/m2 HD-MTX intravenous infusion as a part of consolidation treatment based on the 2013 Indonesian ALL Protocol. In total, 68 cycles were evaluated. Serum MTX concentrations were measured using enzyme immunoassay. MTX toxicity was categorized using common toxicity criteria (CTCAE) 3.0 version. The association between MTX level and clinical toxicity was assessed by non-parametric analysis. Results: The 24-hours MTX level was median 29.8 ng/mL (0.065 µmol/L) (IQR 8.1–390.6) with a modest decrease in 48-hours MTX serum level in all cycles (median 28.3 ng/mL and 0.062 µmol/L; IQR 0.35–28.7; p <0.05). The two most common toxicities were hepatotoxicity (32.2%) and neutropenia (30.9%). Nephrotoxicity and febrile neutropenia occurred in 8.8% and 5.8% of patients, respectively, with low percentage of mucositis (4.3%) and thrombocytopenia (5.6%) recorded. No statistically significant association was found between MTX levels and clinical toxicity, except for liver toxicity.Conclusion: Serum MTX levels at 24-hours and 48-hours are low, followed by only 4.4% grade III/IV hepatotoxicity and 26,4% grade III/IV neutropenia. There is no significant association between the clinical toxicity and MTX levels at the two points of measurement. An attempt to increase the MTX dose and/or to introduce a loading dose should be considered in subsequent ALL protocol as supported by further pharmacokinetic MTX studies in the Indonesian population.

Keywords

Main Subjects