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

Nur Suryawan,Harry Raspati,Ponpon Idjradinata,Lelani Reniarti,Nur Sari,Lulu Rakhmilla,Muhammad Bashari,Zulfan Zazuli,Gertjan Kaspers,Eddy Supriyadi,Susi Susanah

doi: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.

Highlights

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
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
There is no significant association between the clinical toxicity and MTX levels at the two points of measurement

Summary

Introduction

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. Nur Melani Sari et al monitoring for various parameters, which creates a challenge for pediatric oncologists in developing countries due to the lack of resources to routinely screen patients (Jonsson et al, 2011; Foster et al, 2017; Gauri Kapoor et al, 2012). This has made many pediatric oncologist reluctant to use MTX or modify its dosage (Gauri Kapoor et al, 2012). The dose for HD-MTX in Indonesian ALL Protocol has been modified from 500 mg/m2 in 2006 to 1,000 mg/ m2 continuous infusion without loading dose, in 2013 (Wijayanti and Supriyadi, 2017; Yakin et al, 2017)

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