TY - JOUR
T1 - Monitoring Of High-Dose Methotrexate (Mtx)-Related Toxicity and Mtx Levels in Children with Acute Lymphoblastic Leukemia
T2 - A Pilot-Study in Indonesia
AU - Sari, Nur Melani
AU - Rakhmilla, Lulu E.
AU - Bashari, Muhammad Hasan
AU - Zazuli, Zulfan
AU - Suryawan, Nur
AU - Susanah, Susi
AU - Reniarti, Lelani
AU - Raspati, Harry
AU - Supriadi, Eddy
AU - Kaspers, Gertjan J. L.
AU - Idjradinata, Ponpon
N1 - Funding Information: The authors would like to grateful Universitas Padjadjaran by financially support this study from Internal Grant on Fundamental Research Grant Scheme 2018. Publisher Copyright: © 2021. All rights reserved. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/7/1
Y1 - 2021/7/1
N2 - 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.
AB - 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.
KW - 2013 ALL Indonesian protocol
KW - Acute lymphoblastic leukemia
KW - high dose methotrexate
KW - toxicity
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85111733648&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/34319023
UR - http://www.scopus.com/inward/record.url?scp=85111733648&partnerID=8YFLogxK
U2 - https://doi.org/10.31557/APJCP.2021.22.7.2025
DO - https://doi.org/10.31557/APJCP.2021.22.7.2025
M3 - Article
C2 - 34319023
SN - 1513-7368
VL - 22
SP - 2025
EP - 2031
JO - Asian Pacific journal of cancer prevention
JF - Asian Pacific journal of cancer prevention
IS - 7
ER -