Asian Pac J Cancer Prev

Jul 1;22(7):2025-2031.
 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
Nur Melani Sari 1, Lulu E Rakhmilla 2, Muhammad Hasan Bashari 3, Zulfan Zazuli 4 5, Nur Suryawan 1, Susi Susanah 1, Lelani Reniarti 1, Harry
Raspati 1, Eddy Supriyadi 6, Gertjan J L Kaspers 7 8, Ponpon Idjradinata 1
Affiliations expand. DOI: 10.31557/APJCP.2021.22.7.2025
Free PMC article

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: 2013 ALL Indonesian protocol; Acute Lymphoblastic Leukemia; Toxicity; high dose methotrexate.

High-Dose Methotrexate-Related Toxicity in Children with

Acute Lymphoblastic Leukemia

Program: Oral and Poster Abstracts

Session: 612. Acute Lymphoblastic Leukemias: Clinical and Epidemiological: Poster II

Hematology Disease Topics & Pathways:

ALL, Lymphoid Leukemias, Research, Non-Biological therapies, epidemiology, Clinical Research, Chemotherapy, pediatric, Diseases,

Therapies, Lymphoid Malignancies, Adverse Events, Study Population, Human

Sunday, December 11, 2022, 6:00 PM-8:00 PM

Christina Egnell Gustafsson, MD1,2*, Grete Götzsche Frederiksen2*, Josefine Thorwaldson2*, Mats Heyman3,4, Arja Harila-Saari, PhD,

MD5,6  and Susanna Ranta2,4*

1
Karolinska University Hospital, Bromma, Stockholm, Sweden
2
Department of Women's and Children's Health, Karolinska institutet, Stockholm, Sweden
3
Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden
4
Karolinska University Hospital, Stockholm, Sweden
5
Uppsala University Hospital, Uppsala, Sweden
6
Department of Women's and Children's Health, Uppsala University, Uppsala, Sweden

Introduction: High-dose methotrexate (HD-MTX) is a key component in treatment of acute lymphoblastic leukemia (ALL) but

associates with several toxicities. In addition to myelosuppression and emesis, HD-MTX has specific adverse effects such as oral

mucositis, nephrotoxicity, hepatotoxicity, dermatitis, and methotrexate-related stroke like syndrome. Toxicity during prior courses

of HD-MTX, delayed MTX elimination and pre-existing nephropathy are associated with toxicity, but information on other risk

factors is scarce.

Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL2008 protocol included an intensive consolidation with HD-

MTX for non-high risk patients. We aimed to describe the incidence of and risk factors for HD-MTX induced toxicity during

consolidation therapy.

Method: This is a retrospective study, including patients aged 2-<18 years with ALL, treated according to the non-high risk arm of

the NOPHO ALL2008 protocol in Stockholm and Uppsala, Sweden, during 2008-2019. Data on toxicities during the consolidation

was collected after the three HD-MTX courses (5 g/m 2) during consolidation. Concomitant chemotherapeutic agents were

pegylated asparaginase, vincristine and oral mercaptopurine. The registered toxicities included hematological toxicity (transfusions

and/or neutropenia), infections or mucositis requiring hospitalization, administration of intravenous antibiotics or parenteral

nutrition, liver toxicity, dermatitis, increased creatinine and CNS toxicity (definitions in Table). Clinical variables included age,
immunophenotype, renal ultrasound at diagnosis, blood cell count and creatinine at diagnosis and at start of HD-

MTX, BMI standard deviation scores (BMI-SDS), and weight change during induction.

Results: The study cohort comprised 143 patients with 426 high-dose HD-MTX courses in total. The median age at diagnosis was

5.1 years (IQR 5.09). Toxicity was common, especially after the first HD-MTX course (Figure). Every fifth patient was hospitalized

due to mucositis after the first HD-MTX and 79% of those needed parenteral nutrition. Infections were frequent; 49.7% were

admitted to in-patient care with infection after the first HD-MTX, of whom all but one (70/71) were treated with intravenous

antibiotics and 15% had a positive blood culture. Hematological toxicity, whilst most frequent after the first HD-MTX, was common

after all three HD-MTX courses.

A significantly higher risk of recurrent toxicity after the first HD-MTX was found for mucositis (Odds ratio (OR) 5.4; 95% confidence

interval (CI) 1.1- 26.1; p=0.034), dermatitis (OR 32.8; 95% CI 5.5-197; p=<0.001), delayed nephrotoxicity (OR 59.0; 95% CI 11.2-307;

p=<0.001). Liver toxicity and acute nephrotoxicity were not associated with an increased risk of recurrence after subsequent HD-

MTX courses.

When risk factors were analyzed separately for the first HD-MTX course, mucositis was more frequent in patients with weight loss

(> 5%) during induction (p=0.007). The median BMI-SDS at diagnosis was also lower in patients with mucositis than those without

(p=0.081). High MTX concentration (MTX >1 µM at hour 42) at first HD-MTX was associated with an increased need of

thrombocyte- (p=0.021) and erythrocyte transfusion (p=0.041).

Mildly (42-hour plasma MTX ≥1.0-3.9 µM), moderately (42-hour plasma MTX ≥4.0-9.9 µM) or severely delayed (42-hour plasma MTX

≥10 µM) elimination was seen in 38.0% (moderate; 5.6%; severe; 1.4%), 17.6% (moderate 2.1%) and 19.9% (moderate; 1.4%; severe;

0.7%) after first, second and third HD-MTX courses, respectively. Higher MTX concentration and slower clearance to non-toxic

levels was associated with acute and delayed nephrotoxicity after the first HD-MTX (p=0.001).

Conclusion: Our study demonstrated that severe toxicities that warrant hospitalization are very common, especially after the first

HD-MTX. Low BMI at diagnosis and weight loss during induction was related to higher risk for mucositis and high MTX

concentration and delayed excretion predicted nephrotoxicity after the first HD-MTX.