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Age- and Intravenous Methotrexate-Associated Leukoencephalopathy and Its Neurological Impact in Pediatric Patients with Lymphoblastic Leukemia.

ABSTRACT: Methotrexate (MTX) is associated with leukoencephalopathy (LE) in children treated for lymphoblastic leukemia/lymphoma (ALL/LBL). However, large-scale studies with systematic MR acquisition and quantitative volumetric lesion information remain limited. Hence, the prevalence of lesion burdens and the potential risk factors of LE in this population are still inconclusive. FLAIR-MRI scans were acquired at the end of treatment in children who were treated for ALL/LBL, which were quantitatively analyzed for LE. Voxels were assigned to the lesion segmentation if indicated by two raters. Logistic and linear regression models were used to test whether lesion presence and size were predicted by risk factors such as age at diagnosis, gender, intrathecal (IT-) or intravenous (IV-)MTX dose, CNS invasion, and acute neurological events. Patients with a pre-existing neurological condition or low-quality MR scan were excluded from the analyses. Of the 129 patients, ten (8%) suffered from CNS invasion. Chemotherapy-associated neurological events were observed in 13 patients (10%) during therapy, and 68 patients (53%) showed LE post-treatment. LE was more frequent in cases of lower age and higher cumulative IV-MTX doses, while the extent of LE and neurological symptoms were associated only with IV-MTX doses. Neurological events were not significantly associated with LE, even though symptomatic patients demonstrated a higher ratio of LE (n = 9/13) than asymptomatic patients (n = 59/116). This study suggests leukoencephalopathy frequently occurs in both symptomatic and asymptomatic leukemia patients. Younger children and patients treated with higher cumulative IV-MTX doses might need more regular screening for early detection and follow-up of associated sequelae.

SUBMITTER: Rijmenams I

PROVIDER: S-EPMC8073318 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ObjectivesIt is well known that transporter and enzyme genes could be regulated by microRNA (miRNA) at the post-transcriptional level, and single-nucleotide polymorphisms (SNPs) in miRNA, which are involved in the miRNA production and structure, may impact the miRNA expression level and then influence drug transport and metabolism. In this study, we aim to evaluate the association between miRNA polymorphisms and high-dose methotrexate (HD-MTX) hematological toxicities in Chinese pediatric patients with acute lymphoblastic leukemia (ALL).MethodA total of 181 children with ALL were administered with 654 evaluable cycles of HD-MTX. Their hematological toxicities were evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events v5. The association between 15 candidate SNPs of miRNA and hematological toxicities (leukopenia, anemia, and thrombocytopenia) was analyzed using Fisher's exact test. Further multiple backward logistic regression analysis was used to explore the independent risk factors for grade 3/4 hematological toxicities.ResultRs2114358 G>A in pre-hsa-miR-1206 was related to HD-MTX-related grade 3/4 leukopenia after multiple logistic regression [GA + AA vs. GG: odds ratio (OR): 2.308, 95% CI: 1.219-4.372, P = 0.010], and rs56103835 T > C in pre-hsa-mir-323b was associated with HD-MTX-related grade 3/4 anemia (TT + TC vs. CC: OR: 0.360, 95% CI: 0.239-0.541, P = 0.000); none of the SNPs were significantly associated with grade 3/4 thrombocytopenia. Bioinformatics tools predicted that rs2114358 G>A and rs56103835 T>C would impact the secondary structure of pre-miR-1206 and pre-miR-323b, respectively, and then probably influence the expression level of mature miRNAs and their target genes.ConclusionRs2114358 G>A and rs56103835 T>C polymorphism may potentially influence HD-MTX-related hematological toxicities, which may serve as candidate clinical biomarkers to predict grade 3/4 hematological toxicities in pediatric patients with ALL.

Project description:ObjectivesThe most common form of pediatric cancer is acute lymphoblastic leukemia (ALL). Magnetic resonance (MR) neuroimaging studies have revealed leukoencephalopathy (LE) in pediatric ALL, but the impact of LE on long-term neurocognitive performance remains unknown. This study aims to objectively characterize the prevalence, extent, and intensity of LE, and their association with later neurocognitive performance.Materials and methodsPediatric patients (N = 377) treated for ALL without irradiation underwent MR neuroimaging at 4 time points throughout therapy (end of remission induction [MR1], end of consolidation [MR2], and week 31 [MR3] and week 120 [end therapy, MR4] of continuation treatment) and neurocognitive evaluations at the end of therapy and 2 years later. Generalized estimation equation models with logit link were developed to explore the association between LE prevalence and extent with time points throughout therapy, age at diagnosis (≤5 years or >5 years), treatment risk arm (low risk or standard/high risk), and sex. General linear models were also developed to investigate the association between neuroimaging metrics during treatment and neurocognitive performance at 2-year follow-up.ResultsThe prevalence of LE was greatest (22.8%, 74/324) after consolidation therapy. The prevalence of LE increased at MR2 relative to MR1 regardless of treatment risk arm (both P's < 0.001), age group (both P's < 0.001), or sex (male, P < 0.001; female, P = 0.013). The extent of white matter affected also increased at MR2 relative to MR1 regardless of treatment risk arm (standard/high risk, P < 0.001; low risk, P = 0.004), age group (both P's < 0.001), or sex (male, P < 0.001; female, P = 0.001). Quantitative relaxation rates were significantly longer in LE compared with that in normal-appearing white matter in the same examination (T1, P < 0.001; T2, P < 0.001). The LE prevalence early in therapy was associated with increased parent ratings of conduct problems (P = 0.039) and learning difficulties (P = 0.036) at 2-year follow-up compared with that at the end of therapy. A greater extent of LE early in therapy was associated with decreasing performance on a measure of processing speed (P = 0.003) from the end of therapy to 2-year follow-up. A larger extent of LE at the end of therapy was associated with decreased performance in reading (P = 0.004), spelling (P = 0.003), and mathematics (P = 0.019) at 2-year follow-up and increasing problems with attention (omissions, P = 0.045; β, P = 0.015) and memory (list A total recall, P = 0.010) at 2-year follow-up compared with that at the end of therapy.ConclusionsIn this large cohort of pediatric patients treated for ALL without irradiation, asymptomatic LE during therapy can be seen in almost a quarter of patients, involves as much as 10% of the white matter volume, and is associated with decreasing neurocognitive performance, increasing parent reports of conduct problems, and learning difficulties in survivors.

Project description:IntroductionMethotrexate (MTX), a folic acid antagonist and nucleotide synthesis inhibitor, is a cornerstone drug used against acute lymphoblastic leukemia (ALL), but its mechanism of action and resistance continues to be unraveled even after decades of clinical use.MethodsTo better understand the mechanisms of this drug, we accessed the intracellular metabolic content of 13 ALL cell lines treated with MTX by 1H-NMR, and correlated metabolome data with cell proliferation and gene expression. Further, we validated these findings by inhibiting the cellular antioxidant system of the cells in vitro and in vivo in the presence of MTX.ResultsMTX altered the concentration of 31 out of 70 metabolites analyzed, suggesting inhibition of the glycine cleavage system, the pentose phosphate pathway, purine and pyrimidine synthesis, phospholipid metabolism, and bile acid uptake. We found that glutathione (GSH) levels were associated with MTX resistance in both treated and untreated cells, suggesting a new constitutive metabolic-based mechanism of resistance to the drug. Gene expression analyses showed that eight genes involved in GSH metabolism were correlated to GSH concentrations, 2 of which (gamma-glutamyltransferase 1 [GGT1] and thioredoxin reductase 3 [TXNRD3]) were also correlated to MTX resistance. Gene set enrichment analysis (GSEA) confirmed the association between GSH metabolism and MTX resistance. Pharmacological inhibition or stimulation of the main antioxidant systems of the cell, GSH and thioredoxin, confirmed their importance in MTX resistance. Arsenic trioxide (ATO), a thioredoxin inhibitor used against acute promyelocytic leukemia, potentiated MTX cytotoxicity in vitro in some of the ALL cell lines tested. Likewise, the ATO+MTX combination decreased tumor burden and extended the survival of NOD scid gamma (NSG) mice transplanted with patient-derived ALL xenograft, but only in one of four ALLs tested.ConclusionAltogether, our results show that the cellular antioxidant defense systems contribute to leukemia resistance to MTX, and targeting these pathways, especially the thioredoxin antioxidant system, may be a promising strategy for resensitizing ALL to MTX.

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Age- and Intravenous Methotrexate-Associated Leukoencephalopathy and Its Neurological Impact in Pediatric Patients with Lymphoblastic Leukemia.

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