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Methotrexate Associated Renal Impairment Is Related to Delayed Elimination of High-Dose Methotrexate.

ABSTRACT: Although Methotrexate (MTX) is an effective drug for the treatment of acute lymphoblastic leukemia (ALL), the toxicity remains a significant problem. In this prospective study, fifty-four patients with ALL were enrolled. 3 g or 5 g MTX/m(2) was administered over 24 hours. Serum MTX concentrations were determined in 24, 48, and 96 hours after MTX infusion. Serum creatinine concentrations and creatinine clearance rate (CCR) were determined before and 24 and 48 hours after MTX infusion. A total of 173 courses of MTX infusion were administered. The serum creatinine concentrations did not change much after MTX infusion while the CCR was gradually decreased. MTX clearance status was independently related to CCR decrease, with the risk of 8.07 to develop renal impairment in patients with delayed MTX elimination. Serum creatinine concentration, serum creatinine ratio, CCR, and CCR ratio at 24 hours were all related to MTX elimination delay. Patients with serum creatinine level >35.0 μmol/L, creatinine ratio >1.129, or CCR <100.0 mL/min were more likely to undergo MTX elimination delay. In conclusion, MTX could induce transient renal impairment and compromised renal function will delay MTX clearance. The serum creatinine concentration and the ratio and CCR are useful tools for evaluating MTX elimination status.

SUBMITTER: Yang SL

PROVIDER: S-EPMC4491404 | biostudies-other | 2015

REPOSITORIES: biostudies-other

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Project description:Acute kidney injury due to high-dose methotrexate (HDMTX) is a serious, life-threatening toxicity that can occur in pediatric and adult patients. Glucarpidase is a treatment approved by the Food and Drug Administration for high methotrexate concentrations in the context of kidney dysfunction, but the guidelines for when to use it are unclear. An expert panel was convened to provide specific, expert consensus guidelines for the use of glucarpidase in patients who develop HDMTX-induced nephrotoxicity and delayed methotrexate excretion. The guideline provides recommendations to identify the population of patients who would benefit from glucarpidase rescue by more precisely defining the absolute methotrexate concentrations associated with risk for severe or life-threatening toxicity at several time points after the start of an HDMTX infusion. For an HDMTX infusion ≤24 hours, if the 36-hour concentration is above 30 µM, 42-hour concentration is above 10 µM, or 48-hour concentration is above 5 µM and the serum creatinine is significantly elevated relative to the baseline measurement (indicative of HDMTX-induced acute kidney injury), glucarpidase may be indicated. After a 36- to 42-hour HDMTX infusion, glucarpidase may be indicated when the 48-hour methotrexate concentration is above 5 µM. Administration of glucarpidase should optimally occur within 48-60 hours from the start of the HDMTX infusion, because life-threatening toxicities may not be preventable beyond this time point.Implications for practiceGlucarpidase is a rarely used medication that is less effective when given after more than 60 hours of exposure to high-dose methotrexate, so predicting early which patients will need it is imperative. There are no currently available consensus guidelines for the use of this medication. The indication on the label does not give specific methotrexate concentrations above which it should be used. An international group of experts was convened to develop a consensus guideline that was specific and evidence-based to identify the population of patients who would benefit from glucarpidase.

Project description:OBJECTIVE:Severe myelosuppression is a serious concern in the management of rheumatic disease patients receiving methotrexate (MTX) therapy. This study was intended to explore factors associated with the development of MTX-related myelosuppression and its disease severity. METHODS:We retrospectively examined a total of 40 cases of MTX-related myelosuppression that had been filed in the registries of participating rheumatology and hematology divisions. Data before onset were compared with those of 120 controls matched for age and sex. Cytopenia was graded according to the National Cancer Institute criteria for adverse events. Data before and at onset were compared between the severe and non-severe groups. RESULTS:Non-use of folic acid supplements, concurrent medications, and low renal function were significantly associated with the development of myelosuppression (p < 0.001, p < 0.001, and p = 0.002, respectively). In addition, significantly lower MTX dosages, higher blood cell counts, and lower hemoglobin levels were seen in the myelosuppression group (p < 0.001). No patients exhibited leukocytopenia, neutropenia, or thrombocytopenia in routine blood monitoring taken within the past month. One-fourth developed myelosuppression within the first two months (an early-onset period). Myelosuppression was severe in approximately 40% of patients. Hypoalbuminemia and non-use of folic acid supplements were significantly associated with the severity of pancytopenia (p = 0.001 and 0.008, respectively). Besides these two factors, early onset and the use of lower doses of MTX were significantly associated with the severity of neutropenia (p = 0.003, 0.007, 0.003, and 0.002, respectively). CONCLUSIONS:Myelosuppression can occur abruptly at any time during low-dose MTX therapy, but severe neutropenia is more likely to occur in the early-onset period of this therapy. Contrary to our expectations, disease severity was not dependent on MTX doses. Serum albumin levels and folic acid supplementation are the important factors affecting the severity of MTX-related pancytopenia and neutropenia.

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:Background:The role of Methylene tetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms in the efficacy and toxicity of MTX-based therapy remains uncertain. Our purpose was to clarify whether these two polymorphisms are associated with the outcome of chemotherapy in a cohort of Chinese osteosarcoma (OS) patients treated by high-dose MTX. Methods:109 OS patients who had sequentially received high-dose MTX therapy were included in this study. Plasma MTX level was measured routinely at 0, 24, 48 and 72?h after the administration of MTX. Two variants of MTHFR were genotyped using TaqMan SNP Genotyping Assay, including rs1801133 (C667T) and rs1801131 (A1298C). The extent of toxicity induced by MTX, including hematological toxicity, hepatic toxicity, renal toxicity and mucositis, was scored from grade 1 to 4. Severe toxicity was defined as a grade score of ?3. Patients were dichotomized as follows: grade <3 or ?3 for toxicity, and ?0.2 µmol/L or >0.2 µmol/L for plasma MTX level at 72?h. The frequencies of genotypes and allele were compared between the dichotomized groups with the Chi-square test. Results:24.8% (27/109) of the patients were found to have significantly high plasma MTX level at the 72?h. Patients with high MTX level at 72?h were found to have significantly higher frequency of genotype TT of rs1801133 (p?=?0.002). As for rs1801131, no significant association was found with plasma MTX level. Patients with severe hepatic toxicity or mucositis were found to have remarkably higher incidence of genotype TT of rs1801133 than those with mild toxicity (33.3% vs. 14.8%, p?=?0.04 for hepatic toxicity; 34.8% vs. 19.8%, p?=?0.05 for mucositis). Conclusions:Variant rs1801133 was confirmed to have remarkable influence on the MTX-induced toxicity. We recommend identification of the genotype of MTHFR variant prior to the application of high-dose MTX to OS patients, which could be an important predictor to screen severe toxicities and thus improve treatment outcomes.

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Methotrexate Associated Renal Impairment Is Related to Delayed Elimination of High-Dose Methotrexate.

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