Clinical and Pharmacokinetic Risk Factors for High-dose Methotrexate-induced Toxicity in Children with Acute Lymphoblastic Leukemia: A Logistic Regression Analysis

Rask, Charlotte Ulrikka; Albertioni, Freidoun; Bentzen, Søren M.; Schrøeder, Henrik; Peterson, Curt

doi:10.1080/028418698429586

Cited by 89 publications

(83 citation statements)

References 22 publications

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“…The toxicity of HDM is primarily related to the duration of exposure to the drug prior to leucovorin administration rather than to the peak MTX concentration. 22,24,25 MTX and its polyglutamated metabolites inhibit dihydrofolate reductase, thereby lowering cellular pools of reduced folates. 12 The lack of reduced folate cofactors is responsible for the inhibition of the synthesis of purines and pyrimidines.…”

Section: Discussionmentioning

confidence: 99%

Dose reduction of coadministered 6-mercaptopurine decreases myelotoxicity following high-dose methotrexate in childhood leukemia

Nygaard

Schmiegelow

2003

Leukemia

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High-dose methotrexate (HDM) given concurrently with oral 6-mercaptopurine (6 MP) may be followed by myelotoxicity, which may necessitate treatment interruption and thus interfere with the efficacy of the treatment of childhood acute lymphoblastic leukemia (ALL). Through inhibition of purine de novo synthesis and enhancement of the bioavailability, HDM may increase the incorporation into DNA of 6-thioguanine nucleotides, the cytotoxic metabolites of 6 MP.A total of 26 children diagnosed 3/1996-4/2001 with ALL received five courses of HDM (5 g/m 2 /24 h with leucovorin rescue) at 8 weeks intervals during their first year of maintenance therapy with oral methotrexate (20 mg/m 2 /week) and 6MP (75 mg/m 2 /day). The dose of oral 6MP was reduced to a median of 51% (75% range: 39-62%, maximum 74%) of the standard dose from 2 weeks prior to until 2 weeks after HDM, because the previous HDM had led to a thrombocyte nadir p60 Â 10 9 /l and/or a neutrophil nadir p0.7 Â 10 9 /l. The 6MP dose reductions raised the median thrombocyte nadir following HDM from 46 Â 10 9 /l (range: 6-214) to 133 Â 10 9 /l (range: 21-305; Po0.001) and the median neutrophil nadir from 0.5 Â 10 9 /l (range: 0.0-1.4) to 0.9 Â 10 9 /l (range: 0.2-3.2; Po0.001). The effect of 6MP dose reductions was not significantly related to risk group, gender, age, or thiopurine methyltransferase genotype. With 6MP dose reductions, the median duration of treatment interruption following HDM was reduced from 8 to 0 days (Po0.001).The reduction of 6MP dosage during HDM can significantly reduce the risk of severe myelotoxicity and prevent treatment interruptions.

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Section: Discussionmentioning

confidence: 99%

Dose reduction of coadministered 6-mercaptopurine decreases myelotoxicity following high-dose methotrexate in childhood leukemia

Nygaard

Schmiegelow

2003

Leukemia

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“…High plasma methotrexate concentrations have been associated with increased toxicity, delayed clearance of methotrexate, and delay of subsequent courses of chemotherapy. 8,9 It is therefore important to maintain plasma concentrations within the putative cytotoxic range for leukemic blasts, but below those associated with significant toxicity. This study successfully targeted patients to concentrations within the range expected for a 5 g/m 2 dose of methotrexate, which has been associated with excellent outcome in newly diagnosed patients with ALL.…”

Section: Discussionmentioning

confidence: 99%

Individualized methotrexate dosing in children with relapsed acute lymphoblastic leukemia

et al. 2000

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Although high-dose methotrexate has been extensively studied in children with newly diagnosed acute lymphoblastic leukemia (ALL), there are fewer data in children with relapsed ALL, many of whom have been heavily pretreated and have subclinical kidney dysfunction. We characterized the pharmacokinetics of adaptively controlled methotrexate given as a 24-h infusion during consolidation therapy in 24 children with relapsed ALL. To achieve the target steady-state concentration of 65 M, dosage adjustments were required in 14 patients, with doses ranging from 2854 to 6700 mg/m 2 per course. The mean steady-state plasma concentration (Cp ss ) of 68.0 M was different (P = 0.025) than the predicted Cp ss (mean = 87.4 M; range 35.7-184 M) had no adjustment in dose been made. The coefficient of variation in Cp ss was reduced from 41% to 18% by individualizing doses. Predisposing factors that correlated with decreased methotrexate clearance were female sex (P = 0.03), age greater than 6 years (P = 0.01), and prior history of heavy amphotericin B treatment (Ͼ30 mg/kg) (P = 0.03), but no factor predicted low clearance as well as the measured initial methotrexate clearance during the infusion (P Ͻ 0.0001). There was no life-threatening toxicity with the regimen. We conclude that dosage individualization decreases interpatient variability and avoids potentially toxic methotrexate exposures in heavily pretreated ALL patients. Leukemia (2000) 14, 221-225.

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“…[7][8][9] HDM often causes significant bone marrow toxicity which carries a risk of infections and a need for transfusions. 10 This myelosuppression may lead to treatment interruptions and a reduction of the dose intensity, which can affect the cure rate. [11][12][13] MTX may increase the bioavailability of 6MP, 14 and in addition, through inhibition of de novo purine synthesis, enhance the availability of 6TGN and its incorporation into DNA.…”

Section: Introductionmentioning

confidence: 99%

6-Mercaptopurine dosage and pharmacokinetics influence the degree of bone marrow toxicity following high-dose methotrexate in children with acute lymphoblastic leukemia

Schmiegelow

Bretton-Meyer

2001

Leukemia

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were compared, white cell and absolute neutrophil count (ANC) nadir, lymphocyte count nadir, thrombocyte count nadir, and hemoglobin nadir after HDM decreased significantly with increasing doses of oral 6MP. Three percent of the HDM courses given without oral 6MP (SR consolidation) were followed by an ANC nadir Ͻ0.5 × 10 9 /l compared to 50% of the HDM courses given during SR/IR maintenance therapy. Similarly, only 13% of the HDM courses given as SR-ALL consolidation induced a thrombocyte count nadir Ͻ100 × 10 9 /l compared to 58% of the HDM courses given during maintenance therapy. The best-fit model to predict the ANC nadir following HDM during maintenance therapy included the dose of 6MP prior to HDM (␤ = −0.017, P = 0.001), the average ANC level during maintenance therapy (␤ = 0.82, P = 0.004), and E-6TGN (␤ = −0.0029, P = 0.02). The best-fit model to predict the thrombocyte nadir following HDM during maintenance therapy included only mPLATE (␤ = 0.0057, P = 0.046). In conclusion, the study indicates that reductions of the dose of concurrently given oral 6MP could be one way of reducing the risk of significant myelotoxicity following HDM during maintenance therapy of childhood ALL. Leukemia (2001) 15, 74-79.

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Clinical and Pharmacokinetic Risk Factors for High-dose Methotrexate-induced Toxicity in Children with Acute Lymphoblastic Leukemia: A Logistic Regression Analysis

Cited by 89 publications

References 22 publications

Dose reduction of coadministered 6-mercaptopurine decreases myelotoxicity following high-dose methotrexate in childhood leukemia

Dose reduction of coadministered 6-mercaptopurine decreases myelotoxicity following high-dose methotrexate in childhood leukemia

Individualized methotrexate dosing in children with relapsed acute lymphoblastic leukemia

6-Mercaptopurine dosage and pharmacokinetics influence the degree of bone marrow toxicity following high-dose methotrexate in children with acute lymphoblastic leukemia

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