The influence of serum methotrexate concentrations and drug dosage on outcome in childhood acute lymphoblastic leukaemia

Pearson, Andrew D.J.; Amineddine, H. A.; Yule, Murray; Mills, Steven A.; Long, David R.; Craft, Alan; Chessells, Judith M.

doi:10.1038/bjc.1991.263

Cited by 28 publications

(8 citation statements)

References 16 publications

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“…This finding was true for both girls and boys and was not influenced by the administration of intensification blocks. This confirms the findings of smaller earlier studies where children who became neutropenic during treatment had a lower risk of late relapse (Pearson et al, 1991;Dolan et al, 1989).…”

Section: Discussionsupporting

confidence: 90%

Continuing (maintenance) therapy in lymphoblastic leukaemia: lessons from MRC UKALL X

et al. 1997

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Summary.The relationship between the prescribed dose of drugs during continuing (maintenance) therapy, the degree of marrow suppression caused, and subsequent event-free survival was examined in a cohort of 740 children with lymphoblastic leukaemia treated on MRC UKALL X. Girls, younger children, and patients who had received intensification treatment, were prescribed lower doses of mercaptopurine, became neutropenic more readily, and had more interruptions of treatment. Children who had one or more episodes of neutropenia with a count of < 0 . 5 × 10 9 /l had a better prognosis than those who never became neutropenic.We conclude that early intensification treatment influences the probability of neutropenia during continuing treatment and that patients exhibiting myelosuppression during this phase of treatment have a better chance of prolonged remission.

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Section: Discussionsupporting

confidence: 90%

Continuing (maintenance) therapy in lymphoblastic leukaemia: lessons from MRC UKALL X

et al. 1997

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“…Considering that the prognosis of ALL is worst in infants [3,4] and that MTX clearance, although the observations are limited to a small number of patients, seems equivalent to or slightly higher than in older children, it can be suggested that full MTX doses can and should be given even to the very young child without a high risk of toxicity, with the aim of maximizing the antileukemic effect [26].…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of HD‐MTX in infants, children, and adolescents with non‐B acute lymphoblastic leukemia

Donelli

Zucchetti

Robatto

et al. 1995

Med. Pediatr. Oncol.

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A retrospective pharmacokinetic analysis was done of methotrexate serum levels after high-dose treatment (HD-MTX, four cycles at two-week intervals of 5 g/sq.1m. over 24 h i.v.) in children with non-B acute lymphoblastic leukemia (ALL) with the specific aim of seeking differences in patients of different ages, including infants under one year. A total of 122 children (seven infants aged 3 months-1 year, 26 children aged 1-3 years, 68 children aged 3-10 years and 21 adolescents aged 10-15 years) with normal liver and renal function, receiving consolidation therapy at the Pediatric Clinic of Monza between May 1988 and April 1992, were enrolled in this study. MTX was given as an intravenous infusion in 24 h and serum concentrations were measured up to at least 72 h after the start of infusion by an enzyme immunoassay (TDX Abbot, Dallas, TX) in order to modulate folinic acid rescue. Pharmacokinetic analysis of MTX levels according to a two-compartment open model indicated that, compared to all children up to 10 years old, in adolescents older than 10 years the drug reached higher concentrations in serum and was cleared at a lower rate. Steady-state levels and AUC were from 60% higher to more than double and the total clearance of the compound, expressed either per square meter surface area or per kg body weight, in each cycle was significantly lower in adolescents > 10 years of age, sometimes being only one-third of the clearance in infants (0.2 vs. 0.6 1/h/kg and 6.6 vs. 10.7 1/h/sq.m). The relationship between each age and systemic clearance was highly significant as measured by regression analysis. Methotrexate systemic clearance progressively decreased as a function of age. Subsequent treatments did not induce changes in MTX pharmacokinetics. These data suggest that the better tolerance of HD-MTX in children may have a pharmacokinetic basis. The faster elimination of MTX in infants, who usually show the worst prognosis, suggests that full doses could be safely used in order to maximize the antileukemic effect without a high risk of toxicity.

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“…1, 2). Importantly, patients tolerant to the starting doses of 6MP and MTX, but for whom maintenance therapy is not intensified, have a poorer outcome compared both with patients who receive reduced drug doses due to leukopenia and with those who are upward dose adjusted to obtain target myelosuppression 36–38,62,63. Furthermore, recurrent unwarranted treatment interruptions due to a rise in aminotransferases are also an adverse factor for risk of relapse 37.…”

Section: Drug Dosagementioning

confidence: 99%

Mercaptopurine/Methotrexate Maintenance Therapy of Childhood Acute Lymphoblastic Leukemia

Schmiegelow

Nielsen

Frandsen

et al. 2014

Journal of Pediatric Hematology/Oncology

202

169

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The influence of serum methotrexate concentrations and drug dosage on outcome in childhood acute lymphoblastic leukaemia

Cited by 28 publications

References 16 publications

Continuing (maintenance) therapy in lymphoblastic leukaemia: lessons from MRC UKALL X

Continuing (maintenance) therapy in lymphoblastic leukaemia: lessons from MRC UKALL X

Pharmacokinetics of HD‐MTX in infants, children, and adolescents with non‐B acute lymphoblastic leukemia

Mercaptopurine/Methotrexate Maintenance Therapy of Childhood Acute Lymphoblastic Leukemia

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