Methotrexate Systemic Clearance Influences Probability of Relapse in Children With Standard-Risk Acute Lymphocytic Leukaemia

Evans, W.J.; Stewart, C. A.; Chen, Chen-Hsin; Crom, William R.; Bowman, W. Paul; Abromowitch, Minnie; Simone, Joseph V.

doi:10.1016/s0140-6736(84)90411-2

Cited by 115 publications

(50 citation statements)

References 12 publications

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“…On examining the EFS in terms of Mtx pharmacokinetics it has been shown that higher peak concentrations and AUC are not associated with improved survival either when oral and IM are combined or separately. This is in contrast to the findings from two previous studies from St Jude's Children's Hospital (Evans et al, 1984;Evans et al, 1986) where slower Mtx clearances and higher steady state serum concentrations were initially associated with an improved EFS rate. However, with further follow up this survival advantage was lost (Evans, 1989).…”

Section: Discussioncontrasting

confidence: 99%

“…In patients with ALL given oral Mtx, higher I h serum concentrations have been related to an improved EFS (Craft et al, 1980). Variability in serum concentration following intravenous high dose Mtx has been shown to be associated with disease free survival, a more rapid clearance and a lower steady state concentration inferring a poor prognosis (Evans et al, 1984;Evans et al, 1986). In order to relate serum Mtx concentration to relapse free survival in childhood ALL sequential Mtx absorption studies have been carried out on 127 children with ALL.…”

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confidence: 99%

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

Pearson

Amineddine²,

Yule³

et al. 1991

Br J Cancer

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Summary Sequential methotrexate (Mtx) absorption studies were undertaken in 127 children undergoing treatment for childhood non-T acute lymphoblastic leukaemia (ALL) to determine whether serum drug concentration, clearance and dosage affect event free survival (EFS). Higher serum concentration and area under the plasma concentration curve (AUC) were not associated with an improved EFS. Methotrexate clearance was not found to be of prognostic significance.Patients who tolerated only low 6-mercaptopurine (6-MP) doses because of neutropaenia and those who randomly were prescribed higher doses of Mtx had a lower rate of leukaemia relapse after the completion of therapy. This suggests that the use of maintenance therapy in maximally tolerated doses may be associated with an increased survival in childhood ALL.

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Section: Discussioncontrasting

confidence: 99%

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confidence: 99%

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

Pearson

Amineddine²,

Yule³

et al. 1991

Br J Cancer

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“…6,7 The systemic exposure to methotrexate (ie, plasma concentration over time) is related to cure and toxicity in children with ALL. 8,9 In a group of children with ALL who were treated and monitored at a single institution (St Jude Children's Research Hospital), with extensive prospective therapeutic drug monitoring, even including pharmacokinetically guided dosage adjustments, we identified variants in the SLCO1B1 gene that were associated with methotrexate clearance in a genome-wide association study (GWAS). 10,11 Herein, we sought to test whether we could replicate these GWAS findings in a large cohort of patients treated with alternative HDMTX schedules on the COG multi-institutional trials P9904 and P9905.…”

Section: Introductionmentioning

confidence: 99%

Genome-wide study of methotrexate clearance replicates SLCO1B1

Ramsey

Panetta

Smith

et al. 2013

Blood

186

150

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Key Points• A genome-wide study of the association of over 5 million SNPs with methotrexate clearance in 1279 patients treated with HDMTX in multicenter COG trials 9904 and 9905.• We replicated the finding that inherited variations in SLCO1B1 are the most important genetic variations influencing methotrexate clearance.Methotrexate clearance can influence the cure of and toxicity in children with acute lymphoblastic leukemia (ALL). We estimated methotrexate plasma clearance for 1279 patients with ALL treated with methotrexate (24-hour infusion of a 1 g/m 2 dose or 4-hour infusion of a 2 g/m 2 dose) on the Children's Oncology Group P9904 and P9905 protocols. Methotrexate clearance was lower in older children (P ‫؍‬ 7 ؋ 10 ؊7 ), girls (P ‫؍‬ 2.7 ؋ 10 ؊4 ), and those who received a delayed-intensification phase (P ‫؍‬ .0022). A genome-wide analysis showed that methotrexate clearance was associated with polymorphisms in the organic anion transporter gene SLCO1B1 (P ‫؍‬ 2.1 ؋ 10 ؊11 ). This replicates findings using different schedules of high-dose methotrexate in St Jude ALL treatment protocols; a combined meta-analysis yields a P value of 5.7 ؋ 10 ؊19 for the association of methotrexate clearance with SLCO1B1 SNP rs4149056. IntroductionHigh-dose methotrexate (HDMTX) is an important element of chemotherapy in the treatment of acute lymphoblastic leukemia (ALL) and other malignancies. [1][2][3][4] Mikkelsen et al 5 showed that a 1 g/m 2 dose given over 24 hours resulted in significantly greater active methotrexate polyglutamates in leukemic cells than the same dose given over 4 hours. In a randomized clinical trial, investigators from the Children's Oncology Group (COG) tested the efficacy and toxicity of a 2 g/m 2 dose over 4 hours versus a 1 g/m 2 dose over 24 hours. 6,7 The systemic exposure to methotrexate (ie, plasma concentration over time) is related to cure and toxicity in children with ALL. 8,9 In a group of children with ALL who were treated and monitored at a single institution (St Jude Children's Research Hospital), with extensive prospective therapeutic drug monitoring, even including pharmacokinetically guided dosage adjustments, we identified variants in the SLCO1B1 gene that were associated with methotrexate clearance in a genome-wide association study (GWAS). 10,11 Herein, we sought to test whether we could replicate these GWAS findings in a large cohort of patients treated with alternative HDMTX schedules on the COG multi-institutional trials P9904 and P9905. MethodsThis study was approved by the institutional review boards of all participating institutions, and informed consent was obtained in accordance with the Declaration of Helsinki. Patients in P9904 included National Cancer Institute (NCI) standard-risk (age 1.00-9.99 years and initial white blood cell count [WBC]Ͻ 50 000/L) patients with an ETV6-RUNX1 translocation or simultaneous trisomies of chromosomes 4 and 10, whereas patients in P9905 included a mixture of NCI standard-risk patients without favorable genetic lesions, NCI high-risk (age...

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“…Several other studies with much lower MTX doses (1 g, 0.9 to 3.7 g, and 1 to 2 g [3,8,19], respectively) found no correlations between plasma MTX concentrations and CCr. Further, the plasma MTX concentrations at 24 and 48 hours in these studies were much lower than in our study eg, the maximum 48 hour MTX concentration in the study of Joannon et al was 1.07 μmol/L [19].…”

Section: Discussionmentioning

confidence: 83%

“…Use of methotrexate (MTX) has led to significant improvements in the long-term survival of children with acute lymphoblastic leukemia (ALL) and is important for extramedullary leukemia prophylaxis in many effective ALL and lymphoma chemotherapeutic regimens [1][2][3][4][5]. Different from other antineoplastic agents, the cytotoxic effects of MTX can be ameliorated by folic acid (leucovorin).…”

mentioning

confidence: 99%

Creatinine clearance rate and serum creatinine concentration are related to delayed methotrexate elimination in children with lymphoblastic malignancies

Mao¹,

Zhang²,

Shen³

et al. 2014

neo

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Methotrexate (MTX) is an effective treatment for childhood acute lymphoblastic leukemia (ALL) or Non-Hodgkin lymphoma (NHL); however, toxicity can arise with high doses MTX (HDMTX), especially in patients with delayed MTX elimination. Routine monitoring of plasma MTX concentrations is clinically important, but unfortunately is not always feasible. The aim of this study was to examine the relationship between MTX elimination and renal function to identify parameters that may be useful for predicting delayed MTX elimination in Chinese children with ALL and NHL. A total of 105 children with ALL and NHL were included in the study. Each patient received HDMTX (3 or 5 g/m 2 ) over 24 hours. Plasma MTX concentrations were measured at 24, 48, and 96 hours. Delayed elimination was indicated by plasma MTX concentrations ≥1.0 at 48 hours or ≥0.1 μmol/L at 96 hours. Creatinine clearance rate (CCr) and serum Cr concentrations were measured at 0, 24, and 48 hours. There were 39 patients (37.1%) with delayed MTX elimination. For patients with delayed MTX elimination, the 24 hour plasma MTX concentration was negatively correlated with the 24 hour CCr (P=0.019). The 48 hour plasma MTX concentration was positively correlated with 24 and 48 hour serum Cr concentrations (P=0.001 and P<0.001, respectively), and negatively correlated with the 24 and 48 CCr (both P<0.001). Both MTX concentrations and elimination time decreased with increasing CCr (P<0.05 and P<0.001, respectively). Receiver operating characteristic curves revealed that the best predictors of delayed MTX elimination were 24 hour CCr <100 mL/min (sensitivity: 67.6%; specificity: 72.1%) and 24 hour Cr concentration >36 mmol/L (sensitivity: 64.7%; specificity: 77.4%) (both P < 0.001). CCr and serum Cr concentration may be useful for monitoring plasma MTX concentrations in children receiving HDMTX for ALL and NHL and for predicting delayed MTX elimination.

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Methotrexate Systemic Clearance Influences Probability of Relapse in Children With Standard-Risk Acute Lymphocytic Leukaemia

Cited by 115 publications

References 12 publications

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

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

Genome-wide study of methotrexate clearance replicates SLCO1B1

Creatinine clearance rate and serum creatinine concentration are related to delayed methotrexate elimination in children with lymphoblastic malignancies

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