High‐dose methotrexate therapy of childhood acute lymphoblastic leukemia: Lack of relation between serum methotrexate concentration and creatinine clearance

Joannon, P; Oviedo, Iris; Campbell, Myriam; Tordecilla, Juan

doi:10.1002/pbc.20032

Cited by 53 publications

(41 citation statements)

References 19 publications

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“…Although MTX is renally excreted, this suggests that the pharmacokinetics is more complex than previously thought. For example, biliary excretion may be important for some patients [23,24]. Another possible mechanism is genetic variation in proteins involved in MTX metabolism may act independently of renal failure.…”

Section: Discussionmentioning

confidence: 99%

High incidence of methotrexate associated renal toxicity in patients with lymphoma: a retrospective analysis

May

Carson

Butler

et al. 2013

Leukemia & Lymphoma

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High dose methotrexate (HDMTX), defined by doses of methotrexate (MTX) ≥ 1g/m2, is a widely used regimen known to cause renal toxicity. The reported incidence of renal toxicity in osteosarcoma patients is 1.8%, but the incidence in hematologic malignancies is not well characterized. In this retrospective study of 649 cycles of HDMTX in 194 patients, renal toxicity occurred in 9.1% of cycles in patients with lymphoma compared to 1.5% in patients with sarcoma. Older age, male sex, decreased baseline CrCl, and increased proton pump inhibitor use among the lymphoma population likely contributed to the observed difference. The incidence of renal toxicity was independent of the incidence of delayed MTX elimination, suggesting that kidney function is only one factor involved in MTX clearance. Renal toxicity prolonged the duration of hospitalization but severe renal insufficiency was uncommon. No significant impact on progression free or overall survival was observed.

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Section: Discussionmentioning

confidence: 99%

High incidence of methotrexate associated renal toxicity in patients with lymphoma: a retrospective analysis

May

Carson

Butler

et al. 2013

Leukemia & Lymphoma

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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]. Hence, the patients in these studies may have experienced a lesser degree of renal function impairment than those in our study [20].…”

Section: Discussionmentioning

confidence: 83%

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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“…For a systemic application, ~500 mg/m 2 MTX is administered intravenously. 35 In contrast, only ~22 mg/m 2 MTX is used within our study and applied directly to the tumor region. Therefore, a high biosafety is expected and the systemic burden is hypothesized to be considerably lower after the utilization of MTX/MNPs.…”

Section: Discussionmentioning

confidence: 99%

Methotrexate-coupled nanoparticles and magnetic nanochemothermia for the relapse-free treatment of T24 bladder tumors

Stapf

Teichgräber

Hilger

2017

IJN

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Heat-based approaches have been considered as promising tools due to their ability to directly eradicate tumor cells and/or increase the sensitivity of tumors to radiation- or chemotherapy. In particular, the heating of magnetic nanoparticles (MNPs) via an alternating magnetic field can provide a handy alternative for a localized tumor treatment. To amplify the efficacy of magnetically induced thermal treatments, we elucidated the superior tumor-destructive effect of methotrexate-coupled MNPs (MTX/MNPs) in combination with magnetic heating (nanochemothermia) over the thermal treatment alone. Our studies in a murine bladder xenograft model revealed the enormous potential of nanochemothermia for a localized and relapse-free destruction of tumors which was superior to the thermal treatment alone. Nanochemothermia remarkably fostered the reduction of tumor volume. It impaired proapoptotic signaling (eg, p-p53), cell survival (eg, p-ERK1/2), and cell cycle (cyclins) pathways. Additionally, heat shock proteins (eg, HSP70) were remarkably affected. Moreover, nanochemothermia impaired the induction of angiogenic signaling by decreasing, for example, the levels of VEGF-R1 and MMP9, although an increasing tumor hypoxia was indicated by elevated Hif-1α levels. In contrast, tumor cells were able to recover after the thermal treatments alone. In conclusion, nanochemothermia on the basis of MTX/MNPs was superior to the thermal treatment due to a modification of cellular pathways, particularly those associated with the cellular survival and tumor vasculature. This allowed very efficient and relapse-free destruction of tumors.

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High‐dose methotrexate therapy of childhood acute lymphoblastic leukemia: Lack of relation between serum methotrexate concentration and creatinine clearance

Abstract: These results suggest that creatinine clearance is not a good parameter to calculate leucovorin rescue. MTX-related toxicity in this group of patients receiving a dose of 1 or 2 g/m(2) and rescued with leucovorin without monitoring serum MTX levels was acceptable.

Cited by 53 publications

References 19 publications

High incidence of methotrexate associated renal toxicity in patients with lymphoma: a retrospective analysis

High incidence of methotrexate associated renal toxicity in patients with lymphoma: a retrospective analysis

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

Methotrexate-coupled nanoparticles and magnetic nanochemothermia for the relapse-free treatment of T24 bladder tumors

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