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

Abstract

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.

Statistical analysis of relation between plasma methotrexate concentration and toxicity in high‐dose methotrexate therapy of childhood nonHodgkin lymphoma

“…However, there have been controversial studies for relation between creatinine concentrations and plasma MTX levels. One study of children who received 3 or 5 g/m 2 of HDMTX has shown a positive correlation between serum creatinine concentrations and blood MTX levels whereas, another study for children who received 1 or 2 g/m 2 failed to show the positive association . Although creatinine clearance is not steady, it is unlikely that creatinine clearance may change during administration of HDMTX, since all patients were strictly monitored and maintained a high urine output and urinary alkalization during HDMTX administration in our study.…”

Renal function as a predicting model for plasma methotrexate concentration after high-dose methotrexate chemotherapy in pediatric malignancy

“…Thus, we investigated the hypothesis that evaluating renal function may be an appropriate means of monitoring plasma MTX concentrations after HDMTX for pediatric cancers. Additionally, previous studies reported the same findings regarding the correlation between Cr clearance and MTX concentration at the same time (7,23,24). On the contrary, other studies such as Joannon et al (25), Evans et al (26) and Relling et al (27) found that plasma MTX concentration was not correlated with Cr clearance.…”

Urine NGAL and KIM-1: tubular injury markers in acute lymphoblastic leukemia survivors

“…One of the first surveys was based on creatinine level during and immediately after MTX infusions. They indicated the detrimental effect of methotrexate on renal function by lowering creatinine clearance and increasing serum creatinine, especially in patients with delayed MTX elimination [26][27][28]. In a group of 20 children with newly diagnosed ALL, treated with MTX at a dose of 5 g/m 2 , Ylinen et al observed an elevated cystatin C concentration 36 h after the infusion, but no changes in NGAL level were noted [29].…”