A pooled subgroup analysis of glucarpidase treatment in 86 pediatric, adolescent, and young adult patients receiving high-dose methotrexate therapy in open-label trials.

Abstract

Delayed methotrexate elimination can occur in patients undergoing high-dose methotrexate cancer treatment. Effectiveness of glucarpidase for rapidly reducing methotrexate concentrations was shown in compassionate-use trials in patients aged 0-84years. We performed post hoc analyses of infants (≥28days to <2years), children (≥2 to <12years), adolescents (≥12 to <15years), and young adults (≥15 to <25years) from four multicenter, open-label, single-arm, glucarpidase compassionate-use trials. Patients had toxic methotrexate levels due to delayed methotrexate elimination and/or renal dysfunction, and received glucarpidase (50U/kg). The primary endpoint was clinically important reduction (CIR) in plasma methotrexate (methotrexate ≤1μmol/L at all post-glucarpidase measurements) based on high-performance liquid chromatography. Among 86 patients included in efficacy analyses, CIR was achieved by zero of one infant (0.0%), five of 16 children (31.3%), seven of 24 adolescents (29.2%), and 26/45 young adults (57.8%). Median methotrexate reduction was 98.7% or higher in each group 15minutes post-glucarpidase. Patients with pre-glucarpidase methotrexate less than 50μmol/L (35/42, 83.3%) were more likely to achieve CIR than those with methotrexate 50μmol/L or higher (1/37, 2.7%). The most common treatment-related adverse event was paresthesia, occurring in three adolescents (4.5%) and six young adults (5.2%). No other treatment-related adverse event occurred in 5% or higher of any age group. After accounting for pre-glucarpidase methotrexate levels, glucarpidase efficacy at inducing CIR in pediatric/young adult patients was consistent, with efficacy observed in the overall study population (i.e., patients aged 0-84), and no unexpected safety findings were observed. These findings demonstrate glucarpidase (50U/kg) is an effective and well-tolerated dose for pediatric, adolescent, and young adult patients.