A pooled subgroup analysis of glucarpidase treatment in 86 pediatric,adolescent, and young adult patients receiving high-dose methotrexate therapy in open-label trials |
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| Authors: | Katherine A Janeway Luis Gros Stefan Schwartz Claire Daugherty Eva Gallardo Christon Hill Emma Thomas Suzanne Ward Carmelo Rizzari |
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| Institution: | 1. Dana-Farber/Boston Children's Cancer and Blood Disorders Center and Harvard Medical School, Boston, Massachusetts, USA;2. Vall d'Hebron Research Institute and Department of Pediatric Hematology and Oncology, Vall d'Hebron University Hospital, Barcelona, Spain;3. Department of Hematology, Oncology and Tumor Immunology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität and Humboldt-Universität zu Berlin, Campus Benjamin Franklin, Berlin, Germany;4. BTG International Inc., Conshohocken, Pennsylvania, USA;5. Protherics Medicines Development Ltd., London, UK;6. Unit of Pediatrics, Foundation IRCCS San Gerardo dei Tintori, Monza, Italy |
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| Abstract: | Background 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 0–84 years. Methods We performed post hoc analyses of infants (≥28 days to <2 years), children (≥2 to <12 years), adolescents (≥12 to <15 years), and young adults (≥15 to <25 years) 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 (50 U/kg). The primary endpoint was clinically important reduction (CIR) in plasma methotrexate (methotrexate ≤1 μmol/L at all post-glucarpidase measurements) based on high-performance liquid chromatography. Results 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 15 minutes post-glucarpidase. Patients with pre-glucarpidase methotrexate less than 50 μmol/L (35/42, 83.3%) were more likely to achieve CIR than those with methotrexate 50 μmol/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. Conclusion 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 (50 U/kg) is an effective and well-tolerated dose for pediatric, adolescent, and young adult patients. |
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| Keywords: | acute kidney injury delayed elimination glucarpidase methotrexate |
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