Abstract
BackgroundHigh-dose methotrexate (HD-MTX) has broad use in the treatment of central nervous system (CNS) malignancies but confers significant toxicity without inpatient hydration and monitoring. Glucarpidase is a bacterial recombinant enzyme dosed at 50 units (u)/kg, resulting in rapid systemic MTX clearance. The aim of this study was to demonstrate feasibility of low-dose glucarpidase to facilitate MTX clearance in patients with CNS lymphoma (CNSL).MethodsEight CNSL patients received HD-MTX 3 or 6 g/m2 and glucarpidase 2000 or 1000u 24 h later. Treatments repeated every 2 weeks up to 8 cycles.ResultsFifty-five treatments were administered. Glucarpidase 2000u yielded > 95% reduction in plasma MTX within 15 min following 33/34 doses (97.1%) and glucarpidase 1000u yielded > 95% reduction following 15/20 doses (75%). Anti-glucarpidase antibodies developed in 4 patients and were associated with MTX rebound. In CSF, glucarpidase was not detected and MTX levels remained cytotoxic after 1 (3299.5 nmol/L, n = 8) and 6 h (1254.7 nmol/L, n = 7). Treatment was safe and well-tolerated. Radiographic responses in 6 of 8 patients (75%) were as expected following MTX-based therapy.ConclusionsThis study demonstrates feasibility of planned-use low-dose glucarpidase for MTX clearance and supports the hypothesis that glucarpidase does not impact MTX efficacy in the CNS.Clinical trial registrationNCT03684980 (Registration date 26/09/2018).
Highlights
Central nervous system lymphoma (CNSL) is an aggressive but treatable malignancy
Study design and treatment This was a phase 1, investigator-initiated clinical study of High-dose methotrexate (HD-MTX) followed by planned-use low-dose glucarpidase for patients with newly diagnosed or relapsed/ refractory primary (PCNSL) or secondary CNS lymphoma (CNSL) (SCNSL) isolated to the central nervous system
Our study demonstrates the feasibility of planned-use low-dose glucarpidase for rapid plasma MTX reduction in patients with CNSL
Summary
Glucarpidase is a bacterial recombinant enzyme that cleaves MTX to inactive byproducts glutamate and 4-deoxy-4-amino-N10-methylpteroic acid (DAMPA), rapidly reducing plasma MTX levels > 95% [6, 7]. It is approved by the Food and Drug Administration for use in patients with MTX toxicity and renal failure at a dose of 50 units (u)/kg. High-dose methotrexate (HD-MTX) has broad use in the treatment of central nervous system (CNS) malignancies but confers significant toxicity without inpatient hydration and monitoring. The aim of this study was to demonstrate feasibility of low-dose glucarpidase to facilitate MTX clearance in patients with CNS lymphoma (CNSL).
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