Routine use of low-dose glucarpidase following high-dose methotrexate in adult patients with CNS lymphoma: an open-label, multi-center phase I study

BMC Cancer. 2022 Jan 13;22(1):60. doi: 10.1186/s12885-021-09164-x.

Abstract

Background: 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. 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).

Methods: Eight 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.

Results: Fifty-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.

Conclusions: This 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 registration: NCT03684980 (Registration date 26/09/2018).

Keywords: CNS lymphoma; Glucarpidase; Methotrexate.

Publication types

  • Clinical Trial, Phase I
  • Multicenter Study

MeSH terms

  • Aged
  • Antineoplastic Agents* / administration & dosage
  • Antineoplastic Agents* / adverse effects
  • Antineoplastic Agents* / therapeutic use
  • Central Nervous System Neoplasms* / drug therapy
  • Central Nervous System Neoplasms* / mortality
  • Female
  • Humans
  • Lymphoma* / drug therapy
  • Lymphoma* / mortality
  • Male
  • Methotrexate* / administration & dosage
  • Methotrexate* / adverse effects
  • Methotrexate* / therapeutic use
  • Middle Aged
  • Recombinant Proteins / administration & dosage
  • Recombinant Proteins / adverse effects
  • Recombinant Proteins / therapeutic use
  • gamma-Glutamyl Hydrolase* / administration & dosage
  • gamma-Glutamyl Hydrolase* / adverse effects
  • gamma-Glutamyl Hydrolase* / therapeutic use

Substances

  • Antineoplastic Agents
  • Recombinant Proteins
  • glucarpidase
  • gamma-Glutamyl Hydrolase
  • Methotrexate

Associated data

  • ClinicalTrials.gov/NCT03684980