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

Lauren R Schaff, Mina Lobbous, Dean Carlow, Ryan Schofield, Igor T Gavrilovic, Alexandra M Miller, Jacqueline B Stone, Anna F Piotrowski, Ugur Sener, Anna Skakodub, Edward P Acosta, Kevin J Ryan, Ingo K Mellinghoff, Lisa M DeAngelis, Louis B Nabors, Christian Grommes, Lauren R Schaff, Mina Lobbous, Dean Carlow, Ryan Schofield, Igor T Gavrilovic, Alexandra M Miller, Jacqueline B Stone, Anna F Piotrowski, Ugur Sener, Anna Skakodub, Edward P Acosta, Kevin J Ryan, Ingo K Mellinghoff, Lisa M DeAngelis, Louis B Nabors, Christian Grommes

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.

Conflict of interest statement

LRS: Research support: BTG; Consultant: DebioPharm; pending patent related to the content of the manuscript. ML, DC, RS, ITG, AMM, JS, AFP, US, AS, EPA, KJR: No disclosures. IKM: Honoraria: Roche; Research Support: Amgen, General Electric, Lilly, Kazia Therapeutics; Consultant: Agios, Black Diamond Therapeutics, DebioPharm, Puma Biotechnology, Voyager Therapeutics, DC Europa Ltd., Kazia Therapeutics, Novartis, Cardinal Health, Roche, Vigeo Therapeutics, Samus Therapeutics.

LMD: Scientific Advisory Board: Sapience Therapeutics; pending patent related to the content of the manuscript. LBN: Scientific Advisory Board: BTG, plc, Karyopharm; pending patent related to the content of the manuscript. CG: Research Support: Pharmacyclics, Bayer, BMS; Consultant: Kite, BTG, ONO; pending patent related to the content of the manuscript.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
Serum methotrexate (MTX) concentrations with glucarpidase. Serum methotrexate concentrations following administration of MTX 3 g/m2 (A) and 6 g/m2 (B) followed by glucarpidase 1000 or 2000u
Fig. 2
Fig. 2
Effect of anti-glucarpidase antibodies on serum methotrexate (MTX concentrations after glucarpidase. (A) MTX concentrations pre- and post-glucarpidase in patients with and without anti-glucarpidase antibody formation. Blue line reflects MTX concentrations in patient with anti-glucarpidase antibodies and red, without. (B) Heat map of MTX rebound data as % of pre-glucarpidase MTX concentration. Cell label represents dose of glucarpidase, either 2000 or 1000 units. Thickened border indicates presence of neutralizing anti-glucarpidase antibody. Patient 6 cycle 1 results not available due to sample loss
Fig. 3
Fig. 3
Methotrexate (MTX) concentrations in cerebrospinal fluid (CSF). Methotrexate concentrations in the serum and cerebrospinal fluid (CSF) pre-, 1 h post-, and 6 h post-glucarpidase. Red bar reflects serum values, blue, cerebrospinal fluid
Fig. 4
Fig. 4
Clinical response in patients treated with methotrexate (MTX) and glucarpidase. (A) Radiographic response to MTX in combination with glucarpidase, assessed using International PCNSL Collaborative Group Guidelines. Displayed is the change in target lesion diameter from baseline (%) by magnetic resonance imaging. Negative values indicate tumor shrinkage. Red indicates progression of disease (PD); orange, stable disease (SD); green, partial response (PR); purple, unconfirmed complete response (CRu); blue, complete response (CR) (B) Kaplan-Meier curves reflecting progression-free (PFS) and overall survival (OS) for study patients

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