"Per aspera ad astra": the transformative contribution of glucarpidase to the improved management of delayed methotrexate elimination after high-dose therapy

Introduction: High-dose methotrexate (HDMTX) is an important therapeutic tool for various malignancies; its use can be associated with severe treatment-emergent toxicities, particularly nephrotoxicity. These can disrupt anticancer treatment and increase morbidity and mortality. Glucarpidase (carboxypeptidase G2), a recombinant bacterial enzyme, rapidly converts toxic levels of circulating methotrexate (MTX) into nontoxic metabolites in patients with delayed MTX elimination and/or at risk of MTX toxicity. The reduction in MTX-associated toxicity and mortality can improve patients' outcomes. MTX elimination prevents the progression of renal toxicity and may minimize treatment disruptions by facilitating resumption of anticancer treatment, including HDMTX rechallenge. Currently, glucarpidase is underused in clinical practice, partly due to accessibility issues and uncertainty regarding treatment timings. Areas covered: This review aims to provide clarity into the optimal application of glucarpidase by exploring its history and development, reviewing the clinical benefits reported in clinical trials and from real-world experiences, and critically considering recommendations for its administration. Expert opinion: Glucarpidase is an invaluable tool in the management of MTX toxicity, allowing rapid and effective reduction of MTX toxic drug levels, especially in patients with compromised renal function. To update glucarpidase administration algorithms, research is needed to evaluate its efficacy in patients with moderate MTX elevations.