A recent study presented at the American Society of Hematology meeting in San Diego, CA, indicates that glucarpidase significantly improves clinical outcomes in patients with high-dose methotrexate (HDMTX)-associated acute kidney injury (AKI). The study, the largest of its kind, compared outcomes of 708 adults with HDMTX-AKI, with 209 receiving glucarpidase and 499 not receiving the treatment. The research highlights the potential of glucarpidase to enhance kidney recovery and reduce mortality in this patient population.
Improved Kidney Recovery and Reduced Mortality
The study, conducted by researchers from Brigham and Women’s Hospital/Dana-Farber Cancer Institute and Harvard Medical School across 27 major cancer centers in the US, defined HDMTX-AKI as a ≥1.5-fold increase in serum creatinine (SCr) within 4 days following HDMTX treatment. The results demonstrated that patients treated with glucarpidase had a 2.41-fold higher adjusted odds of kidney recovery at hospital discharge (95% CI, 1.33–4.37) compared to those not treated with the drug.
Furthermore, the benefits of glucarpidase were even more pronounced when administered early (within 60 hours of HDMTX initiation) and in patients with severe AKI (stage 3). In these subgroups, the odds ratios for kidney recovery were 4.67 (95% CI, 2.33–9.36) and 7.22 (95% CI, 2.70–19.31), respectively. The adjusted mortality rate at 90 days was also significantly lower in the glucarpidase group (10.1%) compared to the non-glucarpidase group (18.2%), with a hazard ratio of 0.45 (95% CI, 0.26–0.88).
Additional Benefits
Beyond kidney recovery and mortality, glucarpidase treatment was associated with a lower likelihood of neutropenia and transaminitis at day 7. The rate of kidney recovery by day 14 was also higher in the glucarpidase group (31.4%) compared to the non-glucarpidase group (22.1%), with a hazard ratio of 0.58 (95% CI, 0.34-0.97).
Expert Commentary
Dr. Shruti Gupta, MD, MPH, Director of Onconephrology in the Division of Renal Medicine, Brigham and Women’s Hospital, emphasized the significance of the study, stating, “This is the largest study to date of HDMTX-AKI. It’s also the first to rigorously examine whether glucarpidase improves clinical outcomes in patients with HDMTX toxicity compared to controls not treated with glucarpidase.”
Dr. David E. Leaf, MD, MMSc, of the Division of Renal Medicine, Brigham and Women’s Hospital, and Harvard Medical School, added, “There is currently wide variation in the use of glucarpidase across institutions. Although this is an observational study, our data strongly support use of glucarpidase in patients with HDMTX-AKI, particularly in those who can receive it early (first 60 hours following initiation of HDMTX) and those with severe (stage 3) AKI.”
About High-Dose Methotrexate and Glucarpidase
HDMTX, defined as methotrexate doses >500 mg/m2, is a critical component in the treatment of osteosarcoma, leukemia, and lymphoma involving the central nervous system. However, it can lead to HDMTX-induced AKI in up to 12% of patients, causing significant toxicity, including bone marrow suppression and hepatotoxicity.
Voraxaze (glucarpidase) is a carboxypeptidase that cleaves methotrexate into inactive metabolites for nonrenal elimination. It is indicated to reduce toxic plasma methotrexate concentrations (greater than 1 micromole per liter) in adult and pediatric patients with delayed methotrexate clearance due to impaired renal function.
