Glucarpidase significantly improves kidney recovery and reduces certain toxicities in adults experiencing acute kidney injury (AKI) following high-dose methotrexate (MTX) treatment, according to a recent study involving 708 patients across 28 cancer centers in the U.S. The research, utilizing a sequential target trial emulation framework, demonstrated that glucarpidase administration was associated with a 2.7-fold increase in the odds of kidney recovery at hospital discharge (95% CI, 1.69–4.31). These findings, published in Blood, highlight the potential of glucarpidase to improve outcomes in this vulnerable patient population.
Enhanced Kidney Recovery and Reduced Toxicities
The study's primary endpoint, kidney recovery at hospital discharge, was defined as survival to discharge with serum creatinine less than 1.5 times baseline and without dialysis dependence. Key secondary endpoints included time-to-kidney recovery, neutropenia and transaminitis on day 7, and time-to-death. The results indicated that patients treated with glucarpidase experienced faster time-to-kidney recovery (adjusted hazard ratio [aHR], 1.88, 95% CI, 1.18–3.33) and lower risks of grade ≥2 neutropenia (adjusted odds ratio [aOR], 0.50, 95% CI, 0.28–0.91) and grade ≥2 transaminitis (aOR, 0.50, 95% CI, 0.28–0.91) on day 7. There was no significant difference in time-to-death between the groups (aHR, 0.76; 95% CI, 0.49–1.18).
Clinical Significance and Context
High-dose methotrexate is a common and effective chemotherapy agent, particularly in treating lymphomas and leukemias affecting the central nervous system. However, it is associated with significant toxicities, including AKI, neutropenia, and hepatotoxicity. AKI occurs in approximately 9% of patients receiving methotrexate. Glucarpidase, a recombinant enzyme that cleaves methotrexate, has been approved by the FDA since 2012 for treating patients with toxic levels of methotrexate due to kidney failure. However, prior to this study, robust clinical data supporting its use were limited.
Study Design and Patient Population
The study included adults aged 18 years or older who received high-dose intravenous methotrexate and developed methotrexate-associated AKI, defined as a ≥1.5-fold increase in serum creatinine within 4 days after methotrexate initiation compared to baseline. Patients with end-stage kidney disease or those likely to die within 2 days of methotrexate initiation were excluded. Of the 708 patients included, 209 (29.5%) received glucarpidase. The researchers used multivariable logistic and Cox regression models to compare outcomes between patients who received glucarpidase within 4 days of MTX initiation and those who did not.
Implications for Clinical Practice
The findings suggest that glucarpidase may offer substantial benefits in improving both renal and extrarenal outcomes in patients with MTX-AKI. "The study very clearly shows that glucarpidase improved the primary outcome of kidney recovery at time of hospital discharge, time-to-kidney-recovery, and potentially has benefits to other organs," said Dr. Shruti Gupta, MD, MPH, of Brigham and Women's Hospital and Harvard Medical School, lead author of the study. The results may help reduce the observed intrahospital variation in glucarpidase use, which has been attributed to limited data on its clinical effectiveness beyond simply lowering methotrexate levels.
