An FDA-approved drug called glucarpidase could serve as an antidote to kidney toxicity in patients receiving the chemotherapy drug methotrexate (MTX), according to a new study by researchers at Mass General Brigham. Using data from 28 major US cancer centers*, researchers examined the association between treatment with glucarpidase, which rapidly removes MTX from the blood, and outcomes in patients with MTX-induced acute kidney injury (AKI). . They found that patients who received glucarpidase had significantly higher chances of kidney recovery compared to those who did not receive this treatment. The results are published in Blood.
“Glucarpidase is unique because it is one of the few potential antidotes available to counteract the high rates of toxicity caused by chemotherapy,” said first author Shruti Gupta, MD, an associate physician in the Division of Renal Medicine at Brigham and Women’s Hospital ( BWH). ), founding member of Mass General Brigham Health System. Gupta is also director of Onconephrology at BWH and the Dana-Farber Cancer Institute. “Although glucarpidase was approved by the FDA in 2012, our study is the first to provide a comprehensive evaluation of its potential clinical benefits.”
Due to its ability to cross the blood-brain barrier, MTX is one of the most widely used chemotherapeutic agents worldwide for cancers affecting the central nervous system. However, high doses of MTX (defined as doses ≥ 500 g/m2) often cause serious complications such as AKI, liver toxicity, and neutropenia (i.e., low white blood cell count). Glucarpidase converts MTX in the blood to inactive metabolites within 15 minutes of administration. Despite its potent biochemical effects, no studies have examined whether these effects translate into clinical benefits. Due to this lack of evidence, there is widespread variation in the use of glucarpidase.
The study, funded by BTG International Inc., a SERB pharmaceutical company, addresses this knowledge gap. The researchers used detailed data from multiple cancer centers to mimic the conditions of a randomized clinical trial, a research method known as objective trial emulation. This approach can estimate the results of an entire clinical trial without the costs, timelines, and biases inherent in clinical trials, especially for relatively rare events in a specific patient population.
“Emulation of objective trials is a way to effectively analyze real-world data and draw causal inferences from them, especially when clinical trials are not available and would be impractical to conduct,” said senior author David E. Leaf, MD, director. of clinical research and translational research in acute kidney injury in the BWH Division of Renal Medicine. “We worked with dozens of our collaborators across 28 sites to extract granular data from medical records, all through manual chart review, which allowed us to account for key variables in our models. This allowed us to have a high degree of confidence in our findings “
The authors evaluated data collected between 2000 and 2022 from 708 patients with MTX-induced AKI, including 209 who received glucarpidase within four days of MTX exposure and 499 who did not. They compared the kidney recovery of the two groups at the time of hospital discharge, based on changes in serum creatinine levels. The researchers also examined the speed of kidney recovery, as well as the incidence of other adverse events, such as liver toxicity and neutropenia.
The analysis revealed that glucarpidase treatment was associated with a 2.7-fold increase in the odds of renal recovery compared to no glucarpidase treatment. Patients who received glucarpidase also had faster renal recovery and a lower risk of severe neutropenia or liver toxicity compared to those who did not receive it.
The authors hope their findings will encourage clinicians to use glucarpidase in patients with renal toxicity from MTX.
“FDA approval is only the first step. If people don’t use the drug, patients don’t benefit from it,” Leaf said. “Our findings offer clinicians evidence-based data supporting glucarpidase.”
Literary paternity: In addition to Gupta and Leaf, General Brigham authors include Sarah A. Kaunfer, Shobana Krishnamurthy, Rafia Ali, Osman A. Yilmam, Sophia L. Wells, Jessica L. Ortega, Olivia L. Green-Lingren, Jian Ni, and Meghan . E. Hiss.