An FDA-approved medication called glucarpidase could serve as an antidote to kidney toxicity in patients receiving the chemotherapy drug methotrexate (MTX), according to a new study by investigators at Mass General Brigham. Using data from 28 major U.S. cancer centers, the researchers examined the association between glucarpidase treatment – which rapidly clears MTX from the blood – and outcomes of 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 get this treatment. Results are published in Blood.
"Glucarpidase is unique because it's one of the very 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), a founding member of the Mass General Brigham healthcare system. Gupta is also the director of Onconephrology at BWH and Dana-Farber Cancer Institute. "Even though glucarpidase was approved by the FDA in 2012, our study is the first to provide a comprehensive assessment of its potential clinical benefits."
Due to its ability to penetrate the blood-brain barrier, MTX is one of the most common chemotherapeutic agents used worldwide for cancers involving the central nervous system. However, high doses of MTX (defined as doses ≥ 500 g/m2) often cause severe complications such as AKI, liver toxicity, and neutropenia (i.e., low white blood cell count). Glucarpidase converts MTX in the blood into inactive metabolites within 15 minutes of its administration. Despite its potent biochemical effects, no study has examined whether these effects translate into clinical benefit. Due to this evidence gap, there is widespread variation in the use of glucarpidase.
The study, funded by BTG International Inc., a SERB Pharmaceuticals 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 a target trial emulation. This approach can estimate the outcomes of a full clinical trial without the costs, timescale, and biases inherent in clinical trials, especially for relatively rare events in a specific patient population.
Target trial emulation is a way to effectively analyze real-world data and to draw causal inferences from it, especially when clinical trials are unavailable and would be impractical to perform. We worked with dozens of our collaborators across 28 sites to extract granular data from medical records – all by 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."
David E. Leaf, MD, senior author, director of clinical and translational research in acute kidney injury at BWH's Division of Renal Medicine
The authors evaluated data collected between 2000 and 2022 from 708 patients with MTX-induced AKI, including 209 who received glucarpidase within four days following MTX exposure and 499 who did not. They compared kidney recovery for the two groups at the time of hospital discharge, based on changes in serum creatinine levels. The investigators 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 chances of kidney recovery compared with no glucarpidase. Patients who received glucarpidase also had faster kidney recovery and a lower risk of severe neutropenia or liver toxicity compared to those who did not receive it.
The authors hope that their findings will encourage doctors to use glucarpidase for patients with kidney toxicity from MTX.
"FDA approval is only the first step. If people aren't using the drug, then patients aren't benefiting from it," said Leaf. "Our findings offer clinicians evidence-based data supporting glucarpidase."
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