A new study suggests that glucarpidase, an FDA-approved drug, may act as a remedy for kidney damage in patients undergoing treatment with the chemotherapy drug methotrexate (MTX). Researchers at Mass General Brigham analyzed data from 28 prominent cancer centers across the U.S. to investigate how glucarpidase treatment—which helps eliminate MTX from the bloodstream—affects the outcomes for patients suffering from acute kidney injury (AKI induced by MTX). Their findings revealed that patients treated with glucarpidase had a significantly greater likelihood of recovering kidney function compared to those who did not receive this treatment. The results are featured in the journal Blood.
“Glucarpidase is distinctive because it’s among the very few effective antidotes available to combat serious toxicities resulting from chemotherapy,” explained Dr. Shruti Gupta, the principal author and an associate physician in the Renal Medicine Division at Brigham and Women’s Hospital. Gupta also leads Onconephrology at BWH and the Dana-Farber Cancer Institute. “Although the FDA approved glucarpidase in 2012, our research is the first to extensively evaluate its potential clinical advantages.”
MTX, known for crossing the blood-brain barrier, is frequently utilized globally for treating cancers within the central nervous system. However, administering high doses of MTX (≥ 500 mg/m2) can lead to severe side effects, including AKI, liver damage, and low white blood cell counts (neutropenia). Glucarpidase works by transforming MTX in the bloodstream into non-active metabolites within just 15 minutes of administration. Despite its strong biochemical impact, research had not previously confirmed if these effects lead to practical clinical benefits, resulting in varied use of glucarpidase.
This investigation, backed by BTG International Inc., part of SERB Pharmaceuticals, aims to fill that knowledge void. The research team gathered detailed information from various cancer centers to replicate a randomized clinical trial’s conditions—a technique referred to as target trial emulation. This method allows researchers to evaluate outcomes similar to a full clinical trial without the associated costs, time constraints, and potential biases, particularly in populations with relatively rare conditions.
“Target trial emulation is an effective way to analyze real-world data and draw causal conclusions, especially when traditional clinical trials are infeasible,” stated Dr. David E. Leaf, the senior author and director of clinical and translational research in acute kidney injury at BWH’s Renal Medicine Division. “Collaborating with numerous partners across 28 sites, we meticulously sourced data from medical records through manual chart reviews, enabling us to control for important variables in our analyses and thus have high confidence in our conclusions.”
The study examined data from 2000 to 2022, assessing 708 patients diagnosed with MTX-induced AKI—209 patients received glucarpidase within four days after MTX exposure, while 499 did not. The research compared kidney recovery between the two groups at discharge by evaluating changes in serum creatinine levels. Additionally, they investigated the speed of kidney recovery and the occurrence of other complications such as liver toxicity and neutropenia.
The results indicated that glucarpidase treatment was linked to a 2.7-fold enhancement in kidney recovery compared to the non-treated group. Furthermore, patients who received glucarpidase showed quicker recovery of kidney function and a decreased risk of severe neutropenia or liver toxicity in comparison to those who did not receive the treatment.
The authors aspire that their results will motivate healthcare providers to consider glucarpidase as a treatment option for patients experiencing kidney damage due to MTX.
“Receiving FDA approval is only the initial phase. If healthcare professionals do not prescribe the medication, then patients miss out on potential benefits,” added Leaf. “Our results provide clinicians with evidence-based insights advocating for the use of glucarpidase.”
Authorship: Alongside Gupta and Leaf, authors from Mass General Brigham 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. Sise.
