Glucarpidase improves recovery after chemotherapy-induced kidney toxicity
Key takeaways:
- Patients who received glucarpidase for acute kidney injury from methotrexate treatment had improved kidney function.
- Recovery time also improved for patients who received glucarpidase.
Glucarpidase significantly improved kidney function for patients who developed acute kidney injury from high-dose methotrexate, according to results of a large, multicenter observational study.
Glucarpidase (Voraxaze, BTG International) also accelerated kidney recovery time and resulted in lower odds for other adverse events, including neutropenia and transaminitis.
“Especially for patients with severe kidney toxicity from methotrexate — which is where we saw a particularly pronounced benefit — our data suggest that glucarpidase should be the standard of care,” David E. Leaf, MD, MMSc, associate professor of medicine at Harvard Medical School and director of clinical and translational research in acute kidney injury in the division of renal medicine at Brigham and Women’s Hospital, told Healio.
Background and methods
High-dose methotrexate is a chemotherapy drug frequently used to treat lymphoma or leukemia that involves the central nervous system due to its ability to penetrate the blood-brain barrier, according to study background.
Approximately 9% of adults who receive methotrexate develop acute kidney injury, and this complication has been linked to higher mortality risk.
Methotrexate also can cause hepatotoxicity and neutropenia.
In 2012, the FDA approved glucarpidase as an antidote to reduce methotrexate levels. However, its use in practice has varied due to high cost and limited data on clinical outcomes.
“It was approved without actually having much clinical data to back up its use,” Shruti Gupta, MD, MPH, assistant professor at Harvard Medical School and director of onco-nephrology at Brigham and Women’s Hospital and Dana-Farber Cancer Institute, told Healio. “Its approval was largely based on biochemical data, and the fact that it clears 99% of methotrexate from the blood very rapidly — within 15 minutes. What motivated our study was to actually test whether glucarpidase improves clinical outcomes.”
Gupta, Leaf and colleagues analyzed outcomes among 708 adults with high-dose methotrexate-associated acute kidney injury treated at 28 U.S. cancer centers between 2000 and 2022.
The researchers defined acute kidney injury as at least a 1.5-fold increase in serum creatinine within 4 days following treatment with methotrexate.
Kidney recovery at hospital discharge served as the primary endpoint. Time to kidney recovery in the first 14 days after treatment served as a key secondary endpoint. Other endpoints included neutropenia and transaminitis 7 days after treatment.
Results
More than one-quarter (29.5%; median age, 64 years; interquartile range, 51-71; 70.8% men; 84.2% white) of the cohort received glucarpidase. The other 70.5% (median age, 64 years; interquartile range, 55-71; 69.5% men; 84.4% white) did not.
Glucarpidase administration occurred at a median 54 hours (interquartile range, 44-66) after methotrexate initiation. All glucarpidase treatments occurred within 96 hours following methotrexate initiation.
Patients who received glucarpidase had significantly higher odds of kidney recovery (adjusted OR = 2.7; 95% CI, 1.69-4.31).
Patients with stage III acute kidney injury appeared to derive more benefit than those with stage I or stage II, but the difference did not reach statistical significance.
“Among those with stage III acute kidney injury, the odds of kidney recovery was nearly 5-fold higher among those treated with glucarpidase vs. those not treated with glucarpidase,” Leaf said. “If there’s anywhere where the data are a little bit more nebulous, I think it’s with the patients with more mild kidney injury, though even in those patients we found benefit.”
Patients who received glucarpidase also had a faster time to kidney recovery (adjusted HR = 1.88; 95% CI, 1.18-3.33).
Additionally, they had lower odds of developing grade 2 or higher neutropenia (adjusted OR = 0.5; 95% CI, 0.28-0.91) and grade 2 or higher transaminitis (adjusted OR = 0.31; 95% CI, 0.13-0.77).
“I was skeptical that we were going to find a benefit,” Leaf said. “This biochemical effect — where the levels of methotrexate in the blood basically disappear within a few minutes — may not translate into clinical benefit because by the time patients receive this antidote, it’s usually a couple days after they’ve received the methotrexate. By that time, the methotrexate is already inside your cells in the kidney, in the liver. Glucarpidase does not get into the cells. It only gets rid of the methotrexate that’s in the blood. That’s why I and many researchers were dubious of its effects. I was very excited with the results.”
Glucarpidase-related adverse events included nausea (5.7%), diarrhea (0.5%) and paresthesia (0.5%).
Researchers acknowledged study limitations, including unbalanced comorbidities among cohorts and lack of data on cancer therapies used following methotrexate.
“It’s nice to be able to tell a patient, ‘We’re hopeful [and] cautiously optimistic that your kidney function will improve with this drug,’” Gupta said.
‘Alleviates’ concerns
Leaf did not expect researchers to conduct a randomized phase 3 trial to further evaluate glucarpidase.
“There has never been a randomized clinical trial in this setting and likely never will be,” he said. “It would not be feasible to be able to recruit the numbers of patients that you would need for such a study. Further, many physicians might feel that there would be a lack of clinical equipoise to randomize patients to a placebo. In other words, it might not be ethical to conduct such a study, especially given the data that we now have.”
However, future studies investigating glucarpidase for patients with lower stages of acute kidney injury or for those who otherwise would not currently qualify for it are warranted, he said.
“If there was ever going to be a randomized clinical trial, I think those are the patients where it would make sense to study further,” Leaf said. “But when we’re looking at patients, we don’t just look at the staging. We also look at the duration of the kidney injury, the methotrexate levels, other organs involved, and the overall trajectory. Are things overall getting better or worse? So it’s a little bit more complicated in the real world.”
Researchers also could evaluate whether glucarpidase benefits patients with high methotrexate levels but no acute kidney injury, Leaf said. The timing of glucarpidase administration also could be assessed, he added.
However, current data should encourage more clinicians to use glucarpidase immediately, researchers concluded.
“Our hope is that when clinicians are reluctant to use it, they can look at these data and see there’s actually good data and evidence to back up that this works,” Gupta said. “It’s not just for improving odds of kidney recovery, but also for prevention of some of those extrarenal toxicities, like neutropenia and elevated liver enzymes. Hopefully, these data will alleviate some of the concerns of skeptics who aren’t currently using glucarpidase.”
For more information:
David E. Leaf, MD, MMsc, can be reached at deleaf@bwh.harvard.edu.
Shruti Gupta, MD, MPH, can be reached at sgupta21@bwh.harvard.edu.
Collapse