Glucarpidase May Improve Renal Outcomes in Lymphoma, Leukemia

Patients with lymphoma or leukemia and methotrexate-induced kidney injury who received glucarpidase treatment had improved renal outcomes and faster recovery times.

Patients with lymphoma or leukemia involving the central nervous system with methotrexate (MTX)–induced acute kidney injury (AKI) experienced improved renal and extrarenal outcomes following treatment with glucarpidase, a recombinant enzyme that cleaves MTX, according to a trial which utilized data from 28 cancer centers across the U.S. which was published in Blood.

Among 708 patients with MTX-AKI who were evaluated, 209 (29.5%) received glucarpidase and 499 (70.5%) did not. Treatment with glucarpidase was associated with a 2.7-fold higher adjusted odds of kidney recovery versus no glucarpidase treatment. Patients treated with glucarpidase also had faster time-to-kidney recovery and lower risks of grade 2 (moderate) or higher neutropenia and grade 2 or higher transaminitis on day 7. There was no difference in time-to-death.

“In this multicenter cohort study of 708 adults with MTX-AKI from 28 cancer centers across the U.S., patients treated with glucarpidase had a higher adjusted odds of kidney recovery as well as faster time-to-kidney recovery compared [with] those not treated with glucarpidase. They also had a lower adjusted odds of grade 2 or higher neutropenia and transaminitis,” Dr. Shruti Gupta and study co-authors wrote in the journal.

Gupta currently serves as an Instructor of Medicine at Harvard Medical School, as well as Director of Onco-Nephrology, Associate Physician in the Division of Renal Medicine in the Department of Medicine, Brigham and Women's Hospital and Dana-Farber Cancer Institute.

Glucarpidase rapidly deactivates circulating MTX, but its impact on clinical outcomes remains unproven, leading to inconsistent use and varying recommendations. In the absence of randomized clinical trial data, a target trial emulation framework offers an alternative approach, applying rigorous principles such as specified inclusion criteria and adjustments for baseline characteristics to reduce biases. With that being said, investigators then evaluated the effect of glucarpidase on outcomes like kidney recovery, neutropenia, hepatotoxicity, mucositis, and mortality among patients with MTX-associated AKI across numerous U.S. cancer centers.

Breaking Down the Investigation

Adult patients aged 18 years or older who received high-dose intravenous (IV) MTX and developed MTX-AKI, defined as a greater than or equal to 1.5-fold increase in serum creatinine within 4 days after initiation of MTX compared with the baseline value obtained immediately prior. However, patients with end-stage kidney disease were excluded as were those who were moribund (likely to die within two days) at the time of MTX initiation.

The investigators created a trial in which adult patients with MTX-AKI received or did not receive glucarpidase. Using data from patients treated at 28 cancer centers across the U.S. from 2000 to 2022, investigators reviewed data from electronic medical records or charts. These data included demographics and comorbidities, malignancy type, MTX infusion characteristics, concomitant chemotherapy and treatments, baseline and follow-up laboratory values at 7 days (±2) following MTX, 24-hour plasma MTX levels, initial severity of AKI in the first four days following MTX and oliguria in the first four days following MTX initiation. Investigators also collected data on the timing and dose of glucarpidase and associated side effects, in addition to daily data on IV fluids, leucovorin and urine pH.

Investigators collected daily data on serum creatinine (SCr) for the first 14 days following MTX initiation, at hospital discharge, and on days 30 (±15), 60 (±15), and 90 (±30), along with data on receipt of kidney replacement therapy (KRT) and mortality, as well as data on neutropenia, transaminitis and mucositis on day 7 (±2) following MTX initiation. Notably, patients were grouped according to glucarpidase treatment within four days following initiation of MTX.

The primary end point of the study was kidney recovery at hospital discharge, defined as survival to discharge with SCr less than 1.5-fold baseline and without dialysis-dependence. Additionally, key secondary end points were time-to-kidney recovery, neutropenia and transaminitis on day 7 and time-to-death.

Additional Data From the Study and Next Steps For Research

“Patients treated versus not treated with glucarpidase were similar with respect to age, sex, race, duration and dose of MTX infusion, and most baseline laboratory values. However, glucarpidase-treated patients were more likely to have hypertension, diabetes mellitus, and other comorbidities, and to have received concomitant nephrotoxic medications,” study authors noted in the journal article.

Patients treated with glucarpidase exhibited higher plasma MTX concentrations at 24, 36 and 48 hours, along with more severe AKI versus those not treated with glucarpidase. These patients also received greater volumes of intravenous fluids and leucovorin. While their urine pH at MTX initiation was lower, no significant differences in urine pH were observed between the groups over time. Overall, 6.4% of patients (45 patients) required KRT, including 33 glucarpidase-treated patients and 12 non-glucarpidase-treated patients.

Furthermore, the odds of kidney recovery in patients versus those not treated with glucarpidase was higher among those with stage 3 AKI compared with stages 1 or 2; however, this did not reach statistical significance. Glucarpidase-treated patients had a decreased odds of grade 2 or higher neutropenia on day 7 but not more than or equal to grade 3 (severe) neutropenia, as well as had a lower odd of grade 2 or higher transaminitis, but not any grade of transaminitis. A sensitivity analysis adjusted for a smaller number of covariates with respect to grade 2 or higher transaminitis resulted in similar findings. The odds of mucositis (of any grade) and the odds of kidney impairment or death at day 90 were similar between groups. Additionally, the odds of MTX rechallenge within 30 days was lower in glucarpidase- treated patients.

Looking to mortality, a total of 99 patients (14%) died within 90 days. Cancer-related disease progression was the most common cause of death, occurring in 18 of 33 glucarpidase-treated patients (54.5%) and in 40 of 66 non- glucarpidase-treated patients (60.6%) who died.

“We found that patients with MTX-AKI treated with glucarpidase had a higher adjusted odds of kidney recovery compared to those not treated with glucarpidase. Randomized clinical trials are needed to confirm our findings, and also to explore the efficacy of glucarpidase in patients with plasma MTX levels that do not meet thresholds suggested by current guidelines, authors concluded.

Reference:

“Glucarpidase for Treatment of High-Dose Methotrexate Toxicity” by Dr. Shruti Gupta, et al., Blood.

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