Clinical Outcomes in Patients with High-Dose Methotrexate Toxicity Treated with Vs. without Glucarpidase

Background. High-dose methotrexate (HDMTX) is a cornerstone of treatment for lymphoma and leukemia involving the central nervous system, but can cause significant toxicity, which manifests predominantly as acute kidney injury (AKI) as well as bone marrow suppression and hepatotoxicity. Glucarpidase is a recombinant bacterial enzyme that cleaves 99% of circulating MTX to inactive metabolites within 15 minutes of its administration. It is approved for use in the setting of supratherapeutic MTX levels to mitigate renal and extrarenal toxicity. Despite its potent biochemical effects, no study has rigorously examined whether glucarpidase improves clinical outcomes in patients with HDMTX toxicity compared to controls not treated with glucarpidase. This key evidence gap has led to wide variation in the use of glucarpidase across institutions.

Methods. We examined the clinical outcomes of patients with HDMTX-associated AKI (HDMTX-AKI) treated with and without glucarpidase across a large multicenter cohort of 684 adults from 26 major cancer centers across the US from 2000 to 2022. HDMTX-AKI was defined as a ≥1.5-fold increase in serum creatinine (SCr) within 4 days following treatment with HDMTX. We collected data on demographics, comorbidities, medications, laboratory values, and outcomes.

The primary outcome was renal recovery, defined as a return of SCr to <1.5-fold baseline and absence of renal replacement therapy-dependence at hospital discharge. Prespecified subgroup analyses included those treated with glucarpidase in the first 60 hours following MTX initiation, and those with AKI stage 3 (increase in SCr ≥3-fold baseline) in the first 4 days following treatment with HDMTX. Secondary outcomes included absence of neutropenia, transaminitis, and mucositis on day 7.

We used multivariable logistic regression to adjust for potential confounders. Models were adjusted for age, sex, race, baseline eGFR, body mass index, hypertension, diabetes mellitus, coronary artery disease, congestive heart failure, chronic liver disease, baseline WBC count, serum albumin, and LDH, MTX dose and infusion duration, urine pH, volume of IV fluids administered, leucovorin dose, and maximum fold-change in SCr, oliguria, and receipt of concomitant nephrotoxins in the first 4 days following MTX initiation.

Results. Among the 684 patients with HDMTX-AKI, 207 (30.3%) were treated with glucarpidase and 477 (69.7%) were not. All patients treated with glucarpidase received it within the first 96 hours following initiation of HDMTX. The median time from HDMTX initiation to glucarpidase receipt was 54 hours (IQR, 44-66), with 65% of the patients receiving it within 60 hours, and 85% within 72 hours. Patients treated vs. not treated with glucarpidase were similar with respect to age, sex, race, MTX dose and infusion duration, and most baseline labs, including SCr, but had high higher plasma MTX levels at 24 and 36 hours and more severe AKI ( Table).

Glucarpidase receipt was associated with a 2.43-fold higher adjusted odds of renal recovery (95% CI, 1.38-4.27) compared to no glucarpidase receipt ( Figure). The magnitude of association was considerably higher when the analysis was restricted to those treated with glucarpidase in the first 60 hours (odds ratio 4.94 [95% CI, 2.42-10.06] and to those with AKI stage 3 (odds ratio 7.08 [95% CI, 2.27-22.10]) ( Figure). Glucarpidase receipt was also associated with a higher likelihood of recovery from neutropenia and normalization of alanine aminotransferase (ALT) by day 7 ( Figure). There was no significant association between glucarpidase receipt and mucositis on day 7 ( Figure).

Conclusions. In the largest study to date of HDMTX-AKI and the only one, to our knowledge, to include control patients, we found that patients who received glucarpidase had considerably higher odds of renal recovery, as well as recovery from neutropenia and normalization of liver enzymes, compared to those who did not receive glucarpidase. The magnitude of association with renal recovery was particularly evident in those treated with glucarpidase in the first 60 hours and in those with AKI stage 3. Though this is an observational study with the potential for residual confounding, our data support use of glucarpidase in patients with HDMTX-AKI, particularly in the first 60 hours following initiation of MTX.