Glucarpidase for treatment of high-dose methotrexate toxicity
Shruti Gupta, Sarah Allison Kaunfer, Kevin L. Chen, Julie‐Alexia Dias, Anitha Vijayan, Arun Rajasekaran, Jason Prosek, Huong L. Truong, Anthony C. Wood, Claude Bassil, Amanda D. Renaghan, Chintan V. Shah, Jingjing Zhang, Ilya Glezerman, Christopher A. Carlos, Katherine J. Kelly, Christopher J. Passero, Jan Drappatz, Ala Abudayyeh, Daniel Sanghoon Shin, C. John Sperati, Bradley Yelvington, Swetha Rani Kanduri, Javier A. Neyra, Daniel Edmonston, Anushree C. Shirali, Anip Bansal, Abdallah Sassine Geara, Zain Mithani, Susan Ziolkowski, Arash Rashidi, Jonathan Jakubowski, Ashwini Pujari, David A. Bond, Emily Dotson, Sarah Wall, John T. Patton, Jason N. Barreto, Sandra M. Herrmann, M. Salman Sheikh, Rachid Baz, Jamie Lee, Nicholas Lucchesi, Michael David Kolman, Muhammad Ahsan Rasheed, Afsheen Afzal, Dasol Kang, Amrita Mahesh, Raymond K. Hsu, Anthony Nicolaysen, Kibrewessen Tefera, Claire F. Schretlen, Ryan M. Miller, Juan Carlos Q. Velez, Alexander H. Flannery, Abinet M. Aklilu, Shuchi Anand, Soniya Chandrasekhara, Vicki Donley, Ashka Patel, Jian Ni, Shobana Krishnamurthy, Rafia Ali, Osman A Yilmam, Sophia L. Wells, Jessica L. Ortega, Olivia Green‐Lingren, Rebecca Karp Leaf, Meghan E. Sise, Lakshmi Nayak, Ann S. LaCasce, Nelson Leung, David E. Leaf
Abstract
ABSTRACT: High-dose methotrexate (MTX) results in high rates of acute kidney injury (AKI), neutropenia, and hepatotoxicity. Glucarpidase is a recombinant enzyme that cleaves MTX, but clinical data supporting its use are scarce. We examined the association between glucarpidase administration and outcomes in adults with MTX-AKI from 28 cancer centers across the United States using a sequential target trial emulation framework. The primary end point was kidney recovery at hospital discharge, defined as survival to discharge with serum creatinine <1.5-fold baseline and without dialysis dependence. Key secondary end points were time to kidney recovery, neutropenia, and transaminitis on day 7, and time to death. Using multivariable logistic and Cox regression models, we compared outcomes in patients who received glucarpidase within 4 days following MTX initiation with those in patients who did not. Among 708 patients with MTX-AKI, 209 (29.5%) received glucarpidase. Overall, 183 (25.8%) had a primary end point event. Glucarpidase receipt was associated with a 2.70-fold higher adjusted odds of kidney recovery (95% confidence interval [CI], 1.69-4.31) compared with no glucarpidase receipt. Patients treated with glucarpidase also had faster time to kidney recovery (adjusted hazard ratio [aHR], 1.88; 95% CI, 1.18-3.33) and lower risks of grade ≥2 neutropenia (adjusted odds ratio [aOR], 0.50; 95% CI, 0.28-0.91) and grade ≥2 transaminitis (aOR, 0.50; 95% CI, 0.28-0.91) on day 7. There was no difference in time to death (aHR, 0.76; 95% CI, 0.49-1.18). These data suggest glucarpidase may improve both renal and extrarenal outcomes in patients with MTX-AKI.