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Multicenter Study
. 2025 Apr 24;145(17):1858-1869.
doi: 10.1182/blood.2024026211.

Glucarpidase for treatment of high-dose methotrexate toxicity

Shruti Gupta  1   2   3 , Sarah A Kaunfer  1 , Kevin L Chen  4 , Julie-Alexia Dias  4 , Anitha Vijayan  5   6 , Arun Rajasekaran  7 , Jason M Prosek  8 , Huong L Truong  9   10 , Anthony Wood  11   12 , Claude Bassil  13 , Amanda D Renaghan  14 , Chintan V Shah  15 , Jingjing Zhang  16 , Ilya Glezerman  17   18 , Christopher Carlos  19 , Katherine Kelly  20 , Christopher J Passero  21 , Jan Drappatz  22 , Ala Abudayyeh  23 , Daniel Sanghoon Shin  24 , C John Sperati  25 , Bradley J Yelvington  26 , Swetha R Kanduri  27 , Javier A Neyra  7   28 , Daniel Edmonston  29 , Anushree C Shirali  30 , Anip Bansal  31 , Abdallah Geara  32 , Zain Mithani  33 , Susan L Ziolkowski  34 , Arash Rashidi  35 , Jonathan Jakubowski  5 , Ashwini Pujari  7 , David A Bond  36 , Emily Dotson  37 , Sarah Wall  36 , John Patton  36 , Jason N Barreto  9 , Sandra M Herrmann  38 , Mohammad S Sheikh  38 , Rachid Baz  12 , Jamie Lee  12 , Nicholas Lucchesi  14 , Michael Kolman  15   39 , Muhammad Ahsan Rasheed  16 , Afsheen Afzal  17   18 , Dasol Kang  17   18 , Amrita Mahesh  19 , Raymond K Hsu  19 , Anthony Nicolaysen  40 , Kibrewessen Tefera  40 , Claire Schretlen  25   41 , Ryan M Miller  26 , Juan Carlos Velez  27 , Alexander H Flannery  42 , Abinet M Aklilu  29   43 , Shuchi Anand  34 , Soniya Chandrasekhara  44 , Vicki Donley  35 , Ashka Patel  45 , Jian Ni  46 , Shobana Krishnamurthy  1 , Rafia Ali  1 , Osman A Yilmam  1 , Sophia L Wells  1 , Jessica L Ortega  1 , Olivia L Green-Lingren  1 , Rebecca K Leaf  3   47 , Meghan E Sise  3   48 , Lakshmi Nayak  3   49   50 , Ann S LaCasce  3   50 , Nelson Leung  38 , David E Leaf  1   3
Affiliations
Multicenter Study

Glucarpidase for treatment of high-dose methotrexate toxicity

Shruti Gupta et al. Blood. .

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.

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Conflict of interest statement

Conflict-of-interest disclosure: S.G. was a scientific coordinator for the ASCEND trial (GlaxoSmithKline); served as a consultant for Secretome, Proletariat Therapeutics, and Alexion; and received research support from BTG International, Dana-Farber Cancer Institute’s Wong Foundation, Janssen, and AstraZeneca. D.E.L. received research support from BioPorto, BTG International Ltd, and Metro International Biotech LLC; and served as a consultant for Sidereal Therapeutics, Casma Therapeutics, MexBrain, Entrada Therapeutics, and CardioRenal Systems, Inc. A.V. served as a consultant for Fresenius, NxStage, and Astute; and has received honoraria from Fresenius, Baxter, and Quanta. A.R. has received royalties from Wolters-Kluwer and Elsevier; and research support from Angion Biomedica Corp. J.D. received research support from AstraZeneca and Servier; and is a stockholder of Pfizer, Gilead, and GlaxoSmithKline. A.G. served as a consultant for Kaneka, GlaxoSmithKline, Novartis, Vera, Chinook, ValenzaBio, Alexion Travere, and Calliditas; and received grant support from Amgen, Aurinia Pharmaceuticals, Travere, Chinook, Vera, and ValenzaBio. D.A.B. served as a consultant for Nurix Therapeutics, SeaGen, Novartis, and Kite/Gilead; and received research funding from Novartis, Nurix Therapeutics, Incyte, GenMab, Kite/Gilead, and Bristol Myers Squibb. M.E.S. received research funding from Angion, Otsuka, Gilead, AbbVie, Cabaletta, Novartis, and EMD Serono; served as a consultant for Resonance; is a Data Safety and Monitoring Board member of Alpine Immunosciences; and served on the scientific advisory boards of Vera, Travere, Calliditas, Mallinckrodt, and Novartis. A.S.L. has served as a consultant for Genmab, Pierre Fabre, Seagen, Kite Pharma, and Research to Practice Speaker’s Bureau. A.C.S is a consultant for OnVIv; and has served as a consultant for Vivace Therapeutics. L.N. has received consulting fees from Ono, Brave Bio, Genmab, and Curis; has received support from Ono, Kite/Gilead, Miltenyi, Curis, Merck, Astra Zeneca, and Kazia; honorariums from Ono and Astra Zeneca; royalties from Wolters Kluwer/UpToDate Inc; and grant support from the Leukemia & Lymphoma Society. R.K.L received consulting fees from Alnylam Pharma and Recordati Pharma; and received grant support from Disc Medicine. N.L. received grant funding from Omeros; and is a stockholder of AbbVie and Checkpoint Therapeutics. The remaining authors declare no competing financial interests.

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