用于治疗大剂量甲氨蝶呤毒性的羧肽酶G2

Glucarpidase for treatment of high-dose methotrexate toxicity.

作者信息

Gupta Shruti, Kaunfer Sarah A, Chen Kevin L, Dias Julie-Alexia, Vijayan Anitha, Rajasekaran Arun, Prosek Jason M, Truong Huong L, Wood Anthony, Bassil Claude, Renaghan Amanda D, Shah Chintan V, Zhang Jingjing, Glezerman Ilya, Carlos Christopher, Kelly Katherine, Passero Christopher J, Drappatz Jan, Abudayyeh Ala, Shin Daniel Sanghoon, Sperati C John, Yelvington Bradley J, Kanduri Swetha R, Neyra Javier A, Edmonston Daniel, Shirali Anushree C, Bansal Anip, Geara Abdallah, Mithani Zain, Ziolkowski Susan L, Rashidi Arash, Jakubowski Jonathan, Pujari Ashwini, Bond David A, Dotson Emily, Wall Sarah, Patton John, Barreto Jason N, Herrmann Sandra M, Sheikh Mohammad S, Baz Rachid, Lee Jamie, Lucchesi Nicholas, Kolman Michael, Rasheed Muhammad Ahsan, Afzal Afsheen, Kang Dasol, Mahesh Amrita, Hsu Raymond K, Nicolaysen Anthony, Tefera Kibrewessen, Schretlen Claire, Miller Ryan M, Velez Juan Carlos, Flannery Alexander H, Aklilu Abinet M, Anand Shuchi, Chandrasekhara Soniya, Donley Vicki, Patel Ashka, Ni Jian, Krishnamurthy Shobana, Ali Rafia, Yilmam Osman A, Wells Sophia L, Ortega Jessica L, Green-Lingren Olivia L, Leaf Rebecca K, Sise Meghan E, Nayak Lakshmi, LaCasce Ann S, Leung Nelson, Leaf David E

机构信息

Division of Renal Medicine, Brigham and Women's Hospital, Boston, MA.

Adult Survivorship Program, Dana-Farber Cancer Institute, Boston, MA.

出版信息

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

DOI:10.1182/blood.2024026211

PMID:39760780

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.

摘要

大剂量甲氨蝶呤（MTX）会导致较高的急性肾损伤（AKI）、中性粒细胞减少和肝毒性发生率。羧肽酶G2是一种可裂解MTX的重组酶，但支持其使用的临床数据较少。我们使用序贯目标试验模拟框架，研究了美国28个癌症中心成年MTX-AKI患者中羧肽酶G2给药与预后之间的关联。主要终点是出院时肾脏恢复情况，定义为出院存活且血清肌酐<基线值的1.5倍且无需依赖透析。关键次要终点是肾脏恢复时间、第7天的中性粒细胞减少和转氨酶升高以及死亡时间。我们使用多变量逻辑回归和Cox回归模型，比较了MTX开始使用后4天内接受羧肽酶G2治疗的患者与未接受治疗的患者的预后情况。在708例MTX-AKI患者中，209例（29.5%）接受了羧肽酶G2治疗。总体而言，183例（25.8%）发生了主要终点事件。与未接受羧肽酶G2治疗相比，接受该治疗与肾脏恢复的校正比值高2.70倍相关（95%置信区间[CI]，1.69-4.31）。接受羧肽酶G2治疗的患者肾脏恢复时间也更快（校正风险比[aHR]，1.88；95%CI，1.18-3.33），且第7天发生≥2级中性粒细胞减少（校正比值比[aOR]，0.50；95%CI，0.28-0.91）和≥2级转氨酶升高（aOR，0.50；95%CI，0.28-0.91）的风险更低。死亡时间无差异（aHR，0.76；95%CI，0.49-1.18）。这些数据表明，羧肽酶G2可能改善MTX-AKI患者的肾脏和肾外预后。