德国雷根斯堡大学医院Daniel Wolff团队研究了艾克利单抗治疗复发性或难治性慢性移植物抗宿主病的疗效与安全性。相关论文发表在2024年9月19日出版的《新英格兰医学杂志》上。

集落刺激因子1受体（CSF1R）依赖性单核细胞和巨噬细胞是慢性移植物抗宿主病（GVHD）的关键介质，GVHD是异基因造血干细胞移植的主要长期并发症。CSF1R阻断抗体艾克利单抗在慢性GVHD中显示出有前景的临床活性。

在这项2期临床、跨国、关键、随机研究中，研究组评估了三种不同剂量的艾克利单抗对复发性或难治性慢性移植物抗宿主病患者的疗效。将患者随机分配接受艾克利单抗静脉注射，剂量分别为每2周每公斤体重0.3mg（0.3mg剂量组），每2周每公斤体重1mg（1mg剂量组），每4周每公斤体重3mg（3mg剂量组）。主要终点是前六个周期的总体缓解（完全或部分缓解）；关键次要终点是患者报告的慢性移植物抗宿主病症状负担减轻，通过在改良Lee症状量表上减少5分以上来评估（范围为0至100，得分越高表示症状越严重）。如果95%置信区间的下限超过30%，则将达到主要终点。

研究组共招募了241名患者（0.3mg剂量组80名，1mg剂量组81名，3mg剂量组8名）。所有组均达到主要终点；0.3mg剂量组中74%（95%置信区间[CI]，63至83）的患者、1mg剂量组中67%（95%CI，55至77）的患者和3mg剂量组中50%（95%CI39至61）的患者观察到总体缓解。在三个剂量组中，分别有60%、69%和41%的患者在改良Lee症状量表上减少了5分以上。最常见的不良事件是与CSF1R阻断相关的剂量依赖性短暂实验室异常。0.3mg剂量组6%的患者、1mg剂量组22%的患者和3mg剂量组18%的患者发生了导致停用艾克利单抗的不良事件。

研究结果表明，用艾克利单抗靶向CSF1R依赖性单核细胞和巨噬细胞，显著提高了复发性或难治性慢性移植物抗宿主病患者的缓解率。

附：英文原文

Title: Axatilimab in Recurrent or Refractory Chronic Graft-versus-Host Disease

Author: Daniel Wolff, Corey Cutler, Stephanie J. Lee, Iskra Pusic, Henrique Bittencourt, Jennifer White, Mehdi Hamadani, Sally Arai, Amandeep Salhotra, Jose A. Perez-Simon, Amin Alousi, Hannah Choe, Mi Kwon, Arancha Bermúdez, Inho Kim, Gerard Socié, Saurabh Chhabra, Vedran Radojcic, Timothy O’Toole, Chuan Tian, Peter Ordentlich, Zachariah DeFilipp, Carrie L. Kitko

Issue&Volume: 2024-09-19

Abstract:

BACKGROUND

Colony-stimulating factor 1 receptor (CSF1R)–dependent monocytes and macrophages are key mediators of chronic graft-versus-host disease (GVHD), a major long-term complication of allogeneic hematopoietic stem-cell transplantation. The CSF1R-blocking antibody axatilimab has shown promising clinical activity in chronic GVHD.

METHODS

In this phase 2, multinational, pivotal, randomized study, we evaluated axatilimab at three different doses in patients with recurrent or refractory chronic GVHD. Patients were randomly assigned to receive axatilimab, administered intravenously, at a dose of 0.3 mg per kilogram of body weight every 2 weeks (0.3-mg dose group), at a dose of 1 mg per kilogram every 2 weeks (1-mg dose group), or at a dose of 3 mg per kilogram every 4 weeks (3-mg dose group). The primary end point was overall response (complete or partial response) in the first six cycles; the key secondary end point was a patient-reported decrease in chronic GVHD symptom burden, as assessed by a reduction of more than 5 points on the modified Lee Symptom Scale (range, 0 to 100, with higher scores indicating worse symptoms). The primary end point would be met if the lower bound of the 95% confidence interval exceeded 30%.

RESULTS

A total of 241 patients were enrolled (80 patients in the 0.3-mg dose group, 81 in the 1-mg dose group, and 80 in the 3-mg dose group). The primary end point was met in all the groups; an overall response was observed in 74% (95% confidence interval [CI], 63 to 83) of the patients in the 0.3-mg dose group, 67% (95% CI, 55 to 77) of the patients in the 1-mg dose group, and 50% (95% CI, 39 to 61) of the patients in the 3-mg dose group. A reduction of more than 5 points on the modified Lee Symptom Scale was reported in 60%, 69%, and 41% of the patients in the three dose groups, respectively. The most common adverse events were dose-dependent transient laboratory abnormalities related to CSF1R blockade. Adverse events leading to discontinuation of axatilimab occurred in 6% of the patients in the 0.3-mg dose group, 22% in the 1-mg dose group, and 18% in the 3-mg dose group.

CONCLUSIONS

Targeting CSF1R-dependent monocytes and macrophages with axatilimab resulted in a high incidence of response among patients with recurrent or refractory chronic GVHD.

DOI: NJ202409193911107

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa2401537