From University Hospital Regensburg, Regensburg, Germany (D.W.); Dana-Farber Cancer Institute and Harvard Medical School (C.C.) and Massachusetts General Hospital (Z.D.), Boston, and Syndax Pharmaceuticals, Waltham (V.R., T.O., P.O.) - all in Massachusetts; Fred Hutchinson Cancer Center, Seattle (S.J.L.); Washington University School of Medicine, St. Louis (I.P.); Centre Hospitalier Universitaire Sainte-Justine, Montreal (H.B.), and the University of British Columbia, Vancouver General Hospital, Vancouver (J.W.) - both in Canada; the Medical College of Wisconsin, Milwaukee (M.H., S.C.); Stanford Health Care, Stanford (S.A.), and City of Hope Medical Center, Duarte (A.S.) - both in California; Hospital Universitario Virgen del Rocío Instituto de Biomedicina de Sevilla (IBiS), CSIC, Universidad de Sevilla, Seville (J.A.P.-S.), Hospital General Universitario Gregorio Marañón, Instituto de Investigación Biomédica Gregorio Marañón, and Universidad Complutense de Madrid, Madrid (M.K.), and Hospital Universitario Marqués de Valdecilla (IDIVAL), University of Cantabria, Santander (A.B.) - all in Spain; the M.D. Anderson Cancer Center, Houston (A.A.); the James Cancer Hospital and Solove Research Institute and Ohio State University Wexner Medical Center, Columbus (H.C.); Seoul National University College of Internal Medicine, Seoul, South Korea (I.K.); Hôpital Saint-Louis and University Paris Cité, Paris (G.S.); Incyte Corporation, Wilmington, DE (C.T.); and Vanderbilt University Medical Center, Nashville (C.L.K.).
N Engl J Med. 2024 Sep 19;391(11):1002-1014. doi: 10.1056/NEJMoa2401537.
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.
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%.
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.
Targeting CSF1R-dependent monocytes and macrophages with axatilimab resulted in a high incidence of response among patients with recurrent or refractory chronic GVHD. (Funded by Syndax Pharmaceuticals and Incyte; AGAVE-201 ClinicalTrials.gov number, NCT04710576.).
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）的主要介导者，GVHD 是异基因造血干细胞移植的一种主要长期并发症。CSF1R 阻断抗体 axatilimab 在慢性 GVHD 中显示出有前景的临床活性。
在这项 2 期、多国、关键、随机研究中，我们评估了 axatilimab 在三种不同剂量下在复发或难治性慢性 GVHD 患者中的作用。患者被随机分配接受静脉内给药的 axatilimab，剂量分别为每公斤体重 0.3 毫克（0.3mg 剂量组）、每公斤体重 1 毫克（1mg 剂量组）或每公斤体重 3 毫克（3mg 剂量组），每两周一次。主要终点是前六个周期的总体反应（完全或部分反应）；关键次要终点是患者报告的慢性 GVHD 症状负担减轻，通过改良 Lee 症状量表（范围为 0 至 100，分数越高表示症状越严重）评分降低超过 5 分来评估。如果 95%置信区间的下限超过 30%，则主要终点将得到满足。
共有 241 名患者入组（0.3mg 剂量组 80 例，1mg 剂量组 81 例，3mg 剂量组 80 例）。所有组均达到了主要终点；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% CI，39 至 61）的患者观察到总体反应。三个剂量组中分别有 60%、69%和 41%的患者报告改良 Lee 症状量表评分降低超过 5 分。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。axatilimab 导致停药的不良事件分别发生在 0.3mg 剂量组 6%、1mg 剂量组 22%和 3mg 剂量组 18%的患者中。
用 axatilimab 靶向 CSF1R 依赖性单核细胞和巨噬细胞可使复发或难治性慢性 GVHD 患者的反应发生率很高。（由 Syndax 制药公司和 Incyte 公司资助；AGAVE-201 ClinicalTrials.gov 编号，NCT04710576）。
