德国弗莱堡大学医学中心Robert Zeiser研究团队探讨了鲁索替尼治疗急性移植物抗宿主病的疗效。该成果于2020年4月22日发表在《新英格兰医学杂志》上。

急性移植物抗宿主病（GVHD）仍然是同种异体干细胞移植的主要局限，并非所有患者都对标准糖皮质激素治疗有反应。在一项临床2期试验中，选择性Janus激酶（JAK1和JAK2）抑制剂鲁索替尼在糖皮质激素抵抗性急性GVHD患者中显示出潜在疗效。

研究组进行了一项多中心、随机、开放标签的临床3期试验，招募了309名12岁以上同种异体干细胞移植后糖皮质激素抵抗性急性GVHD的患者，将其随机分组，其中154例口服鲁索替尼，155例接受九种常用治疗方法（对照组），比较两组的疗效和安全性。

鲁索替尼组治疗第28天的总体缓解率为62%，显著高于对照组（39%）。鲁索替尼组在第56天的持久总缓解率为40%，显著高于对照组（22%）。治疗6个月时，鲁索替尼组和对照组的估计累积反应丧失发生率分别为10%和39%。

鲁索替尼组的中位无失败生存期为5.0个月，显著长于对照组（1.0个月）。鲁索替尼组的中位总生存期为11.1个月，对照组为6.5个月，死亡风险比为0.83。治疗28天后，最常见的不良事件包括血小板减少症、贫血和巨细胞病毒感染。

总之，针对急性移植物抗宿主病患者，与对照治疗相比，鲁索替尼疗法可显著改善疗效，但血小板减少症发生率较高。

附：英文原文

Title: Ruxolitinib for Glucocorticoid-Refractory Acute Graft-versus-Host Disease

Author: Robert Zeiser, M.D.,, Nikolas von Bubnoff, M.D.,, Jason Butler, F.R.A.C.P.,, Mohamad Mohty, M.D., Ph.D.,, Dietger Niederwieser, M.D.,, Reuven Or, M.D.,, Jeff Szer, F.R.A.C.P.,, Eva M. Wagner, M.D.,, Tsila Zuckerman, M.D.,, Bruyère Mahuzier, Pharm.D.,, Judith Xu, M.Sc.,, Celine Wilke, M.D.,, Kunal K. Gandhi, M.D., M.P.H.,, and Gérard Socié, M.D., Ph.D.

Issue&Volume: 2020-04-22

Abstract: AbstractBackground

Acute graft-versus-host disease (GVHD) remains a major limitation of allogeneic stem-cell transplantation; not all patients have a response to standard glucocorticoid treatment. In a phase 2 trial, ruxolitinib, a selective Janus kinase (JAK1 and JAK2) inhibitor, showed potential efficacy in patients with glucocorticoid-refractory acute GVHD.

Methods

We conducted a multicenter, randomized, open-label, phase 3 trial comparing the efficacy and safety of oral ruxolitinib (10 mg twice daily) with the investigator’s choice of therapy from a list of nine commonly used options (control) in patients 12 years of age or older who had glucocorticoid-refractory acute GVHD after allogeneic stem-cell transplantation. The primary end point was overall response (complete response or partial response) at day 28. The key secondary end point was durable overall response at day 56.

Results

A total of 309 patients underwent randomization; 154 patients were assigned to the ruxolitinib group and 155 to the control group. Overall response at day 28 was higher in the ruxolitinib group than in the control group (62% [96 patients] vs. 39% [61]; odds ratio, 2.64; 95% confidence interval [CI], 1.65 to 4.22; P<0.001). Durable overall response at day 56 was higher in the ruxolitinib group than in the control group (40% [61 patients] vs. 22% [34]; odds ratio, 2.38; 95% CI, 1.43 to 3.94; P<0.001). The estimated cumulative incidence of loss of response at 6 months was 10% in the ruxolitinib group and 39% in the control group. The median failure-free survival was considerably longer with ruxolitinib than with control (5.0 months vs. 1.0 month; hazard ratio for relapse or progression of hematologic disease, non–relapse-related death, or addition of new systemic therapy for acute GVHD, 0.46; 95% CI, 0.35 to 0.60). The median overall survival was 11.1 months in the ruxolitinib group and 6.5 months in the control group (hazard ratio for death, 0.83; 95% CI, 0.60 to 1.15). The most common adverse events up to day 28 were thrombocytopenia (in 50 of 152 patients [33%] in the ruxolitinib group and 27 of 150 [18%] in the control group), anemia (in 46 [30%] and 42 [28%], respectively), and cytomegalovirus infection (in 39 [26%] and 31 [21%]).

Conclusions

Ruxolitinib therapy led to significant improvements in efficacy outcomes, with a higher incidence of thrombocytopenia, the most frequent toxic effect, than that observed with control therapy.

DOI: 10.1056/NEJMoa1917635

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa1917635