ROCK2 Inhibition With Belumosudil (KD025) for the Treatment of Chronic Graft-Versus-Host Disease.
ROCK2 Inhibition With Belumosudil (KD025) for the Treatment of Chronic Graft-Versus-Host Disease.
复制标题
DOI：
10.1200/jco.20.02754
复制
发表时间：
2021-06-10
期刊：
影响因子：
--
通讯作者：
Lee SJ
中科院分区：
文献类型：
--
作者：
Jagasia M;Lazaryan A;Bachier CR;Salhotra A;Weisdorf DJ;Zoghi B;Essell J;Green L;Schueller O;Patel J;Zanin-Zhorov A;Weiss JM;Yang Z;Eiznhamer D;Aggarwal SK;Blazar BR;Lee SJ
rho-associated coiled-coil-containing protein kinase-2（ROCK 2）信号通路调节Th 17/调节性T细胞平衡并控制促纤维化通路。Belumosudil（KD 025）的选择性ROCK 2抑制可能为慢性移植物抗宿主病（cGVHD）的管理提供一种新的方法。一项关于belumosudil的IIa期、开放标签、剂量探索研究招募了54名既往接受过1 - 3线治疗（LOT）的cGVHD患者。主要终点为总缓解率（ORR）。从cGVHD诊断到入组的中位时间为20个月。78%的患者患有重度cGVHD，50%的患者累及≥ 4个器官，73%的患者患有上一次LOT难治性cGVHD，50%的患者既往接受过≥ 3次LOT。总体中位随访时间为29个月，Belumosudil 200 mg每日一次、200 mg每日两次和400 mg每日一次的ORR（95% CI）分别为65%（38%-86%）、69%（41%-89%）和62%（38%-82%）。缓解具有临床意义，中位缓解持续时间为35周，与生活质量改善和皮质类固醇（CS）剂量减少相关。19%的患者停止CS治疗。6个月和12个月的无失败生存率分别为76%（62%至85%）和47%（33%至60%）。2年总生存率为82%（69%~ 90%）。Belumosudil耐受性良好，血细胞减少发生率低。未发生非预期不良事件，感染风险也未明显增加，包括巨细胞病毒感染和再激活。Belumosudil治疗导致高ORR和总生存率，并显示生活质量改善，CS剂量减少和毒性有限。该研究的数据表明，belumosudil可能被证明是治疗难治性cGVHD患者的有效疗法。
The rho-associated coiled-coil–containing protein kinase-2 (ROCK2) signaling pathway regulates the Th17/regulatory T cells balance and controls profibrotic pathways. Selective ROCK2 inhibition with belumosudil (KD025) may offer a novel approach to the management of chronic graft-versus-host disease (cGVHD). A phase IIa, open-label, dose-finding study of belumosudil enrolled 54 patients with cGVHD who had received one to three prior lines of therapy (LOTs). The primary end point was overall response rate (ORR). The median time from cGVHD diagnosis to enrollment was 20 months. Seventy-eight percent of patients had severe cGVHD, 50% had ≥ 4 organs involved, 73% had cGVHD refractory to their last LOT, and 50% had received ≥ 3 prior LOTs. With an overall median follow-up of 29 months, the ORR (95% CI) with belumosudil 200 mg once daily, 200 mg twice daily, and 400 mg once daily was 65% (38% to 86%), 69% (41% to 89%), and 62% (38% to 82%), respectively. Responses were clinically meaningful, with a median duration of response of 35 weeks, and were associated with quality-of-life improvements and corticosteroid (CS) dose reductions. CS treatment was discontinued in 19% of patients. The failure-free survival rate was 76% (62% to 85%) and 47% (33% to 60%) at 6 and 12 months, respectively. The 2-year overall survival rate was 82% (69% to 90%). Belumosudil was well-tolerated, with low rates of cytopenia. There were no unexpected adverse events and no apparent increased risk of infection, including cytomegalovirus infection and reactivation. Belumosudil treatment resulted in a high ORR and overall survival rate and demonstrated quality-of-life improvements, CS dose reductions, and limited toxicity. Data from the study indicated that belumosudil may prove to be an effective therapy for patients with treatment-refractory cGVHD.