Ruxolitinib 在移植物抗宿主病（GvHD）中的研究（RIG）：一项多中心、随机的 2 期临床试验，旨在确定 Ruxolitinib 和最佳可用治疗（BAT）在激素难治性急性移植物抗宿主病（aGvHD）中的反应率，与 BAT 相比（NCT02396628）。

Ruxolitinib in GvHD (RIG) study: a multicenter, randomized phase 2 trial to determine the response rate of Ruxolitinib and best available treatment (BAT) versus BAT in steroid-refractory acute graft-versus-host disease (aGvHD) (NCT02396628).

机构信息

Department of Hematology, Oncology and Stem Cell Transplantation, Medical Center, Faculty of Medicine, University of Freiburg, Hugstetter Str. 55, D-79106, Freiburg, Germany.

German Cancer Consortium (DKTK), partner site Freiburg, Freiburg, Germany.

出版信息

BMC Cancer. 2018 Nov 19;18(1):1132. doi: 10.1186/s12885-018-5045-7.

DOI:10.1186/s12885-018-5045-7

PMID:30453910

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6245867/

Abstract

BACKGROUND

Graft-versus-Host Disease (GvHD) causes significant morbidity and mortality in patients after allogeneic stem cell transplantation. Donor T-cells cause inflammation and tissue damage in GvHD target organs such as liver, gut and skin. Cytokine receptor associated kinases JAK1 and JAK2 are critical for inflammatory cytokine response in GvHD. Ruxolitinib is a small molecule inhibitor of JAK1 and JAK2. Preliminary data indicated substantial clinical activity in patients with steroid-refractory (SR) acute and chronic GvHD.

METHODS

The RIG-study is an investigator-initiated open-label, multicenter, prospective randomized controlled two-arm phase 2 study, comparing the efficacy of ruxolitinib and best available treatment (BAT) versus BAT in steroid-refractory acute GvHD (SR-aGvHD). Patients with acute skin, intestinal or liver GvHD > grade 1 and failure of previous treatment are eligible. The trial aims to include 160 patients who will be randomized in a 1:1 ratio and stratified by GvHD grade (≤ grade 3 versus grade 4) and number of previous immunosuppressive treatments (≤ 3 versus ≥4). The primary endpoint is the overall response rate at day 28, defined as: Improvement of at least one stage in the severity of acute GvHD in one organ without deterioration in any other organ, or disappearance of any GvHD signs from all organs without requirement for new systemic immunosuppressive treatment. Secondary objectives include time to response, overall survival, event-free survival, non-relapse mortality (NRM), failure-free survival, graft failure rates, quality of life and changes in serum levels of pro-inflammatory cytokines and GvHD-related biomarkers.

DISCUSSION

This randomized prospective trial will provide further evidence if the retrospectively collected data demonstrating activity of ruxolitinib for SR-aGvHD can be reproduced. A major advantage of ruxolitinib might be the limited and predictable toxicity profile compared to other immunosuppressive therapies that mainly includes viral reactivation and cytopenias. This trial will establish candidate biomarkers to predict and monitor responses to ruxolitinib. As a next step ruxolitinib might be tested upfront against steroids or in a preemptive manner to prevent GvHD to occur.

TRIAL REGISTRATION

NCT02396628 (registration date 17.07.2015); DRKS00007939 (registration date 26.03.2015).

摘要

背景

移植物抗宿主病（GvHD）可导致异基因造血干细胞移植后患者发生显著的发病率和死亡率。供体 T 细胞可引起 GvHD 靶器官（如肝、肠道和皮肤）的炎症和组织损伤。细胞因子受体相关激酶 JAK1 和 JAK2 对 GvHD 中的炎症细胞因子反应至关重要。鲁索替尼是 JAK1 和 JAK2 的小分子抑制剂。初步数据表明，在类固醇难治性（SR）急性和慢性 GvHD 患者中具有显著的临床活性。

方法

RIG 研究是一项由研究者发起的、开放性标签、多中心、前瞻性随机对照 2 期研究，比较了鲁索替尼与最佳可用治疗（BAT）治疗类固醇难治性急性 GvHD（SR-aGvHD）的疗效。患有急性皮肤、肠道或肝脏 GvHD>1 级且先前治疗失败的患者符合条件。该试验旨在纳入 160 名患者，他们将以 1:1 的比例随机分组，并按 GvHD 分级（≤3 级与≥4 级）和之前免疫抑制治疗的数量（≤3 次与≥4 次）进行分层。主要终点是第 28 天的总体缓解率，定义为：一个器官的急性 GvHD 严重程度至少提高 1 个级别，而任何其他器官无恶化，或所有器官的任何 GvHD 迹象消失而无需新的全身免疫抑制治疗。次要目标包括反应时间、总生存、无事件生存、非复发死亡率（NRM）、无失败生存、移植物衰竭率、生活质量以及促炎细胞因子和 GvHD 相关生物标志物血清水平的变化。

讨论

这项随机前瞻性试验将进一步证实回顾性收集的数据表明鲁索替尼对 SR-aGvHD 的活性可以重现。与主要包括病毒再激活和细胞减少的其他免疫抑制治疗相比，鲁索替尼的一个主要优势可能是有限且可预测的毒性特征。该试验将建立候选生物标志物来预测和监测对鲁索替尼的反应。作为下一步，鲁索替尼可能会在类固醇之前进行测试，或预防性地用于预防 GvHD 的发生。