Topical ruxolitinib for chronic cutaneous graft-versus-host disease: a single-centre, randomised, double-blind, intra-patient-controlled phase 2 trial.

Topical corticosteroids remain the mainstay for cutaneous cGVHD but their use is limited by adverse effects.

局部皮质类固醇仍是皮肤cGVHD的主要治疗方法，但其使用受到副作用的限制。

We aimed to evaluate the clinical activity and safety of ruxolitinib 1·5% cream for epidermal or superficially sclerotic cutaneous cGVHD.

我们的目标是评估鲁索替尼1.5%乳膏对于表皮或表浅硬化的皮肤cGVHD的临床活性和安全性。

Methods

In this single-centre, randomised, double-blind, intra-patient-controlled phase 2 trial at Memorial Sloan Kettering Cancer Center (NY, USA), patients aged 12 years or older with history of allogenic haematopoietic stem cell transplantation, with clinically confirmed, histologically confirmed, or both, cutaneous cGVHD involving at least 2% body surface area were randomly assigned to the body side receiving topical ruxolitinib 1·5% cream twice daily for 28 days; placebo vehicle was applied to contralateral lesional skin as a control.

在这项单中心、随机、双盲、患者内对照的2期临床试验中，患者年龄在12岁或以上，有异基因造血干细胞移植史，临床和/或组织学证实的皮肤cGVHD涉及至少2%的体表面积，被随机分配到每天两次使用局部鲁索替尼1.5%乳膏28天的一侧；对照侧则应用安慰剂载体。

The primary endpoint was the absolute day-28 between-side difference in affected lesional body surface area (BSA), recorded as percentage of total BSA on each assigned side and analysed in evaluable patients; baseline between-side BSA differences were controlled for with adjusted mixed-effects regression.

主要终点是第28天两侧受影响病变体表面积（BSA）的绝对差异，记录为每侧指定BSA的百分比，并在可评估患者中进行分析；通过调整混合效应回归控制基线两侧BSA差异。

Only patients who completed the day 28 visit were included in the primary endpoint analysis; all patients who received any study treatment were included in the safety analysis.

只有完成第28天访问的患者才被纳入主要终点分析；所有接受任何研究治疗的患者都被纳入安全性分析。

The trial is closed to enrolment and registered with ClinicalTrials.gov, NCT03954236.

该试验已关闭招募，并在ClinicalTrials.gov上注册，编号为NCT03954236。

The trial is complete.

该试验已完成。

Results

Between June 28, 2019, and Sept 8, 2022, 24 patients were randomly assigned, with a median follow-up of 128 days (IQR 90-280).

在2019年6月28日至2022年9月8日期间，共有24名患者被随机分配，中位随访时间为128天（四分位数间距90-280天）。

Median age was 47·5 years (IQR 32·5-67·5); 13 (54%) were female and 11 (46%) were male.

中位年龄为47.5岁（四分位数间距32.5-67.5）；其中13名（54%）为女性，11名（46%）为男性。

At day 28, 23 patients were evaluable (one patient did not start treatment after screening visit due to intensive care unit admission).

在第28天，有23名患者可进行评估（有一名患者在筛选访问后因重症监护病房住院而未开始治疗）。

Mean affected lesional body surface area changed from 14·3% (SD 7·9) at baseline to 6·2% (6·7) with ruxolitinib and from 14·5% (8·0) to 10·4% (9·1) with placebo vehicle (difference -4·2 percentage points, 95% CI -6·8 to -1·5; p=0·0030); after adjustment for baseline between-side body surface are difference, the difference was -4·0 percentage points (-5·5 to -2·4; p<0·0010).

受影响的病变体表面积的平均值从基线的14.3%（标准差7.9）变化到使用鲁索替尼后的6.2%（6.7），而使用安慰剂的则从14.5%（8.0）变化到10.4%（9.1）（差异为-4.2个百分点，95%置信区间-6.8至-1.5；p=0.0030）；在调整基线两侧体表面积差异后，差异为-4.0个百分点（-5.5至-2.4；p<0.0010）。

Grade 3-5 treatment emergent adverse events were CNS leukaemia, sinusitis, and lung infection (one [4%] each); no treatment-related deaths occurred.

3-5级治疗相关的不良事件包括中枢神经系统白血病、鼻窦炎和肺部感染（各有一例，占4%）；未发生与治疗相关的死亡事件。

interpretation

Topical ruxolitinib showed significant clinical activity and favourable harms profile in active cutaneous cGVHD.

局部应用的鲁索替尼在活动性皮肤慢性移植物抗宿主病中显示出显著的临床活性和良好的安全性。

Ruxolitinib cream could represent a steroid-sparing, skin-directed alternative or second-line therapy, expanding treatment options for patients with cutaneous cGVHD.

鲁索替尼霜可能代表一种节省类固醇、针对皮肤的替代疗法或二线治疗，为患有皮肤慢性移植物抗宿主病的患者扩大治疗选择。

funding

Incyte.

Incyte公司。