局部芦可替尼治疗慢性皮肤移植物抗宿主病：一项单中心、随机、双盲、患者自身对照的2期试验

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中文摘要

背景： 口服芦可替尼是一种Janus激酶（JAK）1/2抑制剂，已获批用于急性和慢性移植物抗宿主病（cGVHD），而局部制剂已获批用于特应性皮炎和白癜风。局部糖皮质激素仍是皮肤cGVHD的主要治疗手段，但其使用受到不良反应的限制。我们旨在评估1.5%芦可替尼乳膏治疗表皮型或浅表硬化型皮肤cGVHD的临床活性和安全性。
方法： 在这项于美国纽约纪念斯隆-凯特琳癌症中心开展的单中心、随机、双盲、患者自身对照的2期试验中，年龄12岁及以上、有异基因造血干细胞移植史、经临床确诊、组织学确诊或两者兼有的皮肤cGVHD且累及至少2%体表面积的患者被随机分配至身体一侧接受局部1.5%芦可替尼乳膏每日两次，共28天；安慰剂赋形剂作为对照应用于对侧病变皮肤。主要终点是第28天受累病变体表面积（BSA）的侧间绝对差异，记录为每个指定侧占总BSA的百分比，并在可评估患者中进行分析；基线侧间BSA差异通过校正混合效应回归进行控制。仅完成第28天访视的患者被纳入主要终点分析；所有接受任何研究治疗的患者均被纳入安全性分析。该试验已停止入组，并在ClinicalTrials.gov注册，注册号为NCT03954236。该试验已完成。
结果： 在2019年6月28日至2022年9月8日期间，24例患者被随机分配，中位随访时间为128天（IQR 90-280）。中位年龄为47.5岁（IQR 32.5-67.5）；13例（54%）为女性，11例（46%）为男性。在第28天，23例患者可评估（1例患者在筛选访视后因入住重症监护室而未开始治疗）。平均受累病变体表面积从基线的14.3%（SD 7.9）变为芦可替尼组的6.2%（6.7），而安慰剂赋形剂组从14.5%（8.0）变为10.4%（9.1）（差异为-4.2个百分点，95% CI -6.8至-1.5；p=0.0030）；在校正基线侧间体表面积差异后，差异为-4.0个百分点（-5.5至-2.4；p<0.0010）。3-5级治疗中出现的不良事件为中枢神经系统白血病、鼻窦炎和肺部感染（各1例[4%]）；未发生治疗相关死亡。
结论： 局部芦可替尼在活动性皮肤cGVHD中显示出显著的临床活性和良好的危害特征。芦可替尼乳膏可能代表一种减少类固醇使用、针对皮肤的替代疗法或二线治疗，为皮肤cGVHD患者扩展了治疗选择。
资助： Incyte。

英文摘要

BACKGROUND: Oral ruxolitinib, a Janus kinase (JAK) 1/2 inhibitor, is approved for both acute and chronic graft-versus-host disease (cGVHD), whereas the topical formulation is approved for atopic dermatitis and vitiligo. Topical corticosteroids remain the mainstay for cutaneous cGVHD but their use is limited by adverse effects. We aimed to evaluate the clinical activity and safety of ruxolitinib 1·5% cream for epidermal or superficially sclerotic cutaneous cGVHD.
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. 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. 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. The trial is closed to enrolment and registered with ClinicalTrials.gov, NCT03954236. The trial is complete.
FINDINGS: Between June 28, 2019, and Sept 8, 2022, 24 patients were randomly assigned, with a median follow-up of 128 days (IQR 90-280). Median age was 47·5 years (IQR 32·5-67·5); 13 (54%) were female and 11 (46%) were male. At day 28, 23 patients were evaluable (one patient did not start treatment after screening visit due to intensive care unit admission). 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). Grade 3-5 treatment emergent adverse events were CNS leukaemia, sinusitis, and lung infection (one [4%] each); no treatment-related deaths occurred.
INTERPRETATION: Topical ruxolitinib showed significant clinical activity and favourable harms profile in active cutaneous cGVHD. Ruxolitinib cream could represent a steroid-sparing, skin-directed alternative or second-line therapy, expanding treatment options for patients with cutaneous cGVHD.
FUNDING: Incyte.