Low-dose ruxolitinib for graft-versus-host disease prevention in haploidentical haematopoietic stem-cell transplantation: a multicentre, open-label, randomised, controlled, phase 3 trial.

Ruxolitinib, a Janus kinase (JAK) 1/2 inhibitor with established activity in steroid-refractory GVHD, has shown promise for prophylaxis in early studies, but there is little evidence from randomised trials in the haploidentical HSCT setting.

Ruxolitinib是一种Janus激酶（JAK）1/2抑制剂，在对类固醇耐药的GVHD中已显示出明确的活性，早期研究显示其在预防方面具有前景，但在半相合HSCT设置中的随机试验中几乎没有证据。

We investigated whether, within a backbone of antithymocyte globulin, calcineurin inhibitor, and short-course methotrexate, replacing mycophenolate mofetil with low-dose ruxolitinib could reduce acute GVHD after haploidentical HSCT.

我们研究了在抗胸腺细胞球蛋白、钙调神经磷酸酶抑制剂和短期甲氨蝶呤的基础上，用低剂量的鲁索替尼替代吗替麦考酚酯是否能减少半相合造血干细胞移植后的急性移植物抗宿主病。

Methods

In this multicentre, open-label, randomised, controlled, phase 3 trial conducted at five centres in China, eligible patients were aged 12-70 years, had haematological malignancies for which allogeneic HSCT was indicated, had a Karnofsky performance status of at least 70 or a Lansky score of at least 70 for patients younger than 16 years, and were undergoing their first myeloablative haploidentical HSCT.

在这项在中国五个中心进行的多中心、开放标签、随机对照的3期试验中，符合条件的患者年龄在12-70岁之间，患有需要异基因造血干细胞移植的血液恶性肿瘤，Karnofsky表现状态至少为70或对于16岁以下的患者Lansky评分为至少70，并且正在接受他们的第一次髓性半相合造血干细胞移植。

Patients were randomly assigned (1:1) to receive antithymocyte globulin, a calcineurin inhibitor, short-course methotrexate, and low-dose ruxolitinib, or standard prophylaxis with antithymocyte globulin, a calcineurin inhibitor, short-course methotrexate, and mycophenolate mofetil.

患者被随机分配（1:1）接受抗胸腺细胞球蛋白、钙调磷酸酶抑制剂、短程甲氨蝶呤和低剂量鲁索替尼，或接受标准预防治疗，包括抗胸腺细胞球蛋白、钙调磷酸酶抑制剂、短程甲氨蝶呤和吗替麦考酚酯。

Randomisation was stratified by centre and patient age (<40 years vs ≥40 years) using computer-generated permuted blocks with random block sizes.

随机分组根据中心和患者年龄（<40岁 vs ≥40岁）进行分层，使用计算机生成的随机排列块和随机块大小。

Oral ruxolitinib was started on day 1 at 5 mg twice daily for patients weighing at least 50 kg and 5 mg once daily for those weighing less than 50 kg, continued up to day 60, and then tapered to day 90 in the absence of grade II-IV acute GVHD.

口服鲁索替尼从第1天开始，对于体重大于或等于50公斤的患者，每天两次，每次5毫克；对于体重小于50公斤的患者，每天一次，每次5毫克，持续至第60天，如果没有出现II-IV级急性移植物抗宿主病（GVHD），则逐渐减量至第90天。

The primary endpoint was the cumulative incidenceof grade II-IV acute GVHD by day 100.

主要终点是截至第100天的II-IV级急性移植物抗宿主病（GVHD）的累积发生率。

Efficacy and safety were analysed in the modified intention-to-treatpopulation, which included all randomly assigned patients who received at least one dose of the assigned prophylaxis, excluding those with major protocol deviations.

在修改后的意向治疗人群中分析了疗效和安全性，该人群包括所有随机分配的患者，这些患者至少接受了一次指定的预防性治疗，排除了那些有重大方案偏差的患者。

This trial is registered with ClinicalTrials.gov, NCT04838704, and is complete.

该试验已在ClinicalTrials.gov注册，注册号为NCT04838704，且已完成。

Results

Between April 1, 2021, and Dec 28, 2023, 215 patients were randomly assigned, of whom 206 were included in the modified intention-to-treatpopulation (103 in the ruxolitinib prophylaxis group and 103 in the standard prophylaxis group).

2021年4月1日至2023年12月28日期间，共有215名患者被随机分配，其中206名被纳入改良意向治疗人群（利妥昔单抗预防组103人，标准预防组103人）。

The median recipient age was 40 years (IQR 24-48), 98 (48%) patients were female and 108 (52%) were male, and all participants were Chinese.

受试者的中位年龄为40岁（四分位数间距24-48岁），98名（48%）患者为女性，108名（52%）为男性，所有参与者均为中国人。

Among surviving patients, the median follow-up was 26·4 months (IQR 20·0-33·3).

在存活的患者中，中位随访时间为26.4个月（四分位数间距20.0-33.3）。

By day 100, grade II-IV acute GVHD occurred in seven (cumulative incidenceof 6·8% [95% CI 1·9-11·7]) of 103 patients in the ruxolitinib prophylaxis group and 38 (36·9% [27·5-46·3]) of 103 patients in the standard prophylaxis group (subdistribution hazard ratio0·15, 95% CI 0·07-0·34; p<0·0001).

到第100天时，103名接受鲁索替尼预防治疗的患者中有7人（累积发生率为6.8% [95% CI 1.9-11.7]）和103名接受标准预防治疗的患者中有38人（累积发生率为36.9% [95% CI 27.5-46.3]）发生了II-IV级急性移植物抗宿主病（GVHD）（亚分布风险比为0.15，95% CI 0.07-0.34；p<0.0001）。

The most common grade 3-4 adverse events in the ruxolitinib prophylaxis group and the standard prophylaxis group were thrombocytopenia (17 [17%] vs 11 [11%]), neutropenia (14 [14%] vs 9 [9%]), anaemia (12 [12%] vs 9 [9%]), and cystitis (7 [7%] vs 10 [10%]).

在鲁索替尼预防组和标准预防组中，最常见的3-4级不良事件是血小板减少症（17例[17%]对11例[11%]）、中性粒细胞减少症（14例[14%]对9例[9%]）、贫血（12例[12%]对9例[9%]）和膀胱炎（7例[7%]对10例[10%]）。

Serious adverse events occurred in 31 (30%) patients in the ruxolitinib prophylaxis group and 36 (35%) patients in the standard prophylaxis group.

鲁索替尼预防组中有31例（30%）患者出现严重不良事件，而标准预防组中有36例（35%）患者出现严重不良事件。

No fatal adverse events occurred in the ruxolitinib prophylaxis group.

在鲁索替尼预防组中没有发生致命的不良事件。

Three deaths occurred in the standard prophylaxis group: pulmonary infection (n=1), sepsis, bacteraemia, or fungaemia (n=1) and transplant-associated thrombotic microangiopathy (n=1).

标准预防组中发生了三例死亡：肺部感染（n=1），败血症、细菌血症或真菌血症（n=1）以及移植相关的血栓性微血管病（n=1）。

No deaths were considered related to the assigned study drug.

没有被认为是与分配的研究药物相关的死亡事件。

interpretation

Low-dose ruxolitinib, used in place of mycophenolate mofetil within a backbone of prophylactic antithymocyte globulin, calcineurin inhibitor, and short-course methotrexate, reduced grade II-IV acute GVHD by day 100 after haploidentical HSCT and had manageable toxicity.

在预防性抗胸腺细胞球蛋白、钙调磷酸酶抑制剂和短期甲氨蝶呤的基础上，低剂量的鲁索替尼替代了麦考酚酸酯，降低了异基因造血干细胞移植后100天内的II-IV级急性移植物抗宿主病，并且毒性可控。

These findings support further evaluation of targeted JAK1/2 inhibition as part of GVHD prophylaxis.

这些发现支持进一步评估靶向JAK1/2抑制作为GVHD预防的一部分。

funding

National Natural Science Foundation of China.

中国国家自然科学基金。