Department of Pediatric Hematology/Oncology and Cell and Gene Therapy, IRCCS Bambino Gesù Children's Hospital, Catholic University of the Sacred Heart, Rome, Italy.
Department of Pediatrics, Seoul National University College of Medicine, Seoul National University Cancer Research Institute, Seoul National University Children's Hospital, Seoul, Republic of Korea.
Blood. 2024 Nov 14;144(20):2095-2106. doi: 10.1182/blood.2023022565.
In REACH4, a phase 1/2, open-label, single-arm, multicenter study, the pharmacokinetics (PK), efficacy, and safety of ruxolitinib were evaluated in treatment-naïve and steroid-refractory pediatric patients with grade 2 to 4 acute graft-versus-host disease (aGVHD; n = 45). Ruxolitinib dosing was based on age and targeted the exposure in adults receiving 10 mg twice daily; group 1 (aged ≥12 to <18 years) received 10 mg twice daily and preliminary starting doses for groups 2 (aged ≥6 to <12 years) and 3 (aged ≥2 to <6 years) were 5 mg twice daily and 4 mg/m2 twice daily, respectively. The phase 1 primary objective was to assess ruxolitinib PK parameters and define an age-appropriate recommended phase 2 dose (RP2D) for patients aged <12 years. The phase 2 primary objective was to measure the activity of ruxolitinib as assessed by overall response rate (ORR) at day 28; the key secondary objective was to assess the durable ORR at day 56. Ruxolitinib exposure was comparable across age groups; starting doses were confirmed as the RP2D. The median duration of ruxolitinib exposure was 3.8 months (range, 0.3-11.2). ORR in all patients was 84.4% (90% confidence interval [CI], 72.8-92.5) at day 28, with a durable ORR at day 56 of 66.7% (90% CI, 53.4-78.2); high response rates were observed across age groups and in both treatment-naïve and steroid-refractory subgroups. Adverse events were consistent with those expected in patients with aGVHD (anemia, decreased neutrophil and leukocyte count) treated with ruxolitinib. In pediatric patients with aGVHD, ruxolitinib showed clinically meaningful efficacy with no new safety signals. This trial was registered at www.clinicaltrials.gov as #NCT03491215.
在 REACH4 这项 1/2 期、开放标签、单臂、多中心研究中，评估了鲁索利替尼在初治和激素难治性 2 至 4 级急性移植物抗宿主病（aGVHD；n=45）儿科患者中的药代动力学（PK）、疗效和安全性。鲁索利替尼的剂量基于年龄，并以接受每日 2 次 10mg 治疗的成人的暴露量为目标；第 1 组（年龄≥12 至<18 岁）接受每日 2 次 10mg，第 2 组（年龄≥6 至<12 岁）和第 3 组（年龄≥2 至<6 岁）的初步起始剂量分别为每日 2 次 5mg 和 4mg/m2 每日 2 次。1 期的主要目标是评估鲁索利替尼的 PK 参数，并确定年龄<12 岁患者的适合 2 期剂量（RP2D）。2 期的主要目标是测量鲁索利替尼的活性，通过第 28 天的总缓解率（ORR）评估；关键次要目标是评估第 56 天的持久 ORR。各年龄组的鲁索利替尼暴露量相当；起始剂量确认为 RP2D。鲁索利替尼暴露的中位持续时间为 3.8 个月（范围：0.3-11.2）。所有患者在第 28 天的 ORR 为 84.4%（90%可信区间 [CI]，72.8-92.5），第 56 天的持久 ORR 为 66.7%（90%CI，53.4-78.2）；各年龄组和初治及激素难治亚组均观察到高缓解率。不良事件与接受鲁索利替尼治疗的 aGVHD 患者（贫血、中性粒细胞和白细胞计数减少）预期的不良事件一致。在患有 aGVHD 的儿科患者中，鲁索利替尼显示出有临床意义的疗效，且无新的安全性信号。该试验在 www.clinicaltrials.gov 上注册为 #NCT03491215。
