Fred Hutchinson Cancer Center, Seattle, Washington.
Department of Pediatrics, Seoul National University College of Medicine, Seoul National University Cancer Research Institute, Wide River Institute of Immunology, Seoul National University Children's Hospital, Seoul, South Korea.
Transplant Cell Ther. 2022 Nov;28(11):771.e1-771.e10. doi: 10.1016/j.jtct.2022.08.021. Epub 2022 Aug 28.
Chronic graft-versus-host disease (cGVHD) is a potentially life-threatening complication of allogeneic hematopoietic stem cell transplantation. Clinical data surrounding cGVHD therapies in younger children are limited and critically needed. Primary endpoints were to determine the recommended pediatric equivalent dose (RPED) and assess pharmacokinetics (PK) and safety. Secondary endpoints included overall response rate (ORR; comprising complete response and partial response) according to the 2014 National Institutes of Health criteria at 24 weeks, overall survival, and duration of response (DOR). Here we present the primary results from the open-label, multicenter, international phase 1/2 iMAGINE study (PCYC-1146-IM), which evaluated the PK, safety, and efficacy of ibrutinib in patients age ≥1 to <22 years with treatment-naive (TN) or relapsed/refractory (R/R) moderate/severe cGVHD. Patients age <12 years received once-daily ibrutinib starting at 120 mg/m and escalating to 240 mg/m (full adult dose equivalent) after 14 days if free from ibrutinib-related grade ≥3 toxicity; patients age ≥12 years received once-daily ibrutinib 420 mg. Fifty-nine patients (12 TN and 47 with R/R cGVHD; median age, 13 years; range, 1 to 19 years) were enrolled. Plasma concentration-time profiles for ibrutinib 240 mg/m (the RPED) were comparable to those observed in adults with cGVHD at a dose of 420 mg/day. Safety was consistent with the known profile of ibrutinib in cGVHD. ORR by 24 weeks was 64% (38 of 59), including 83% (10 of 12) for the TN subgroup and 60% (28 of 47) for R/R. Among 46 responders (median follow-up, 20 months; range, 2 to 32 months), 12-month DOR for each subgroup was 60% (95% confidence interval [CI], 25% to 83%) in TN patients and 58% (95% CI, 35% to 75%) in R/R patients. Responses were durable, with numerically higher rates than those previously observed with ibrutinib in adults, demonstrating that ibrutinib provides clinically meaningful activity with acceptable safety in children with moderate/severe cGVHD.
慢性移植物抗宿主病（cGVHD）是异基因造血干细胞移植后一种潜在危及生命的并发症。关于儿童 cGVHD 治疗的临床数据有限，且非常有必要。主要终点是确定推荐的儿科等效剂量（RPED），并评估药代动力学（PK）和安全性。次要终点包括根据 2014 年 NIH 标准在 24 周时的总缓解率（ORR；包括完全缓解和部分缓解）、总生存率和缓解持续时间（DOR）。在此，我们介绍了开放标签、多中心、国际 1/2 期 iMAGINE 研究（PCYC-1146-IM）的主要结果，该研究评估了伊布替尼在治疗初治（TN）或复发/难治（R/R）中重度 cGVHD 的年龄≥1 至<22 岁的患者中的 PK、安全性和疗效。年龄<12 岁的患者接受伊布替尼 120 mg/m 起始剂量，每天 1 次，在无伊布替尼相关 3 级以上毒性的情况下，14 天后增至 240 mg/m（全成人剂量等效）；年龄≥12 岁的患者接受伊布替尼 420 mg，每天 1 次。59 例患者（12 例 TN 和 47 例 R/R cGVHD；中位年龄 13 岁；范围 1 至 19 岁）入组。240 mg/m 的伊布替尼（RPED）的血浆浓度-时间曲线与在 cGVHD 成人中以 420 mg/天剂量观察到的曲线相似。安全性与伊布替尼在 cGVHD 中的已知特征一致。24 周时的 ORR 为 64%（59 例中有 38 例），其中 TN 亚组为 83%（12 例中有 10 例），R/R 亚组为 60%（47 例中有 28 例）。在 46 例应答者（中位随访时间 20 个月；范围 2 至 32 个月）中，TN 患者和 R/R 患者的每个亚组的 12 个月 DOR 分别为 60%（95%CI，25%至 83%）和 58%（95%CI，35%至 75%）。应答持久，与先前观察到的伊布替尼在成人中的数据相比，数值更高，表明伊布替尼在中重度 cGVHD 的儿童中具有可接受的安全性和有临床意义的疗效。
