Haploidentical hematopoietic cell transplantation (haplo-HCT) is an increasingly used treatment for hematologic malignancies. Although posttransplant cyclophosphamide (PtCy) has improved graft-versus-host disease (GVHD) prophylaxis in haplo-HCT, patients continue to experience life-threatening complications. Interferon gamma and interleukin-6 are central in the pathophysiology of GVHD and cytokine release syndrome (CRS), and both cytokines signal through Janus kinase 1 (JAK-1). We tested the effect of adding the JAK-1 selective inhibitor, itacitinib, to PtCy–haplo-HCT to mitigate these complications and improve overall survival (OS). This open-label, single-arm study evaluated the safety and efficacy of itacitinib combined with standard GVHD prophylaxis after haplo-HCT. A total of 42 patients were treated with itacitinib 200 mg daily from day −3 through +100 or +180, followed by a taper. Itacitinib resulted in low CRS grades, all patients had grade 0 (22%) or grade 1 (78%) CRS and there were no cases of grade 2 to 5 CRS. There were no cases of primary graft failure. No patients developed grade 3 to 4 acute GVHD (aGVHD) through day +180. The cumulative incidence of grade 2 aGVHD at day +100 was 21.9%. The 1-year cumulative incidence of moderate or severe chronic GVHD was 5%. The cumulative incidence of relapse at 2 years was 14%. OS at 1 year was 80%. The cumulative incidence of nonrelapse mortality (NRM) at day 180 was 8%. Itacitinib, when added to standard GVHD prophylaxis, was well tolerated and resulted in low rates of CRS, acute and chronic GVHD, and NRM, and encouraging rates of GVHD-free relapse-free survival and OS after haplo-HCT. This trial was registered at www.ClinicalTrials.gov as #NCT03755414.

中文翻译：

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Itacitinib 用于预防半相合移植中的移植物抗宿主病和细胞因子释放综合征


单倍体造血细胞移植 （haplo-HCT） 是一种越来越多地用于治疗血液系统恶性肿瘤的治疗方法。尽管移植后环磷酰胺 （PtCy） 改善了单倍体 HCT 的移植物抗宿主病 （GVHD） 预防，但患者继续出现危及生命的并发症。干扰素 γ 和白细胞介素-6 是 GVHD 和细胞因子释放综合征 （CRS） 病理生理学的核心，两种细胞因子都通过 Janus 激酶 1 （JAK-1） 发出信号。我们测试了在 PtCy-haplo-HCT 中加入 JAK-1 选择性抑制剂 itacitinib 对减轻这些并发症和提高总生存期 （OS） 的效果。这项开放标签、单臂研究评估了 itacitinib 联合标准 GVHD 预防单倍体 HCT 后的安全性和有效性。共有 42 名患者从第 -3 天到 +100 或 +180 天每天接受伊他替尼 200 mg 治疗，然后逐渐减量。Itacitinib 导致低 CRS 分级，所有患者均为 0 级 （22%） 或 1 级 （78%） CRS，无 2 至 5 级 CRS 病例。没有原发性移植失败的病例。第 +180 天没有患者发展为 3 至 4 级急性 GVHD （aGVHD）。第 +100 天 2 级 aGVHD 的累积发病率为 21.9%。中度或重度慢性 GVHD 的 1 年累积发病率为 5%。2 年时累积复发率为 14%。1 年的 OS 为 80%。第 180 天非复发死亡率 （NRM） 的累积发生率为 8%。当伊他替尼加入标准 GVHD 预防治疗时，耐受性良好，导致 CRS 、急性和慢性 GVHD 以及 NRM 的发生率较低，单倍体 HCT 后无 GVHD 无复发生存率和 OS 率令人鼓舞。该试验在 www.ClinicalTrials.gov 注册为 #NCT03755414。