Blood and Marrow Transplantation and Cellular Immunotherapy, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
Division of Hematology and Oncology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska; Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska.
Biol Blood Marrow Transplant. 2020 Sep;26(9):1612-1619. doi: 10.1016/j.bbmt.2020.05.015. Epub 2020 May 25.
New interventions are needed in advanced chronic graft-versus-host disease (GVHD). In a phase II, single-arm, multicenter trial, we examined the efficacy of ixazomib in patients with chronic GVHD who had progressed after at least 1 previous line of systemic immunosuppressive (IS) therapy. Ixazomib was given as a 4 mg oral dose weekly on days 1, 8, and 15 of a 28-day cycle for up to 6 total cycles. The primary endpoint was 6-month treatment failure, a composite endpoint including death, relapse, and requirement for an additional line of systemic IS therapy. A total of 50 subjects were enrolled at 6 institutions. The median time from the onset of chronic GVHD to enrollment was 2.8 years (interquartile range, 1.5 to 4.3 years). The degree of chronic GVHD at enrollment was National Institutes of Health (NIH)-defined moderate (16%) or severe (84%), predominantly classic (80% versus 20% overlap), with 52% of patients having involvement of 4 or more organs. The patients were heavily pretreated, with 39 (78%) receiving 3 or more previous lines of systemic therapy for chronic GVHD. Of the 50 patients treated, 26 completed 6 months of planned therapy. The 6-month treatment failure rate was significantly lower than the historical benchmark (28% versus 44%; P = .01) previously established in second-line therapy for chronic GVHD. No patient, transplantation, or chronic GVHD variables were significantly associated with 6-month treatment failure. NIH-defined overall response rate was 40% at 6 months. Overall survival was 92% at 6 months and 90% at 12 months. Ixazomib met the primary endpoint of low treatment failure at 6 months in the setting of advanced chronic GVHD. At 6 months, the NIH-defined rate of complete/partial response was 40%, and 52% of patients remained on ixazomib therapy, suggesting that the low treatment failure rate was due in part due to prevention of progressive disease that would have required additional treatment.
新的干预措施在晚期慢性移植物抗宿主病（GVHD）中是必要的。在一项 II 期、单臂、多中心试验中，我们研究了伊沙佐米在至少接受过一线系统性免疫抑制（IS）治疗后进展的慢性 GVHD 患者中的疗效。伊沙佐米作为一个 4 毫克的口服剂量，每周 1 天、8 天和 15 天，28 天为一个周期，最多 6 个周期。主要终点是 6 个月治疗失败，这是一个包括死亡、复发和需要额外一线系统性 IS 治疗的复合终点。共有 6 个机构的 50 名患者入组。从慢性 GVHD 发病到入组的中位时间为 2.8 年（四分位距，1.5 至 4.3 年）。入组时慢性 GVHD 的程度为国立卫生研究院（NIH）定义的中度（16%）或重度（84%），主要为经典型（80%与 20%重叠），52%的患者有 4 个或更多器官受累。患者接受了大量预处理，其中 39 名（78%）接受了 3 种或更多种治疗慢性 GVHD 的先前线系统治疗。在接受治疗的 50 名患者中，有 26 名完成了 6 个月的计划治疗。6 个月的治疗失败率明显低于先前在慢性 GVHD 的二线治疗中建立的历史基准（28%比 44%；P = 0.01）。没有患者、移植或慢性 GVHD 变量与 6 个月治疗失败显著相关。6 个月时，NIH 定义的总缓解率为 40%。6 个月和 12 个月的总生存率分别为 92%和 90%。在晚期慢性 GVHD 中，伊沙佐米在 6 个月时达到了治疗失败率低的主要终点。6 个月时，NIH 定义的完全/部分缓解率为 40%，52%的患者仍在接受伊沙佐米治疗，这表明低治疗失败率部分是由于预防了需要额外治疗的进行性疾病。
