Ixazomib for Chronic Graft-versus-Host Disease Prophylaxis following Allogeneic Hematopoietic Cell Transplantation

Saurabh Chhabra , Alexis Visotcky , Marcelo C. Pasquini , Fenlu Zhu , Xiaoying Tang , Mei-Jie Zhang , Robert Thompson , Sameem Abedin , Anita D'Souza , Binod Dhakal , William R. Drobyski , Timothy S. Fenske , James H. Jerkins , J. Douglas Rizzo , Lyndsey Runaas , Wael Saber , Nirav N. Shah , Bronwen E. Shaw , Mary M. Horowitz , Parameswaran N. Hari , Mehdi Hamadani
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引用次数: 5

Abstract

Chronic graft-versus-host disease (cGVHD) is major cause of morbidity and mortality following allogeneic hematopoietic cell transplantation (HCT). Ixazomib is an oral, second-generation, proteasome inhibitor that has been shown in preclinical models to prevent GVHD. We conducted a phase I/II trial in 57 patients to evaluate the safety and efficacy of ixazomib administration for cGVHD prophylaxis in patients undergoing allogeneic HCT. Oral ixazomib was administered on a weekly basis for a total of 4 doses, beginning days +60 through +90, to recipients of matched related donor (MRD, n = 25) or matched unrelated donor (MUD, n = 26) allogeneic HCT in phase II portion of the study, once the recommended phase II dose of 4 mg was identified in phase I (n = 6). All patients received peripheral blood graft and standard GVHD prophylaxis of tacrolimus and methotrexate. Ixazomib administration was safe and well tolerated, with thrombocytopenia, leukopenia, gastrointestinal complaints, and fatigue the most common adverse events (>10%). In phase II (n = 51), the cumulative incidence of cGVHD at 1 year was 36% (95% confidence interval [CI], 19% to 54%) in the MRD cohort and 39% (95% CI, 21% to 56%) in the MUD cohort. One-year cumulative incidence of nonrelapse mortality (NRM) and relapse was 0% and 20% (95% CI, 8% to 36%) in the MRD cohort, respectively. In the MUD cohort, the respective NRM and relapse rates were 4% (0% to 16%) and 34% (17% to 52%). The outcomes on the study were compared post hoc with contemporaneous matched Center for International Blood and Marrow Transplant Research (CIBMTR) controls. This post hoc analysis showed no significant improvement in cGVHD rates in both the MRD (hazard ratio [HR] = 0.85, P = .64) or MUD cohorts (HR = 0.68, P = .26) on the study compared with CIBMTR controls. B cell activating factor plasma levels were significantly higher after ixazomib dosing in those who remained cGVHD free compared with those developed cGVHD. This study shows that the novel strategy of short-course oral ixazomib following allogeneic HCT is safe but did not demonstrate significant improvement in cGVHD incidence in recipients of MRD and MUD transplantation compared with matched CIBMTR controls. This study is registered at www.clinicaltrials.gov as NCT02250300.

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伊沙唑米预防异基因造血细胞移植后慢性移植物抗宿主病
慢性移植物抗宿主病(cGVHD)是异基因造血细胞移植(HCT)后发病和死亡的主要原因。Ixazomib是一种口服第二代蛋白酶体抑制剂,已在临床前模型中显示可预防GVHD。我们在57名患者中进行了一项I/II期试验,以评估ixazomib在接受同种异体HCT的患者中预防cGVHD的安全性和有效性。一旦在I期(n = 6)确定了推荐的4 mg II期剂量,口服伊沙唑米每周给配相关供体(MRD, n = 25)或匹配非相关供体(MUD, n = 26)异体HCT患者,共4次剂量,从+60天开始到+90天。所有患者接受外周血移植和他克莫司和甲氨蝶呤的标准GVHD预防。Ixazomib给药安全且耐受性良好,血小板减少、白细胞减少、胃肠道不适和疲劳是最常见的不良事件(10%)。在II期(n = 51)中,MRD组1年cGVHD累积发病率为36%(95%可信区间[CI], 19% - 54%), MUD组为39% (95% CI, 21% - 56%)。MRD队列的1年累计非复发死亡率(NRM)和复发率分别为0%和20% (95% CI, 8%至36%)。在MUD队列中,NRM和复发率分别为4%(0%至16%)和34%(17%至52%)。该研究的结果与同期匹配的国际血液和骨髓移植研究中心(CIBMTR)对照进行了比较。事后分析显示,与CIBMTR对照组相比,MRD组(风险比[HR] = 0.85, P = 0.64)或MUD组(风险比[HR] = 0.68, P = 0.26)的cGVHD发生率均无显著改善。与已发生cGVHD的患者相比,未发生cGVHD的患者服用伊沙唑米后血浆B细胞活化因子水平显著升高。这项研究表明,同种异体HCT后短期口服伊沙唑米的新策略是安全的,但与匹配的CIBMTR对照相比,MRD和MUD移植受体的cGVHD发病率没有显着改善。本研究注册于www.clinicaltrials.gov,编号为NCT02250300。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
6.60
自引率
0.00%
发文量
1061
审稿时长
3-6 weeks
期刊介绍: Biology of Blood and Marrow Transplantation publishes original research reports, reviews, editorials, commentaries, letters to the editor, and hypotheses and is the official publication of the American Society for Transplantation and Cellular Therapy. The journal focuses on current technology and knowledge in the interdisciplinary field of hematopoetic stem cell transplantation.
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