Chhabra Saurabh, Visotcky Alexis, Pasquini Marcelo C, Zhu Fenlu, Tang Xiaoying, Zhang Mei-Jie, Thompson Robert, Abedin Sameem, D'Souza Anita, Dhakal Binod, Drobyski William R, Fenske Timothy S, Jerkins James H, Douglas Rizzo J, Runaas Lyndsey, Saber Wael, Shah Nirav N, Shaw Bronwen E, Horowitz Mary M, Hari Parameswaran N, Hamadani Mehdi
Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin; Blood and Marrow Transplant & Cellular Therapy Program, Froedtert & Medical College of Wisconsin, Milwaukee, Wisconsin; Center for International Blood and Marrow Transplant Research, Milwaukee Campus, Milwaukee, Wisconsin.
Department of Biostatistics, Medical College of Wisconsin, Milwaukee, Wisconsin.
Biol Blood Marrow Transplant. 2020 Oct;26(10):1876-1885. doi: 10.1016/j.bbmt.2020.07.005. Epub 2020 Jul 9.
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.
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。伊沙佐米是一种口服的第二代蛋白酶体抑制剂，在临床前模型中已显示可预防移植物抗宿主病。我们对57例患者进行了一项I/II期试验，以评估伊沙佐米给药对接受异基因HCT患者预防cGVHD的安全性和有效性。在研究的II期部分，从第60天至第90天，对匹配相关供体（MRD，n = 25）或匹配无关供体（MUD，n = 26）异基因HCT的受者每周口服一次伊沙佐米，共4剂，一旦在I期（n = 6）确定了推荐的II期剂量4 mg。所有患者均接受外周血移植以及他克莫司和甲氨蝶呤的标准移植物抗宿主病预防。伊沙佐米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），MRD队列中1年时cGVHD的累积发生率为36%（95%置信区间[CI]，19%至54%），MUD队列中为39%（95%CI，21%至56%）。MRD队列中1年非复发死亡率（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%）。将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）对照进行事后比较。这项事后分析显示，与CIBMTR对照相比，该研究中MRD队列（风险比[HR] = 0.85，P = 0.64）或MUD队列（HR = 0.68，P = 0.26）的cGVHD发生率均无显著改善。与发生cGVHD的患者相比，未发生cGVHD的患者在伊沙佐米给药后B细胞活化因子血浆水平显著更高。这项研究表明，异基因HCT后短期口服伊沙佐米的新策略是安全的，但与匹配的CIBMTR对照相比，在MRD和MUD移植受者中cGVHD发生率并未显示出显著改善。该研究已在www.clinicaltrials.gov注册，注册号为NCT02250300。
