Vorinostat plus tacrolimus and mycophenolate to prevent graft-versus-host disease after related-donor reduced-intensity conditioning allogeneic haemopoietic stem-cell transplantation: a phase 1/2 trial.
Vorinostat plus tacrolimus and mycophenolate to prevent graft-versus-host disease after related-donor reduced-intensity conditioning allogeneic haemopoietic stem-cell transplantation: a phase 1/2 trial.
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DOI：
10.1016/s1470-2045(13)70512-6
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发表时间：
2014-01
期刊：
影响因子：
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通讯作者：
Reddy P
中科院分区：
文献类型：
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作者：
Choi SW;Braun T;Chang L;Ferrara JL;Pawarode A;Magenau JM;Hou G;Beumer JH;Levine JE;Goldstein S;Couriel DR;Stockerl-Goldstein K;Krijanovski OI;Kitko C;Yanik GA;Lehmann MH;Tawara I;Sun Y;Paczesny S;Mapara MY;Dinarello CA;DiPersio JF;Reddy P
急性移植物抗宿主病（GVHD）仍然是同种异体造血干细胞移植（HSCT）更广泛应用的重大障碍。 Vorinostat（辛二酰苯胺异羟肟酸）是一种组蛋白脱乙酰酶 (HDAC) 抑制剂，已被证明可以在临床前模型中减轻 GVHD。我们的目的是研究伏立诺他与标准免疫预防相结合，以预防接受相关供者低强度预处理 HSCT 的患者发生 GVHD 的安全性和活性。在这项伏立诺他的前瞻性、单臂 1/2 期研究中，我们在美国的两个中心招募了患有高危血液恶性肿瘤的患者。我们招募了 18 岁或以上的患者，他们是低强度条件 HSCT 的候选者，并且有可用的 8/8-或 7/8-人类白细胞抗原 (HLA) 匹配的相关供体。移植时必须充分控制疾病状况。所有患者均接受预处理方案，包括氟达拉滨 40 mg/m2 每天 4 天（总剂量 160 mg/m2）和白消安 3·2 mg/kg 每天 2 天（总剂量 6·4 mg/kg）。 GVHD预防包括吗替麦考酚酯1克，从第0天到第28天每天3次，以及他克莫司在HSCT前第-3天开始，在没有GVHD的情况下从第56天开始逐渐减少，并在HSCT后第180天停止。研究药物伏立诺他在HSCT后第-10天至第100天开始。该研究的主要终点是第 100 天出现 2-4 级急性 GVHD。根据研究中心接受类似治疗的患者和已发表的文献，我们预计将发生率从 42% 降低至 25%。如果给予伏立诺他至少 21 天，则对患者进行毒性和主要终点评估。接受治疗少于 21 天的患者仍需接受毒性评估，并根据方案进行更换。该试验已在 ClinicalTrials.gov 注册，NCT00810602。 2008 年 3 月至 2013 年 2 月期间，我们招募了 50 名可评估毒性和反应的患者。所有患者在 HSCT 后的预期时间植入中性粒细胞和血小板。第 100 天和第 1 年全血中嵌合体的中位百分比分别为 98%（四分位距 [IQR]，98-100）和 100%（IQR，100-100）。该研究的主要终点是第 100 天 2-4 级急性 GVHD 的累积发生率为 22%（95% 累积发生率：13%、36%）。根据方案，另外 8 名入组患者仅接受毒性评估，因为他们接受研究药物的时间不到 21 天。最常见的非血液学不良事件均为 3 级，包括电解质紊乱 (N=15)、高血糖 (N=10)、感染 (N=4)、粘膜炎 (N=4) 和肝酶升高 (N=3)。发生 1 起 4 级低钾血症事件和 2 起 4 级感染事件。植入后发生的无症状血小板减少症是最常见的血液学 3 级或 4 级不良事件 (N=9)，但这种情况是短暂的，所有病例都很快得到解决。在相关供体降低强度调节 HSCT 后给予伏立诺他与标准 GVHD 预防相结合是安全的，并且似乎可以减少严重的 GVHD。未来的研究需要评估伏立诺他在更广泛的 HSCT 环境中预防 GVHD 的效果。
Acute graft-versus-host disease (GVHD) remains a significant barrier to a more widespread application of allogeneic hematopoietic stem cell transplantation (HSCT). Vorinostat (suberoylanilide hydroxamic acid) is a histone deacetylases (HDAC) inhibitor that has been shown to attenuate GVHD in pre-clinical models. We aimed to study the safety and activity of vorinostat in combination with standard immunoprophylaxis for GVHD prevention in patients undergoing related donor reduced intensity conditioning HSCT. In this prospective, single-arm phase 1/2 study of vorinostat, we recruited patients with high-risk hematologic malignances at two centers in the USA. We enrolled patients aged 18 years or older who were candidates for a reduced intensity conditioning HSCT and had an available 8/8- or 7/8-Human Leukocyte Antigen (HLA) matched related donor. Disease status had to be adequately controlled at the time of transplant. All patients received a conditioning regimen consisting of fludarabine 40 mg/m2 daily for four days (total dose 160 mg/m2) and busulfan 3·2 mg/kg daily for two days (total dose 6·4 mg/kg). GVHD prophylaxis consisted of mycophenolate mofetil 1 gram three times daily from day 0 and through day 28 and tacrolimus beginning on day −3 pre-HSCT and tapered beginning on day 56 and discontinued by day 180 post-HSCT in the absence of GVHD. The investigational agent, vorinostat, was initiated on day −10 through day 100 post-HSCT. The primary endpoint of the study was grade 2–4 acute GVHD by day 100. We expected to reduce the incidence to 25% from 42% based on similarly treated patients from the study centers and published literature. Patients were assessed for both toxicity and the primary endpoint if at least 21 days of vorinostat were administered. Patients who received less than 21 days of therapy were still assessed for toxicity and were replaced in accordance to the protocol. The trial is registered with ClinicalTrials.gov, NCT00810602. Between March 2008 and February 2013, we enrolled 50 patients evaluable for both toxicity and response. All patients engrafted neutrophils and platelets at expected times post-HSCT. The median percentages of chimerism in whole-blood at day 100 and 1-year were 98% (interquartile range [IQR], 98–100) and 100% (IQR, 100–100), respectively. The primary endpoint of the study was met with a day 100 cumulative incidence of grade 2–4 acute GVHD of 22% (95% cumulative incidence: 13%, 36%). Eight additional patients enrolled were assessed for toxicity only, in accordance with the protocol, because they received less than 21 days of study drug. The most common non-hematologic adverse events were all grade 3 and included electrolyte disturbances (N=15), hyperglycemia (N=10), infections (N=4), mucositis (N=4), and elevated liver enzymes (N=3). There was one grade 4 hypokalemia event and two grade 4 infections. Non-symptomatic thrombocytopenia which occurred after engraftment was the most common hematologic grade 3 or 4 adverse event (N=9), but was transient and all cases resolved swiftly. Administration of vorinostat in combination with standard GVHD prophylaxis after related donor reduced intensity conditioning HSCT is safe and appears to reduce severe GVHD. Future studies are needed to assess the effect of vorinostat in the prevention of GVHD in broader HSCT settings.