Case BMT CTN: Antibacterial Prophylaxis in Post-Engraftment Allogeneic HCT

描述(申请人提供)：临床前动物模型和临床试验已经证明细菌感染与异基因造血细胞移植(HCT)后移植物抗宿主病(GVHD)发病之间的相互关系。既往急性移植物抗宿主病是慢性移植物抗宿主病发展的最强预测因子之一，慢性移植物抗宿主病是HCT术后两年以上幸存者死亡的最常见原因。抑制T细胞活化和预防GVHD的方法并没有显著改善急性GVHD的发生率和严重程度。我们假设，在植入后阶段使用有效的、耐受性良好的抗菌药减少或最小化细菌的影响将减少免疫受损的异基因HCT受者的感染，并降低输注的移植物对宿主更具活性的可能性，从而降低GVHD的严重程度。减少植入后感染将减少促炎细胞因子/其他介质的释放，降低急性GVHD和随后的慢性GVHD，并有助于更好的长期治疗结果。具体目标是：1.确定预防性抗菌药物的使用是否能预防同种异体红细胞移植后阶段的感染。我们将利用一项随机、双盲、安慰剂对照试验设计，显示在异基因红细胞移植后植入阶段(最多100天)，使用抗菌药预防(莫西沙星)是否可以预防或减少易感细菌感染。次要目标包括确定无复发死亡率的累积发生率、急性和慢性移植物抗宿主病发生率以及确定每个队列的总体存活率。2.确定从服用安慰剂和莫西沙星研究药物的患者中获得的所有突破性细菌分离株的抗生素耐药性发生率和开始。这一努力将是理解选择和出现多重耐药细菌是否会是延长抗生素预防的有害后果的关键。3.确定服用安慰剂的患者与服用研究药物的患者在遗传、转录和蛋白质组生物标志物上的差异。这一目标将前瞻性地寻找生物标志物，包括IL-113、IL-6、IL-1ra、IL-10和TNF-a等候选分子，以及其他可能预测HCT后感染风险的免疫植入和GVHD标志物。生物统计学家将进行多变量分析，以确定实验室标志物和临床事件(免疫失调与急性和慢性移植物抗宿主病、与方案相关的毒性和总体结果)之间的联系。这种方法将导致建立感染和GVHD的风险概况。我们将采用在BMT CTN内开发的配套协议。相关性(见说明)：2010年美国恶性血液病的新增病例将达到137,260例，死亡病例将达到54,020例。HCT对改善这一患者群体的预后有重大影响。HCT取得进一步进展的明显和关键障碍是感染和移植物抗宿主病。我们建议的使用预防性抗菌药物的研究有可能减少异基因HCT植入后阶段的细菌感染和移植物抗宿主病。

DESCRIPTION (provided by applicant): Pre-clinical animal models and clinical trials have demonstrated the inter-relationships between bacterial infections and onset of graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplant (HCT). Pre-existing acute GVHD is one of the strongest predictors for development of chronic GVHD, the most common cause of mortality in survivors beyond two years after HCT. Inhibition, of T cell activation and GVHD prophylaxis approaches, have not significantly improved acute GVHD incidence and severity rates. We hypothesize that reducing or minimizing the impact of bacterial microbes in the post-engraftment phase with potent, well-tolerated antibacterials will reduce infections in immuno-compromised allogeneic HCT recipients and lower the likelihood that the infused graft will be more activated against the host and thereby reduce the severity of GVHD. Decreasing post-engraftment infections will reduce the release of pro-inflammatory cytokines/other mediators, lower acute GVHD and subsequently chronic GVHD, and contribute to better long- term treatment outcomes. Specific Aims are: 1. Determine if use of prophylactic antibacterial agents prevent infection in the post-engraftment phase of allogeneic HCT. We will utilize a randomized, double-blinded, placebo-controlled trial design to show if susceptible bacterial infections can be prevented or reduced using antibacterial prophylaxis (moxifloxacin) in the post-engraftment phase (up to 100 days) after allogeneic HCT. Secondary objectives include determination of cumulative incidence of non-relapse mortality, acute and chronic GVHD rates and determination of overall survival of each cohort. 2. Determine the incidence and the onset of antibiotic resistance in all breakthrough bacterial isolates obtained from patients receiving placebo versus moxifloxacin study drug. This effort will be critical to understanding whether selection and emergence of multi-drug-resistant bacteria could be a detrimental consequence of extended antibiotic prophylaxis. 3. Determine differences in genetic, transcriptional, and proteomic biomarkers in patients receiving placebo versus study drug. This objective prospectively will identify biomarkers, including candidate molecules such as IL-113, IL-6, IL-1 Ra, IL-10 and TNF-a and other markers of immune engraftment and GVHD that may predict for risk of infection after HCT. Biostatisticians will perform multivariate analyses to identify the link between laboratory marker and clinical events (immune-dysregulation with acute and chronic GVHD, regimen-related toxicity and overall outcome). This approach will lead to creation of a risk profile for infection and GVHD. We will employ companion protocols developed within the BMT CTN. RELEVANCE (See instrucfions): Hematologic malignancies will account for 137,260 new cases and 54,020 deaths in the United States in 2010. HCT has made a significant impact upon improving outcome in this patient population. Distinct and critical barriers to further advances in HCT are infection and GVHD. Our proposed investigations using prophylactic antibacterials have the potential to reduce bacterial infections and GVHD in the post-engraftment phase of allogeneic HCT.