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

BMT CTN 案例：移植后同种异体 HCT 中的抗菌预防

• 批准号: 8316238
• 负责人: HILLARD M LAZARUS
• 金额: $ 14.76万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-30 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8316238
• 关键词: Accounting; Acute Graft Versus Host Disease; Allogenic; Animal Model; Animals; Anti-Bacterial Agents; Antibiotic Prophylaxis; Antibiotic Resistance; Antibiotics; Bacterial Infections; Biological Markers; Cell Transplants; Cessation of life; Clinical; Clinical Research; Clinical Trials; Clinical Trials Design; Companions; Decontamination; Development; Engraftment; Event; Failure; Genetic; Gram-Positive Bacteria; Hematologic Neoplasms; Hematopoietic; Immune; Immunologic Deficiency Syndromes; Immunologic Markers; Incidence; Infection; Infection prevention; Inflammatory; Interleukin-1; Interleukin-10; Interleukin-6; Investigation; Laboratory Markers; Lead; Life; Link; Mediator of activation protein; Microbe; Moxifloxacin; Multi-Drug Resistance; Multivariate Analysis; Mus; Mycoses; Outcome; Patients; Pharmaceutical Preparations; Phase; Placebos; Predisposition; Principal Investigator; Prophylactic treatment; Proteomics; Protocols documentation; Randomized; Recurrent disease; Regimen; Relapse; Risk; Severities; Survivors; T-Cell Activation; T-Lymphocyte; TNF gene; Time; Toxic effect; Transplant Recipients; Transplantation; Treatment outcome; United States; Virus Diseases; anakinra; chronic graft versus host disease; cohort; cost; cytokine; double-blind placebo controlled trial; drug resistant bacteria; graft vs host disease; high risk; improved; mortality; patient population; pre-clinical; prevent; prophylactic

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.

描述（由申请人提供）：临床前动物模型和临床试验已经证明了细菌感染与异基因造血细胞移植（HCT）后移植物抗宿主病（GVHD）发作之间的相互关系。预先存在的急性GVHD是发展为慢性GVHD的最强预测因子之一，慢性GVHD是HCT后两年以上存活者死亡的最常见原因。T细胞活化的抑制和GVHD预防方法没有显著改善急性GVHD的发病率和严重程度。我们假设，使用强效、耐受性良好的抗菌药物减少或最大限度地减少植入后阶段细菌微生物的影响，将减少免疫功能低下的同种异体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。减少移植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。确定预防性使用抗菌药物是否可预防同种异体HCT植入后阶段的感染。我们将采用随机、双盲、安慰剂对照试验设计，以证明在同种异体HCT后的植入后阶段（长达100天），使用抗菌预防性治疗（阿氟沙星）是否可以预防或减少易感细菌感染。次要目的包括确定非复发死亡率的累积发生率、急性和慢性GVHD率以及确定每个队列的总生存率。2.确定从接受安慰剂与阿氟沙星研究药物的患者中获得的所有突破性细菌分离株中抗生素耐药性的发生率和发生时间。这项工作对于理解多重耐药细菌的选择和出现是否是延长抗生素预防的有害后果至关重要。3.确定接受安慰剂与研究药物的患者在遗传、转录和蛋白质组学生物标志物方面的差异。该目的将前瞻性地鉴定生物标志物，包括候选分子如IL-113、IL-6、IL-lRa、IL-10和TNF-α以及可以预测HCT后感染风险的免疫植入和GVHD的其他标志物。生物统计学家将进行多变量分析，以确定实验室标志物与临床事件（免疫失调伴急性和慢性GVHD、方案相关毒性和总体结局）之间的联系。这种方法将导致创建感染和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（见附件）：2010年美国血液恶性肿瘤将导致137，260例新发病例和54，020例死亡。HCT对改善该患者人群的结局产生了显著影响。HCT进一步发展的独特和关键障碍是感染和GVHD。我们提出的使用预防性抗菌药物的研究有可能减少同种异体HCT植入后阶段的细菌感染和GVHD。