Late Effects after Pediatric HSCT: State of the Science, Future Directions

描述(由申请人提供)：随着造血细胞移植(HCT)在过去20年中频率、安全性和有效性的提高，长期存活者的数量显著增加。接受这种密集治疗的儿童有很高的晚期毒性风险。与HCT相关的后遗症是发病率和更重要的死亡率的一个重要原因。移植时年满18岁的HCT幸存者面临着比普通人群高17倍的晚期死亡率风险。这些与非复发相关的晚期死亡中的大多数可归因于感染、心脏和肺部原因。必须查明引起HCT幸存者发病率和死亡率的这些和其他原因的风险因素，以便1)对治疗进行适当的修改，2)为HCT幸存者制定筛查和/或干预试验和健康维持建议。由于这些不良事件中的许多都是罕见的，因此有必要跟踪大量的队列，以便得出有意义的关联。多机构研究使人们能够达到较高的数字，并允许研究结果的概括性，因为它们考虑到了不同地点移植实践的变异性。在过去的几年里，在进行多机构儿科HCT研究的能力方面取得了显著的进步，同时发展了一批熟练的儿科专家，进行了HCT的后效研究。凭借现有的专业知识和基础设施，这一领域可以进入高质量的多中心研究，我们为2011年4月在弗吉尼亚州阿灵顿举行的一次会议寻求资金，该会议旨在定义最佳问题，用最具创新性和信息量的方法解决这些问题，并就如何确定工作的优先顺序和推进工作达成共识。会议组委会由后遗症和多中心儿科HCT研究领域的国际专家组成。会议组织者召集了一个杰出的专家小组，他们同意解决以下方面的问题：1)HCT后迟发效应研究的方法学挑战，2)HCT后迟发效应的生物标志物和/或遗传易感性的研究，以及3)HCT后器官系统功能障碍和与健康相关的生活质量研究的方法。以上第三项将涉及的具体主题包括HCT后的长期免疫缺陷、肺、胃肠道、肝、肾、心血管、神经认知和内分泌功能障碍，以及HCT后的生活质量和功能结果。会议的目标将是确定优先事项，建立工作组推进高优先项目，设定实现既定目标的时间表，并公布会议结论。这次会议将为新一代高质量的多中心晚期效应研究奠定基础，这些研究最终将有助于确定旨在改善接受HCT的儿童的长期结果的方法。 公共卫生相关性：由于骨髓移植在儿童中很少发生，可以让我们更好地了解移植后几年可能发生的不良医疗并发症的严重性和频率的大型研究尚未发生。这项提案要求资金支持一次由公认的儿科移植治疗后晚期并发症专家参加的会议，该会议旨在确定主题的优先顺序，选择最佳方法，并组织具体努力来计划研究。这些研究将使我们能够确定与风险增加相关的移植程序的各个方面，从而适当修改未来的移植方法，并允许为移植幸存者设计筛查或干预试验和健康维护建议。

DESCRIPTION (provided by applicant): As hematopoietic cell transplantation (HCT) has improved in frequency, safety and efficacy over the last two decades, the number of long-term survivors has markedly increased. Children undergoing this intense therapeutic modality are at high risk of a number of late toxicities. HCT-related late effects are a significant cause of morbidity and more importantly, mortality. HCT survivors who are <18yrs of age at the time of transplant face a risk of late mortality that is 17 fold higher than the general population. The majority of these non-relapse related late deaths can be attributed to infectious, cardiac and pulmonary causes. Risk factors for these and other causes of morbidity and mortality in HCT survivors must be identified so that 1) appropriate modifications in therapy can be made and 2) screening and/or intervention trials and health maintenance recommendations for HCT survivors can be developed. Due to the rarity of many of these adverse events, there is a need to follow large cohorts in order to arrive at meaningful associations. Multi-institutional studies allow one to achieve high numbers and also allow generalizability of findings, because they take into account the variability in the transplant practices at the various sites. In the last few years, significant improvements in the ability to perform multi-institutional pediatric HCT studies have combined with the development of a skilled group of pediatric experts in HCT late effects research. With expertise and infrastructure now available to allow this field to move into high-quality multi-center studies, we seek funding for a conference in Arlington, VA in April of 2011 aimed at defining the best questions, approaching them with the most innovative and informative methodologies, and coming to a consensus about how to prioritize the work and move forward. The conference organizing committee is composed of international experts in the fields of late effects and multicenter pediatric HCT research. Conference organizers have assembled a distinguished group of experts who have agreed to address the following areas: 1) methodological challenges in the study of late effects after HCT, 2) studies of biomarkers and/or genetic predisposition to late effects after HCT, and 3) approaches to the study of organ system dysfunction and health-related quality of life after HCT. Specific topics that will be addressed in item number three above include long-term post-HCT immunodeficiency, pulmonary, gastrointestinal, hepatic, renal, cardiovascular, neurocognitive and endocrine dysfunction, and quality of life and functional outcomes after HCT. The goal of the meeting will be to define priorities, establish working groups to move high-priority projects forward, set timelines to achieve established goals, and publish conference conclusions. This meeting will lay the foundation for a new generation of high-quality multi-center late effects studies that will eventually aid in defining approaches aimed at improving long-term outcomes in children undergoing HCT. PUBLIC HEALTH RELEVANCE: Because bone marrow transplantation occurs rarely in children, large studies that could allow us to better understand the seriousness and frequency of adverse medical complications that can occur several years after the transplant have not occurred. This proposal requests funding to support a conference attended by recognized experts in late complications after pediatric transplant therapy aimed at prioritizing topics, choosing the best approaches, and organizing specific efforts to plan studies. These studies will allow us to define aspects of the transplant procedure associated with increased risk, resulting in appropriate modifications of future transplant approaches and allowing the design of screening or intervention trials and health maintenance recommendations for transplant survivors.