Evaluating Effects of Age-related Microbiota Modulations in Hematopoietic Stem Cell Transplant Patients

异基因造血干细胞移植有治愈血液病患者的潜力 恶性肿瘤。然而，HCT与显著的治疗相关死亡率(TRM)有关，范围从20%到20%不等。 30%。(1)。TRM在高龄患者中尤其高(风险比1.84；60岁vs.20岁)和 身体功能下降(危险比2.94，底部四分位数与顶部四分位数)。TRM的一个主要原因是移植物- 抗宿主病(GVHD)，影响40%-60%的患者。我们假设与年龄相关的微生物群 变化会影响HCT的临床结果，除了年龄之外，还有其他因素，如饮食、体力活动 而护理环境也会影响微生物群组的分布。 GVHD与肠道微生物区系紊乱之间的相关性已在几项研究中报道， 尽管目前还不清楚微生物区系是如何导致或预防GVHD的。虽然长期的住院治疗是 对于标准的HCT患者，在更正常的护理环境中护理患者可能会保留自然 微生物区系。我们假设，将护理环境从医院转移到更正常的环境 喜欢家可以保存肠道微生物区系，从而减少肠道炎症和移植物抗宿主病。我们有 在第一阶段试验中成功试行家庭HCT(co-Pis Chao，Sung，Clinicaltrials.gov NCT01725022)，并拥有 将我们的试点扩展到家庭与标准护理的随机第二阶段研究(Clinicaltrials.gov NCT02218151， 赵国章，宋志强)，由NCI 1R01CA203950(赵毕超，宋志强)资助。 虽然年龄不能改变，但克服老龄化的负面影响的其他策略 微生物群的改变可以利用饮食和体力活动进行干预。我们已经开始了I/II阶段， HCT前和围产期优化程序(PPOP)。PPOP有两个部分：临床组件(C-PPOP)，它 为所有Duke HCT患者的HCT前评估建立新的护理标准，并进行了一项研究 构成部分(R-PPOP)，包括额外的评估和干预措施，以优化健康和功能 包括饮食和体力活动。在这项拟议的项目中，我们的目标是：1)评估与年龄相关的微生物组 变化及其对HCT结局的影响，包括TRM(主要终点)、感染、GVHD和 免疫功能；2)评估饮食和体力活动干预对老年微生物群的影响 以及对HCT结果的影响。 这项研究将能够利用杜克大学恶性血液病的现有样本 生物储存库。这项研究可以为白血病和白血病患者GVHD的潜在机制提供新的见解 其他恶性疾病。如果成功，这项研究将确定与年龄相关的微生物群变化对 HCT结果和免疫系统，以及针对老年微生物组的战略，以促进更好地 红细胞压积患者的结局。

Allogeneic hematopoietic stem cell transplant (HCT) has the potential to cure patients with hematologic malignancies. However, HCT is associated with significant treatment related mortality (TRM) ranging from 20- 30%. (1). TRM is particularly high in patients with advanced age (hazard ratio 1.84, age >60 years vs. <20) and decreased physical function (hazard ratio 2.94, bottom quartile vs. top quartile). A major cause of TRM is graft- versus-host disease (GVHD), which affects 40-60% of patients. We hypothesis that age related microbiome changes will affect the HCT clinical outcomes, and in addition to age other factors such as diet, physical activity and the care environment can influence the microbiome profiles as well. Correlations between GVHD and disruptions in the gut microbiota have been reported in several studies, though it remains unclear how the microbiota causes or prevents GVHD. While lengthy hospitalizations are standard for HCT patients, caring for patients in a more normal care environment may preserve the natural microbiota. We hypothesized that shifting the care environment from the hospital to a more normal environment like the home can preserve the gut microbiota, thereby decreasing intestinal inflammation and GVHD. We have successfully piloted home HCT in a phase 1 trial (co-PIs Chao, Sung, clinicaltrials.gov NCT01725022) and have expanded our pilot into a randomized phase 2 study of home vs. standard care (clinicaltrials.gov NCT02218151, co-PIs Chao, Sung) funded by NCI 1R01CA203950 (PI Chao, co-I Sung). While age cannot be changed, other strategies to overcome the negative effects of aging-related microbiome changes can be the use of dietary and physical activity interventions. We have started a Phase I/II, pre- and peri-HCT optimization program (PPOP). PPOP has two pieces: a clinical component (C-PPOP), which establishes a new standard of care for the pre-HCT evaluation of all Duke HCT patients, and a research component (R-PPOP), which includes additional assessments and interventions to optimize health and function including diet and physical activity. In this proposed project we aim to: 1) evaluate the age related microbiome changes and their implications on HCT outcomes including TRM (primary endpoint), infections, GVHD, and immune function; 2) evaluate the effects of a dietary and physical activity intervention on the aged microbiome and implications on HCT outcomes. For this study will be able to utilize existing samples from the Duke Hematologic Malignancies Biorepository. This study can provide new insights into the underlying mechanisms of GVHD in Leukemia and other malignant diseases. If successful, this study will identify the impact of age related microbiome changes on HCT outcomes and the immune system, as well as strategies to target the aged microbiome to promote better outcomes for HCT patients.