DISCIS Study

 描述（由申请方提供）：异基因造血细胞移植（HCT）后的免疫耐受在操作上定义为完全停止免疫抑制（IS）和无后续移植物抗宿主病（GVHD）。急性和慢性GVHD是由供体免疫细胞驱动的免疫损伤的前哨表现，导致发病和死亡，并且经常在IS停药后发展或复发。目前对HCT后耐受性的科学理解是有限的，并且没有经过验证的HCT后免疫耐受性的临床或生物学决定因素。因此，目前IS停药的临床实践是经验性的，显著异质性的，并且在IS停药后并发GVHD。需要对HCT后IS停药和随后的GVHD风险进行综合分析，以推进该领域的研究。我们建议对来自两项主要血液和骨髓移植临床试验网络（CTN）随机试验（CTN 0201和0402）的现有数据（总计n=827）进行稳健的二次分析，以满足这一需求。这些数据的分析是理想的，因为覆盖了相关的患者、移植和GVHD变量，以及IS停药和随后的GVHD的长期随访数据是完整的。我们将采用多状态建模来解决我们的研究问题，因为这种技术可以适应与本分析相关的HCT后的多种健康状态，估计HCT后一系列时间点每种健康状态的概率，并模拟相关协变量对IS停药和IS停药后GVHD结局的影响。我们计划的分析将（1）检查哪些患者、移植和GVHD变量与成功的IS停药相关，（2）确定IS停药后GVHD的发生率，并研究IS停药后GVHD发展的预测因素。

 DESCRIPTION (provided by applicant): Immunologic tolerance after allogeneic hematopoietic cell transplantation (HCT) is operationally defined by complete discontinuation of immune suppression (IS) and the absence of subsequent graft vs. host disease (GVHD). Acute and chronic GVHD, the sentinel manifestations of immunologic injury driven by donor immune cells, result in morbidity and death, and often develop or reoccur after IS discontinuation. Current scientific understanding of tolerance after HCT is limited, and there are no validated clinical or biologic determinants of immune tolerance after HCT. Therefore, current clinical practice of IS discontinuation is empiric, markedly heterogeneous and complicated by GVHD following IS discontinuation. Comprehensive analysis of IS discontinuation after HCT and subsequent risk for GVHD is needed to advance the field. We propose a robust secondary analysis of existing data (total n=827) from two major Blood and Marrow Transplant Clinical Trials Network (CTN) randomized trials (CTN 0201 and 0402) to address this need. Analysis of these data is ideal, as coverage of relevant patient, transplantation, and GVHD variables, as well as long-term follow up data on IS discontinuation and subsequent GVHD is complete. We will employ multi-state modeling to address our research questions, as this technique can accommodate the multiple health states after HCT relevant to this analysis, estimate the probability for each health state a serial time points after HCT, and model the effect of relevant covariates on the outcomes of IS discontinuation and GVHD following IS discontinuation. Our planned analyses will (1) examine which patient, transplant, and GVHD variables are associated with successful IS discontinuation, and (2) determine the incidence of GVHD following IS discontinuation, and investigate predictors of GVHD development after IS discontinuation.