Clinical and genetic risk factors associated with adverse long-term health outcomes after curative therapies in individuals with sickle cell disease

镰状细胞病患者治疗后与不良长期健康结果相关的临床和遗传风险因素

• 批准号: 10154363
• 负责人: Michael R. DeBaun
• 金额: $ 69.11万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-15 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10154363
• 关键词: Academic Medical Centers; Address; Adult; Allogenic; Cessation of life; Child; Chimerism; Clonal Evolution; Cohort Studies; Data; Disease; Enrollment; Family; Fertility; Functional disorder; Funding; Genes; Genotoxic Stress; Goals; Graft Rejection; Health; Heart; Hematopoiesis; Hematopoietic Stem Cell Transplantation; Hospitals; Incidence; Individual; Kidney; Late Effects; Leadership; Longevity; Lung; Malignant Neoplasms; Measurement; Measures; Morbidity - disease rate; Myeloproliferative disease; National Heart, Lung, and Blood Institute; Organ; Outcome; Outcome Study; Pain; Patients; Pediatric Oncology; Positioning Attribute; Prevalence; Prospective cohort; Prospective cohort study; Protocols documentation; Pulmonary Function Test/Forced Expiratory Volume 1; Registries; Renal function; Risk; Sickle Cell Anemia; Testing; Time; Transplantation; United States National Institutes of Health; adult stem cell transplantation; adverse outcome; clinical center; clinical risk; clinically significant; cohort; curative treatments; design; financial toxicity; follow-up; genetic risk factor; health related quality of life; heart function; immune reconstitution; improved; kidney dysfunction; mortality; personalized approach; pulmonary function; sickling; success; survivorship; therapeutic genome editing; therapy outcome; transplant centers; transplantation therapy; young adult

Summary Our primary objective is initiating a personalized approach to curative therapies in children and adults with sickle cell disease (SCD) to maximize benefits and limit adverse outcomes. Limited systematic efforts exist to elucidate long-term health outcomes following curative therapies for SCD. The paradigm of focusing only on the initial cure is analogous to what occurred in pediatric oncology in the 1980s with successful curative therapies. Subsequently, curative therapies were associated with increased risk for organ dysfunction and malignancies, leading to a new field, survivorship in pediatric oncology. With emerging curative therapies for SCD (allogeneic [allo] hematopoietic stem cell transplant [HSCT], gene therapy/editing), long-term health outcomes studies are time-sensitive and critical to inform personalized choices. Unfortunately, adverse outcomes have started to emerge after SCD curative therapy. Specifically, 10% of the deaths following HSCT occur more than 5 years after HSCT. Further, our group has demonstrated therapy-related myeloid neoplasms and clonal hematopoiesis of indeterminate potential (CHIP) may occur when graft rejection/mixed chimerism is present (seen in 5 of 76 patients with SCD after HSCT). Thus, risks of cure in SCD must be measured against the benefits of cure, including stabilization of lung function (FEV1) and improved tricuspid regurgitant jet velocity [TRJV]. Ultimately, the shortened lifespan of individuals with SCD, attributable to declining heart (elevated TRJV), lung (decreased FEV1), and kidney (decreased eGFR) function, for which curative therapies were designed to ameliorate, must be measured against favorable and unfavorable late outcomes. In our multicenter retrospective-prospective cohort, we will test the following hypotheses: 1a): myeloablative curative therapies for children with SCD will result in progressive pulmonary and renal dysfunction when compared to children with SCD receiving standard therapy; 1b): nonmyeloablative HSCT for adults with SCD will result in no significant change in FEV1% predicted, but will lead to accelerated decline in eGFR when compared to adults receiving standard therapy; 2) nonmyeloablative HSCT for adults with SCD will be associated with a clinically significant improvement in TRJV following HSCT; and 3) in adults with SCD, proliferative and genotoxic stress uniformly related to nonmyeloablative allo-HSCT and myeloablative gene editing will lead to post-HSCT therapy-related myeloid neoplasm of recipient origin. We will address these hypotheses with the following aims: 1) evaluate the incidence of pulmonary and renal function in 1a: children with SCD receiving myeloablative curative therapies; and 1b: adults with SCD receiving nonmyeloablative allo-HSCT, compared to a pre-existing cohort of children and adults with SCD; 2) determine whether there is a clinically significant improvement in TRJV in adults with SCD, at least half having TRJV > 2.5 m/s, following nonmyeloablative allo-HSCT, and 3) evaluate the prevalence, incidence and evolution of CHIP following non-myeloablative HSCT or myeloablative gene editing in adults with SCD.

概括 我们的主要目标是在儿童和成人镰状的儿童和成人中启动一种个性化治疗方法 细胞疾病（SCD），以最大程度地提高益处并限制不良后果。存在有限的系统努力来阐明 SCD治愈疗法后的长期健康结果。仅关注初始治疗的范式 与1980年代的小儿肿瘤学中发生的治疗疗法相似。 随后，治疗疗法与器官功能障碍和恶性肿瘤的风险增加有关， 导致了一个新领域，即儿科肿瘤学的生存。使用新兴的SCD治疗疗法（同种异体 [Allo]造血干细胞移植[HSCT]，基因治疗/编辑），长期健康结果研究是 时间敏感且至关重要，以告知个性化选择。不幸的是，不利的结果已经开始 SCD治疗疗法后出现。具体而言，HSCT后10％的死亡发生了5年以上 HSCT之后。此外，我们的小组已经证明了与治疗相关的髓样肿瘤和克隆造血作用 当存在移植排斥/混合嵌合体时，可能发生不确定的电位（芯片）（在76个中的5个中可见 HSCT后SCD患者）。因此，必须根据治愈的益处来测量SCD中治愈的风险， 包括肺功能（FEV1）的稳定和改善的三尖瓣浮射流速度[TRJV]。最终， SCD的个体的寿命缩短，归因于心脏下降（TRJV升高），肺（减少） FEV1）和肾脏（EGFR降低）功能（必须为其修复疗法改善） 可以根据有利和不利的晚期结果进行衡量。在我们的多中心回顾展中 队列，我们​​将测试以下假设：1a）：SCD儿童的髓质治疗疗法将 与患有SCD接受标准的儿童相比，导致进行性肺部和肾功能障碍 治疗; 1B）：SCD成年人的非甲状化HSCT将不会导致FEV1％预测的显着变化， 但是，与接受标准疗法的成年人相比，EGFR会导致EGFR的加速下降； 2） SCD成年人的非元素HSCT将与TRJV的临床显着改善有关 遵循HSCT； 3）在患有SCD的成年人中，与 非乳化性allo-HSCT和髓质基因编辑将导致与HSCT疗法相关的髓样 受体起源的肿瘤。我们将以以下目的解决这些假设：1）评估发病率 1A中的肺和肾功能：患有SCD的儿童接受髓质治疗疗法；和1B： 与先前存在的儿童和成人队列相比 与SCD； 2）确定成人SCD的TRJV是否有显着改善，至少至少 一半的trjv> 2.5 m/s，在非甲状化溶液之后，3）评估患病率，发病率 在患有SCD的成年人中，非绝经HSCT或髓质基因编辑后芯片的演变。