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 我们的主要目标是对患有镰状细胞病的儿童和成人采取个性化的治疗方法 细胞疾病（SCD）以最大限度地提高效益并限制不良后果。阐明这一问题的系统性努力有限 SCD 治疗后的长期健康结果。仅关注初始治愈的范例 这与 20 世纪 80 年代儿科肿瘤学的成功治愈疗法类似。 随后，治疗性疗法与器官功能障碍和恶性肿瘤的风险增加相关， 导致了一个新的领域，即儿科肿瘤学的生存。随着 SCD 的新兴治疗方法（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 时间敏感且对于提供个性化选择至关重要。不幸的是，不良后果已经开始 SCD 根治性治疗后出现。具体来说，10% 的 HSCT 死亡发生时间超过 5 年 造血干细胞移植后。此外，我们的团队已经证明了治疗相关的骨髓肿瘤和克隆造血作用 当存在移植物排斥/混合嵌合现象时，可能会发生不确定电位 (CHIP)（见 76 个中的 5 个） HSCT 后发生 SCD 的患者）。因此，必须根据治愈的益处来衡量 SCD 的治愈风险， 包括肺功能 (FEV1) 的稳定和三尖瓣反流射流速度的改善 [TRJV]。最终， SCD 患者的寿命缩短，归因于心脏功能下降（TRJV 升高）、肺功能下降（下降） FEV1）和肾功能（eGFR 降低），而治疗性疗法旨在改善这些功能，必须 根据有利和不利的后期结果进行衡量。在我们的多中心回顾性前瞻性研究中 队列中，我们将测试以下假设： 1a)：针对 SCD 儿童的清髓治疗将 与 SCD 接受标准的儿童相比，导致进行性肺和肾功能障碍 治疗; 1b)：患有 SCD 的成人的非清髓性 HSCT 不会导致 FEV1% 预测发生显着变化， 但与接受标准治疗的成人相比，会导致 eGFR 加速下降； 2） 对患有 SCD 的成人进行非清髓性 HSCT 将与 TRJV 的临床显着改善相关 HSCT 后； 3) 在患有 SCD 的成人中，增殖应激和基因毒性应激均与 非清髓性异基因 HSCT 和清髓性基因编辑将导致 HSCT 后治疗相关的骨髓细胞 受体来源的肿瘤。我们将通过以下目标来解决这些假设：1）评估发生率 1a 中的肺和肾功能：接受清髓性治疗的 SCD 儿童；和 1b： 接受非清髓性同种异体造血干细胞移植的 SCD 成人患者与既往儿童和成人队列的比较 与SCD； 2) 至少确定成人 SCD 患者的 TRJV 是否有临床显着改善 半数患者在非清髓性异基因 HSCT 后 TRJV > 2.5 m/s，并且 3) 评估患病率、发生率 成人 SCD 患者非清髓性 HSCT 或清髓性基因编辑后 CHIP 的演变。