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.

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