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

摘要 我们的主要目标是为患有镰刀的儿童和成人提供个性化的治疗方法。 细胞疾病(SCD)，以最大限度地提高效益和限制不良后果。只有有限的系统努力才能阐明 SCD根治疗法后的长期健康结果。只关注最初治愈方法的范式 类似于20世纪80年代儿童肿瘤学中发生的事情，有成功的治疗方法。 随后，根治疗法与器官功能障碍和恶性肿瘤的风险增加有关， 导致了一个新的领域，儿科肿瘤学的生存。与新出现的治疗SCD的疗法(异基因治疗 [Allo]造血干细胞移植[HSCT]，基因治疗/编辑)，长期健康结果研究 时间敏感度高，对个性化选择至关重要。不幸的是，不良后果已经开始 经过SCD治疗后出现。具体地说，造血干细胞移植后10%的死亡发生在5年以上。 HSCT后。此外，我们小组还展示了与治疗相关的髓系肿瘤和克隆性造血。 当存在移植物排斥反应/混合嵌合体时，可能会发生不确定的电位(CHIP)(见5/76 HSCT后并发SCD患者)。因此，SCD的治愈风险必须与治愈的益处相比较， 包括稳定肺功能(FEV1)和改善三尖瓣返流速度[TRJV]。最终， SCD患者寿命缩短，可归因于心脏(TRJV)和肺(TRJV)下降(下降 FEV1)和肾功能(EGFR降低)，这些治疗方法都是为了改善，必须 与有利和不利的后期结果进行比较。在我们的多中心回顾中-未来 队列中，我们将检验以下假设：1A)：SCD儿童的清髓性治疗将 与接受标准治疗的SCD儿童相比，导致进行性肺和肾功能障碍 治疗；1b)：对患有SCD的成人进行非清髓性HSCT将不会导致预测的FEV1%发生显著变化， 但与接受标准治疗的成年人相比，会导致EGFR加速下降；2) 成人SCD患者的非清髓性HSCT将与TRJV的临床显著改善相关 在HSCT后；3)在患有SCD的成年人中，增殖和遗传毒性应激一致地与 非清髓性allo-HSCT和清髓性基因编辑将导致HSCT后治疗相关的髓系 起源于接受者的肿瘤。我们将通过以下目标来解决这些假设：1)评估发病率 1a的肺和肾功能：接受清髓治疗的SCD儿童；和1b： 接受非清髓性allo-HSCT的成人SCD患者与先前存在的儿童和成人队列比较 使用SCD；2)确定患有SCD的成年人的TRJV是否有临床上的显著改善，至少 在非清髓性异基因造血干细胞移植后，有一半的人患有特发性肾移植和移植后的2.5m/S，以及3)评估患病率、发病率 成人SCD患者非清髓性HSCT或清髓性基因编辑后CHIP的演变。

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.