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

总结 我们的主要目标是启动一个个性化的方法，以治愈性治疗儿童和成人镰刀 细胞疾病（SCD），以最大限度地提高效益和限制不良后果。有限的系统性努力可以阐明 SCD治愈性治疗后的长期健康结果。只关注最初治疗的范式 类似于20世纪80年代儿科肿瘤学中成功的治愈性疗法。 随后，治愈性治疗与器官功能障碍和恶性肿瘤的风险增加相关， 从而开创了一个新的领域，儿科肿瘤学的存活率。随着SCD（同种异体移植）治疗方法的出现， [allo]造血干细胞移植[HSCT]，基因治疗/编辑），长期健康结果研究 对个性化选择具有时间敏感性和关键性。不幸的是，不利的结果已经开始 SCD治疗后出现。具体而言，HSCT后10%的死亡发生在5年以上 HSCT后此外，我们的小组已经证明了治疗相关的骨髓肿瘤和克隆性造血 当存在移植物排斥/混合嵌合体时，可能发生不确定潜能（CHIP）（见于76例中的5例 HSCT后SCD患者）。因此，SCD的治愈风险必须与治愈的益处进行衡量， 包括稳定肺功能（FEV 1）和改善三尖瓣返流速度（TRJV）。最后， SCD患者的寿命缩短，归因于心脏（TRJV升高）、肺（TRJV降低） FEV 1）和肾功能（eGFR降低），治疗性治疗旨在改善这些功能，必须 根据有利和不利的后期结果来衡量。在我们的多中心回顾性-前瞻性 队列，我们将测试以下假设：1a）：SCD儿童的清髓性治疗将 与接受标准治疗的SCD儿童相比， 治疗; 1b）：成人SCD患者的非清髓性HSCT不会导致FEV1%预测值发生显著变化， 但与接受标准治疗的成人相比，将导致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 HSCT后;和3）在SCD成人中，增殖和遗传毒性应激均与 非清髓性allo-HSCT和清髓性基因编辑将导致HSCT后治疗相关的髓样 受体来源的肿瘤。我们将解决这些假设与以下目标：1）评估发病率 1a：接受清髓性治疗的SCD儿童; 1b： 接受非清髓性allo-HSCT的成人SCD患者与既存儿童和成人队列相比 2）确定成人SCD患者的TRJV是否有临床显著改善，至少 在非清髓性allo-HSCT后，一半患者TRJV > 2.5 m/s，3）评估患病率、发病率 以及SCD成人中非清髓性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.