Optimization of Fetal Hemoglobin Production to Prevent or Reverse Organ Damage and Improve Survival in Patients with Sickle Cell Disease

我们和其他人发现，过早死亡的HbSS患者有更多的肾脏，肝脏和心肺损伤的证据。 我们最近的工作显示，在NIH临床中心筛查的HbSS患者中，只有65%接受了HU治疗，尽管绝大多数患者符合严重到足以保证启动HU的疾病标准。 因为我们是一个转诊中心，大多数患者是由他们的外部血液学家管理，我们还无法控制有多少百分比的患者谁是在外部机构开始胡。 我们的研究还表明，HU治疗本身不足以改善HbSS患者的生存率和减少器官损伤。 相反，接受最高HU剂量治疗且HbF水平最高的患者似乎更有可能存活，并且随着时间的推移，肾、肝和心肺功能障碍的证据较少。 由于其护理的复杂性，通常重点不是将HU推向MTD。 理想情况下，给药算法将使HU剂量滴定过程更容易，更有效，并且对于经常管理HbSS成人患者的主要提供者来说不那么令人生畏。 此外，能够基于患者的血细胞计数和最近HU剂量滴定的时间计算HU剂量的计算机程序将提高HU增加至MTD的患者的百分比。 我们的方案中的羟基脲给药将基于手动推导的书面算法以及NIH临床中心开发的计算机程序。 将在基线和治疗后监测临床、实验室和超声心动图参数，以进一步研究最大HbF反应对HbSS和器官功能相关急性并发症的影响。 该方案最近获得了IRB的批准，我们将在不久的将来开始招募患者。 一份描述我们最近工作的手稿已提交出版。

We and others have found that patients with HbSS who die prematurely have more evidence of renal, hepatic, and cardiopulmonary damage. Our recent work revealed that only 65% of patients with HbSS screened at the NIH Clinical Center were treated with HU despite the vast majority meeting disease criteria severe enough to warrant initiating HU. Because we are a referral center and most patients are managed by their outside hematologist, we have not been able to control what percentage of patients who are followed at outside institutions start HU. Our study also suggests that HU treatment per se is not sufficient to improve survival and decrease organ damage in patients with HbSS. Instead, patients treated with the highest HU doses and who had the highest HbF levels appeared more likely to survive and had less evidence of renal, hepatic, and cardiopulmonary dysfunction over time. Due to the complexity involved in their care, often the focus has not been to push the HU to MTD. Ideally, a dosing algorithm would make the HU dose titration process easier, more effective, and less intimidating for primary providers who frequently manage adult patients with HbSS. Further, a computer program which is able to calculate a HU dose based on patients' blood counts and the timing of most recent HU dose titration would improve the percentage of patients whose HU is increased to MTD. Hydroxyurea dosing in our protocol will be based on a written algorithm which will be derived manually, and by a computer program which was developed at the NIH Clinical Center. Clinical, laboratory, and echocardiographic parameters will be monitored at baseline and after treatment to further study the effect of maximum HbF response on acute complications associated with HbSS and organ function. The protocol was recently approved by the IRB, and we will begin enrolling patients in the near future. A manuscript describing our recent work has been submitted for publication.