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、肝和心肺损伤的证据。我们最近的研究显示，在NIH临床中心筛选的HbSS患者中，只有65%的患者接受了HU治疗，尽管绝大多数患者达到了足够严重的疾病标准，可以启动HU治疗。因为我们是一个转诊中心，大多数病人是由他们的外部血液学家管理的，我们无法控制在外部机构随访的病人开始HU的比例。虽然我们的研究表明，任何HU治疗都可以改善HbSS患者的生存，但在服用推荐剂量15-35 mg/kg/天的患者中效果最为明显。此外，随着时间的推移，HbF水平较高的患者似乎更有可能存活，肝损伤的证据也更少。由于其护理的复杂性，重点往往不是将HU提高到最大耐受剂量（MTD）。理想情况下，一种给药算法将使HU剂量滴定过程更容易，更有效，并且对于经常管理成人HbSS患者的初级提供者来说不那么令人生畏。此外，能够根据患者的血液计数和最近一次HU剂量滴定的时间计算HU剂量的计算机程序将提高HU增加到MTD的患者的百分比。

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 hematologists, we have not been able to control what percentage of patients who are followed at outside institutions start HU. While our study suggests that any HU treatment improves survival in patients with HbSS, the effect was most pronounced in those taking the recommended dose of 15-35 mg/kg/day. Further, patients with higher HbF levels appeared more likely to survive and had less evidence of liver damage over time. Due to the complexity involved in their care, often the focus has not been to push the HU to the maximum tolerated dose (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 is based on a written algorithm which is derived manually, and by a computer program which was developed at the NIH Clinical Center. Clinical, laboratory, and echocardiographic parameters are monitored at baseline and after treatment to further study the effect of maximum HbF response on acute complications associated with HbSS and on organ function. Since the protocol was approved last year, 8 subjects with homozygous sickle cell disease have been enrolled, 7 of whom have initiated the hydroxyurea treatment period with follow-up ranging from almost 1 month to almost 9 months. The protocol also seeks to develop laboratory measures to evaluate clinical response to HU. First, HU is known to exert its beneficial effect by increasing fetal hemoglobin (HbF) levels, thereby decreasing red blood cell sickling. However, HU response not only depends on how much total HbF levels increase, but on the concentration of HbF within each HbF-producing red blood cell (F-cell). We are attempting to measure HbF concentration within each individual F-cell using the ImageStream imaging flow cytometer, and are continuing to work to optimize this technique. We are also working on measuring gamma-globin expression as a means to predict early response to HU. Lastly, because hemoglobin polymerizes and red blood cells sickle upon deoxygenation, red blood cell density increases. Since HbF decreases red blood cell sickling, we are measuring red blood cell density before and during HU treatment. These laboratory studies are ongoing.