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

优化胎儿血红蛋白的产生以预防或逆转器官损伤并提高镰状细胞病患者的生存率

• 批准号: 9157466
• 负责人: Courtney Fitzhugh
• 金额: $ 329.87万
• 依托单位: NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9157466
• 关键词: Acute; Adult; Aftercare; Algorithms; Blood; Cardiopulmonary; Caring; Cell Density; Cells; Clinical; Conflict (Psychology); Disease; Dose; Enrollment; Erythrocyte Transfusion; Erythrocytes; FDA approved; Fetal Hemoglobin; Frequencies; Hematologist; Hemoglobin; Hepatic; Image; Individual; Institution; Kidney; Laboratories; Laboratory Study; Lead; Longitudinal Studies; Maximum Tolerated Dose; Measures; Monitor; Morbidity - disease rate; Myelosuppression; Organ; Pain; Patients; Pharmaceutical Preparations; Pilot Projects; Process; Production; Protocols documentation; Provider; Review Literature; Running; Sample Size; Sickle Cell; Sickle Cell Anemia; Techniques; Time; Titrations; United States National Institutes of Health; Work; Writing; acute chest syndrome; base; computer program; follow-up; gamma Globin; hydroxyurea; improved; liver injury; meetings; mortality; prevent; prospective; response; treatment duration

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.

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，大多数患者都是由他们的外部血液学家管理，我们无法控制在外部机构接受随访的患者开始HU的百分比。 虽然我们的研究表明，任何HU治疗都可以改善HbSS患者的生存率，但在服用推荐剂量15-35 mg/kg/天的患者中效果最明显。 此外，HbF水平较高的患者似乎更有可能存活，并且随着时间的推移肝损伤的证据较少。 由于其护理的复杂性，通常重点不是将HU推到最大耐受剂量（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。 我们方案中的羟基脲给药基于手动推导的书面算法，并通过NIH临床中心开发的计算机程序进行。 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相关急性并发症和器官功能的影响。 自该方案去年获得批准以来，已招募了8名患有纯合子镰状细胞病的受试者，其中7人已开始了羟基脲治疗期，随访时间从近1个月到近9个月不等。 该方案还寻求制定实验室指标，以评价对HU的临床反应。 首先，已知HU通过增加胎儿血红蛋白（HbF）水平发挥其有益作用，从而减少红细胞镰状化。 然而，HU反应不仅取决于总HbF水平增加多少，而且取决于每个产生HbF的红细胞（F细胞）内的HbF浓度。 我们正在尝试使用ImageStream成像流式细胞仪测量每个F细胞内的HbF浓度，并继续努力优化这项技术。 我们也在努力测量γ-珠蛋白的表达作为一种手段来预测早期反应HU。 最后，由于血红蛋白聚合，红细胞在脱氧时呈镰刀状，红细胞密度增加。 由于HbF降低红细胞镰状化，我们在HU治疗前和治疗期间测量红细胞密度。 这些实验室研究正在进行中。