THALASSEMIA CLINICAL RESEARCH NETWORK

地中海贫血的大规模临床研究受到北美任何中心随访患者数量较少的限制。 根据目前RFA的建议，建立一个临床研究网络，为更好地诊断和管理地中海贫血症以及预防该疾病的长期并发症的重要新研究开辟了道路。心脏疾病仍然是输血依赖型重型β地中海贫血患者早期死亡的主要原因，通常与对处方螯合治疗方案的依从性差有关。 丙型肝炎病毒感染在血液供应普遍筛查之前出生的患者中也很常见，并且是发病的重要原因。 本建议中的两项研究将涉及这些疾病的重要方面。 已经观察到，存在显著心脏疾病（主要是左心室功能障碍）的患者在开始强化螯合计划后迅速改善。改善的速度往往太快，无法通过从体内清除大量的铁来解释。 这一观察结果导致了这样的假设，即铁的心脏毒性不是由于组织沉积本身，而是由于局部沉积效应。 这一假说在非转铁蛋白结合血浆铁（NTBPI）的研究中得到了实验支持，NTBPI对心脏和肝脏细胞具有高度毒性。 NTBPI水平在螯合不足的患者中经常升高，并在建立适当的螯合方案后迅速恢复正常。 我们建议评估积极螯合治疗在逆转心肌功能障碍方面的有效性，如临床和专门的超声心动图测量所确定的，并将功能改善与NTBPI和肝脏铁浓度（这是全身铁负荷最准确的相关性）的变化相关联。 这些研究将为地中海贫血患者心肌功能障碍的机制提供直接的见解，也将使我们能够前瞻性地评估积极螯合方案的疗效。 第二个方案旨在评估一种新的药物方案治疗慢性丙型肝炎病毒感染的疗效。 治疗丙型肝炎最有效的药物方案（干扰素-α +利巴韦林）在地中海贫血患者中毒性很大，因为利巴韦林会导致显著的红细胞破坏。 最近开发了一种化学修饰形式的干扰素（PEG-IFN），其在循环中的持续时间比常规干扰素长得多。初步临床研究表明，单独使用PEG-IFN治疗与目前的联合治疗一样有效，并且毒性更小。 因此，我们建议评估丙型肝炎感染的地中海贫血患者对单独用PEG-IFN治疗的反应，以帮助治疗对PEG-IFN单一治疗无反应的患者，用该药物与利巴韦林组合。本研究的终点将包括治疗结束和持续的病毒消除，以及肝脏炎症指标的变化。 这项研究在临床试验网络的背景下进行时，将使我们能够更快地评估一种有前途的新疗法，并具有更大的统计功效。

Large-scale clinical studies in thalassemia have been limited by the small numbers of patients followed at any Center in North America. The establishment of a Clinical Research Network, as proposed in the current RFA, opens the way to important new studies for better diagnosis and management of thalassemia, and the prevention of long-term complications of the disease. Cardiac disease remains the major cause of early death among patients with transfusion-dependent beta-thalassemia major, and is often related to poor compliance with prescribed chelation regimens. Hepatitis C virus infections are also common in patients born before universal screening of the blood supply, and are a significant cause of morbidity. The two studies in this Proposal will address important aspects of these diseases. It has been observed that patients who present with significant cardiac disease, chiefly left ventricular dysfunction, improve rapidly after being started on an intensive chelation program. The rate of improvement is often too rapid to be accounted for by clearance of substantial amounts of iron from the body. This observation has led to the hypothesis that the cardiac toxicity of iron is not due to tissue deposition per se, but to a local depressant effect. This hypothesis has found experimental support in studies of non transferrin-bound plasma iron (NTBPI), which is highly toxic to cardiac and liver cells. Levels of NTBPI are are frequently elevated in inadequately chelated patients, and normalize rapidly after institution of adequate chelation regimens. We propose to evaluate the effectiveness of aggressive chelation therapy in reversing myocardial dysfunction, as determined clinically and by specialized echocardiographic measures, and correlating the improvement in function with changes in NTBPI and hepatic iron concentration (which is the most accurate correlate of total body iron burden). These studies will provide direct insight into mechanisms of myocardial dysfunction in patients with thalassemia, and will also allow us to prospectively evaluate the efficacy of aggressive chelation regimens. The second protocol is designed to assess the efficacy of a new drug regimen in treatment of chronic Hepatitis C virus infections. The most effective drug regimen for treatment of Hepatitis C (interferon-alpha + ribavirin) is quite toxic in thalassemia patients, as ribavirin causes significant red cell breakdown. A chemically-modified form of interferon (PEG-IFN), which persists in the circulation for much longer than conventional interferon, has recently been developed. Preliminary clinical studies suggest that therapy with PEG-IFN alone is as effective as current combination therapy, and has fewer toxicities. We therefore propose to evaluate the response of Hepatitis C-infected thalassemia patients to treatment with PEG-IFN alone, lend to treat patients who do not respond to PEG- IFN monotherapy with this drug in combination with ribavirin. Endpoints of this study will include end-of-treatment and sustained viral elimination, and changes in measures of hepatic inflammation. This study, when carried out in the context of a clinical trials network, will allow us to evaluate a promising new therapy more rapidly and with greater statistical power than would otherwise be possible.