Prevention of Complications in Thalassemia

地中海贫血并发症的预防

• 批准号: 7431878
• 负责人: ELLIOTT P VICHINSKY
• 金额: $ 20.63万
• 依托单位: CHILDREN'S HOSPITAL & RES CTR AT OAKLAND
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-30 至 2012-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7431878
• 关键词: Prevention; Complications; Thalassemia

DESCRIPTION (provided by applicant): Prior work experience in conducting and addressing the research and programmatic objectives of the Research Initiative for the Prevention of Complications of Thalassemia: Since its establishment 17 years ago, the NCTC has developed a growing statewide program dedicated to delivering comprehensive multidisciplinary care, subspecialty services, community outreach, and opportunities to participate in research trials. The primary site of the NCTC is Children's Hospital and Research Center Oakland (CHRCO) and a network of seven satellite medical centers throughout the state of California. As one of only a handful of comprehensive thalassemia centers in the nation, the NCTC is a rare resource and authority on many issues related to thalassemia. It is home to some of the most experienced thalassemia researchers and healthcare providers in the world, has an active and wide-reaching outreach program, and boasts an excellent infrastructure and an exemplary record of research and dissemination. Since 2002, the NCTC has participated in CDC grant U27/CCU92210, offering comprehensive multi-disciplinary care to patients throughout California, providing outreach and education to patients and communities, playing a lead role in national research trials in thalassemia, and enrolling patients from CHRCO in the CDC Thalassemia Universal Data Collection Program and investigations of sero-conversions and suspected blood borne pathogens. In addition to its ongoing participation in the CDC trial Prevention of the Complications of Thalassemia, we have coordinated multi-center research trials, assumed a leading role in the Thalassemia Clinical Research Network, and undertaken numerous basic, clinical, and translational research studies. A clear description of the populations to be reached and how they will be identified, enrolled and made part of all research initiatives: In 2006, the NCTC provided comprehensive care to 140 thalassemia patients at Children's Hospital and Research Center at Oakland (CHRCO), a 12% increase in the number of patients seen in the previous year. Of these 140, 42% have beta thalassemia and 43% are transfusion dependent. Approximately 51% are women and 75% are of Asian descent. Within the entire network of CHRCO and its satellites, nearly 400 patients across California receive care through the NCTC. In 2006, 91% of the patients in the NCTC received a comprehensive annual visit. During these comprehensive annual visits, and via widely disseminated research flyers and outreach efforts (including over 60 activities in 2006), patients are educated about ongoing research initiatives at the NCTC. More than 300 NCTC patients have consented to participate in research studies through the TCRN alone. Outreach to both the identified thalassemia community and the at-risk population has been a top priority and continues to be a mainstay of the NCTC's work. The tremendous influx in the Asian population and growing awareness of thalassemia and its complications have created an increased demand for patient services, education, and counseling statewide. Recently, the NCTC expanded efforts into new Asian communities within the Stockton, Fresno, and San Jose areas and to the Middle Eastern and Indian communities. The NCTC website continues to offer updated information about thalassemia, new research and clinical trial opportunities, and allows individuals to email questions to NCTC. An outline of the surveillance data collection systems in place and how they will be employed and expanded to support and underpin the programs to be implemented under this new project: Infections are the second most common cause of death in thalassemia major. Pathogens are transmitted by blood transfusion, and altered host immunity from hypersplenism and iron overload contribute to the morbidity. Specific transfusion protocols are followed and all transfused patients are screened annually for hepatitis B surface antibody, surface antigen and core antibody and HIV. Transfused patients are also screened annually for hepatitis C surface antibody and if positive, PCR for hepatitis C is measured. Liver function tests are obtained every 3 months and if elevated, patients are again screened for hepatitis B, C, and A; CMV, EBV, Parvovirus, and HIV. These protocols and infrastructure have supported the enrollment of 55 patients from NCTC on CDC U27/CCU922110. Continued funding will allow us to follow these patients annually with ongoing specimen collection and shipping to the CDC and completion of annual data forms. We will also be able to enroll an additional 30 patients over the next funding cycle. A full range of services and screening for complications are available for thalassemia patients at the NCTC. The Hemoglobinopathy Reference Laboratory at NCTC is the reference laboratory for the State of California Newborn Screening Program. We are the only program in North America to universally screen all births for both beta-thalassemia and alpha-thalassemia. Patients are referred to the center through newborn screening and outreach activities. We have been successful in providing annual comprehensive exams to over 90% of patients with the goal of providing annual screening, surveillance and treatment for iron overload, heart disease, liver disease, endocrine dysfunction, nutritional deficiencies and disorders of bone metabolism. Our future goals include expanded screening for cardiac iron deposition using newly available MRI technology and pulmonary hypertension. Indications of research hypotheses and research questions to be addressed and answered throughout the life of this new award cycle Indications of research hypotheses and research questions to be addressed and answered throughout the life of this new award cycle: The NCTC continues to take a leading role as PI or Co-Pi on almost all of the protocols for the TCRN. In addition, several investigators at the NCTC are recipients of K and other research awards and are coordinating independent studies in thalassemia. Examples of current research hypotheses under investigation include: 1) Deferoxamine (DFO) and deferiprone (L1) combination therapy improves left ventricular function more rapidly than DFO/placebo therapy among transfusion dependent beta-thalassemia patients with abnormal resting ejection fractions, 2) Arginine and sidenafil will both show clinical efficacy in the treatment of pulmonary hypertension, 3) Nine months of administration of low-dose subcutaneous decitabine can produce clinically significant (2-3g/dl) increases in total hemoglobin in patients with thalassemia intermedia, 4) Antioxidant therapy with a combination of RS-Alpha-Lipoic Acid (LA) and L-Carnitine (ALCAR) will produce a measurable decline in oxidative stress in patients with thalassemia, 5) Increased platelet activation and hypercoagulability is the primary cause of the development of pulmonary hypertension, and 6) Zinc supplementation can improve bone health as measured by bone mineral density, bone strength, and markers of bone formation and resorption in beta-thalassemia patients. Presentation of completed and in-process studies undertaken with an indication of how new data and research will contribute to enhanced outcome-based initiatives for patient identification, clinical care and follow-up, including family and caregiver dynamics: A major focus of the NCTC is to undertake outcome-based research that will result in improved diagnosis and treatment of patients with thalassemia and assistance for their families. Our multi-disciplinary approach to outcome-based research addresses the wide spectrum of problems facing this disease that range from cultural obstacles affecting immigrants to new iron chelators, nutrition, management of medical complications, and experimental therapy. These subjects are briefly summarized here and are referred to throughout the text. We are California's Reference Hemoglobinopathy Center for newborn screening and the NIH-sponsored central Hemoglobin Diagnosis Laboratory for North America. This has given us the opportunity to prospectively monitor the epidemiology of thalassemia. Long-term, prospective follow-up of newborns who have undergone DNA and genetic modifier diagnosis has enabled us to better understand the genotype/phenotype correlations. Information from these studies has led to the establishment of North America's only universal alpha-thalassemia screening program, defined the clinical importance of Hb H Constant Spring, Hb E Thalassemia and other new variants. In addition, there is ongoing research to understand the cultural and social impact of thalassemia on the changing ethnic groups. Iron overload and its management: The NCTC is the principal investigator on several approaches to improve iron chelation and monitor their toxicity. This includes the development of new chelators, including long-acting starch Desferal, and combination therapy with deferasirox and Desferal. In addition, we are the co-investigator on several prospective trials evaluating deferiprone, deferasirox, continuous desferal for cardiac disease or cardiac hemosiderosis. Linked to the new chelators is a comprehensive program addressing non-invasive technology to diagnosis iron overload including new studies measuring pituitary, gonadal, and cardiac iron with SQUID and MR. Management of complications: Treatment of thalassemia requires evidence-based information. Our program focuses on prospective studies to prevent and improve the diagnosis and treatment of complications. Complications and therapy under study include aspirin, arginine, sildenafil for pulmonary hypertension, antioxidant supplementation, combination therapy for hepatitis surveillance programs of blood safety, new approaches to cardiac disease, preimplantation therapy for pregnancy and the problem of transitioning patients into adulthood. New therapy: Our approach to therapy has focused on fetal hemoglobin F modulator trials, including hydroxyurea, darbepoietin, and recently Decitabine. In addition, we have been prospectively evaluating new approaches to stem cell transplantation in order to decrease morbidity and increase access for patients without allogeneic matches.

描述（由申请人提供）： 先前在开展和解决预防地中海贫血并发症研究计划的研究和计划目标方面的工作经验：自 17 年前成立以来，NCTC 制定了一项不断发展的全州计划，致力于提供全面的计划多学科护理、亚专业服务、社区外展以及参与研究试验的机会。 NCTC 的主要站点是奥克兰儿童医院和研究中心 (CHRCO) 以及遍布加利福尼亚州的七个卫星医疗中心网络。 作为全国为数不多的综合性地中海贫血中心之一，NCTC 在与地中海贫血相关的许多问题上是稀有的资源和权威。 它是世界上一些最有经验的地中海贫血研究人员和医疗保健提供者的所在地，拥有积极且广泛的外展计划，并拥有优良的基础设施和模范的研究和传播记录。 自 2002 年以来，NCTC 参与了 CDC 拨款 U27/CCU92210，为整个加州的患者提供全面的多学科护理，为患者和社区提供外展和教育，在国家地中海贫血研究试验中发挥主导作用，并从 CHRCO 招募患者参与疾病预防控制中心地中海贫血通用数据收集计划以及血清转化和可疑血源性病原体的调查。 除了持续参与 CDC 预防地中海贫血并发症试验外，我们还协调了多中心研究试验，在地中海贫血临床研究网络中发挥了主导作用，并开展了大量基础、临床和转化研究。 清楚地描述了要接触的人群以及如何识别、登记他们并使其成为所有研究计划的一部分：2006 年，NCTC 在奥克兰儿童医院和研究中心 (CHRCO) 为 140 名地中海贫血患者提供了全面护理。与上一年相比，就诊的患者数量增加了 12%。在这 140 名患者中，42% 患有β地中海贫血，43% 患有输血依赖症。 大约 51% 是女性，75% 是亚裔。 在 CHRCO 及其卫星的整个网络中，加州各地近 400 名患者通过 NCTC 接受护理。 2006年，NCTC 91%的患者接受了全面的年度就诊。 在这些全面的年度访问期间，并通过广泛散发的研究传单和外展活动（包括 2006 年的 60 多项活动），患者了解了 NCTC 正在进行的研究活动。 仅通过 TCRN 就有 300 多名 NCTC 患者同意参与研究。 向已确定的地中海贫血社区和高危人群进行宣传一直是重中之重，并且仍然是 NCTC 工作的支柱。亚洲人口的大量涌入以及对地中海贫血及其并发症的认识不断提高，导致全州范围内对患者服务、教育和咨询的需求不断增加。最近，NCTC 将工作范围扩大到斯托克顿、弗雷斯诺和圣何塞地区的新亚裔社区以及中东和印度社区。 NCTC 网站继续提供有关地中海贫血、新研究和临床试验机会的最新信息，并允许个人通过电子邮件向 NCTC 发送问题。 现有监测数据收集系统的概述，以及如何使用和扩展这些系统，以支持和巩固该新项目下实施的计划：感染是重型地中海贫血的第二大常见死因。 病原体通过输血传播，脾功能亢进和铁超负荷导致的宿主免疫力改变导致发病。遵循特定的输血方案，并且每年对所有输血患者进行乙型肝炎表面抗体、表面抗原和核心抗体以及艾滋病毒筛查。 每年还对输血患者进行丙型肝炎表面抗体筛查，如果呈阳性，则测量丙型肝炎 PCR。 每 3 个月进行一次肝功能检查，如果肝功能升高，则再次对患者进行乙型、丙型和甲型肝炎筛查； CMV、EBV、细小病毒和 HIV。 这些协议和基础设施支持 NCTC 的 55 名患者在 CDC U27/CCU922110 上注册。持续的资助将使我们能够每年跟踪这些患者，持续采集样本并将其运送到疾病预防控制中心，并填写年度数据表。我们还将能够在下一个资助周期内招募另外 30 名患者。 NCTC 为地中海贫血患者提供全方位的服务和并发症筛查。 NCTC 的血红蛋白病参考实验室是加州新生儿筛查计划的参考实验室。 我们是北美唯一对所有新生儿进行 β 地中海贫血和 α 地中海贫血筛查的项目。 通过新生儿筛查和外展活动将患者转介至该中心。 我们已成功为90%以上的患者提供年度综合检查，目标是对铁超载、心脏病、肝病、内分泌功能障碍、营养缺乏和骨代谢紊乱进行年度筛查、监测和治疗。 我们未来的目标包括利用新的 MRI 技术和肺动脉高压扩大心脏铁沉积的筛查范围。 在这个新的奖励周期中需要解决和回答的研究假设和研究问题的指示 在这个新奖励周期的整个生命周期中需要解决和回答的研究假设和研究问题的指示：NCTC 继续在 TCRN 的几乎所有协议中作为 PI 或 Co-Pi 发挥主导作用。 此外，NCTC 的几位研究人员是 K 奖和其他研究奖的获得者，并正在协调地中海贫血的独立研究。 目前正在调查的研究假设的例子包括：1) 去铁胺 (DFO) 和去铁酮 (L1) 联合治疗在静息射血分数异常的输血依赖性 β 地中海贫血患者中比 DFO/安慰剂治疗更快地改善左心室功能，2) 精氨酸和西地那非在治疗肺动脉高压方面均显示出临床疗效，3）小剂量皮下注射地西他滨九个月可产生临床显着效果(2-3g/dl) 中间型地中海贫血患者的总血红蛋白增加，4) RS-α-硫辛酸 (LA) 和左旋肉碱 (ALCAR) 联合抗氧化治疗将显着降低地中海贫血患者的氧化应激地中海贫血患者，5) 血小板活化和高凝状态增加是肺动脉高压发生的主要原因，6) 补充锌可以改善骨骼健康（通过骨测量） β-地中海贫血患者的矿物质密度、骨强度以及骨形成和吸收的标志物。 介绍已完成和正在进行的研究，并表明新数据和研究将如何有助于加强基于结果的患者识别、临床护理和随访举措，包括家庭和护理人员动态：NCTC 的一个主要重点是开展基于结果的研究，改善地中海贫血患者的诊断和治疗并为其家人提供援助。 我们以结果为基础的研究的多学科方法解决了这种疾病面临的广泛问题，从影响移民的文化障碍到新的铁螯合剂、营养、医疗并发症的管理和实验治疗。 这里简要总结了这些主题，并在全文中引用。 我们是加州新生儿筛查参考血红蛋白病中心和 NIH 资助的北美中央血红蛋白诊断实验室。 这使我们有机会前瞻性监测地中海贫血的流行病学。 对接受过 DNA 和基因修饰诊断的新生儿进行长期、前瞻性随访，使我们能够更好地了解基因型/表型相关性。 这些研究的信息促成了北美唯一的通用 α 地中海贫血筛查计划的建立，明确了 Hb H Constant Spring、Hb E 地中海贫血和其他新变异的临床重要性。 此外，正在进行的研究旨在了解地中海贫血对不断变化的种族群体的文化和社会影响。 铁过载及其管理：NCTC 是多种改善铁螯合和监测其毒性方法的主要研究者。这包括开发新的螯合剂，包括长效淀粉 Desferal，以及地拉罗司和 Desferal 的联合治疗。 此外，我们还是几项前瞻性试验的共同研究者，这些试验评估去铁酮、地拉罗司、持续去铁治疗心脏病或心脏含铁血黄素沉着症。 与新螯合剂相关的是一项综合计划，旨在利用非侵入性技术诊断铁超载，包括使用 SQUID 和 MR 测量垂体、性腺和心脏铁的新研究。 并发症的管理：地中海贫血的治疗需要循证信息。我们的计划侧重于预防和改善并发症的诊断和治疗的前瞻性研究。 正在研究的并发症和治疗包括阿司匹林、精氨酸、治疗肺动脉高压的西地那非、补充抗氧化剂、肝炎血液安全监测项目的联合治疗、治疗心脏病的新方法、妊娠植入前治疗以及患者过渡到成年的问题。 新疗法：我们的治疗方法侧重于胎儿血红蛋白 F 调节剂试验，包括羟基脲、达贝泊汀和最近的地西他滨。 此外，我们一直在前瞻性地评估干细胞移植的新方法，以降低发病率并增加无同种异体匹配患者的移植机会。