Hypertension Intervention to Reduce Osteonecrosis in Children with Acute Lymphoblastic Leukemia

高血压干预减少急性淋巴细胞白血病儿童骨坏死

• 批准号: 10591587
• 负责人: Seth Evan Karol
• 金额: $ 22.41万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10591587
• 关键词: 10 year old; 20 year old; Acute Lymphocytic Leukemia; Address; Adolescent and Young Adult; Adult; Affect; Age; Ambulatory Blood Pressure Monitoring; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Attenuated; Autoimmune Diseases; Award; Biological Markers; Biology; Blood; Blood Vessels; Bone necrosis; Cessation of life; Child; Childhood Acute Lymphocytic Leukemia; Clinic; Clinical; Clinical Investigator; Clinical Trials; Clinical Trials Design; Combination Drug Therapy; Data; Development; Development Plans; Diagnosis; Echocardiography; Elasticity; Endothelium; Enrollment; Evaluation; Functional disorder; Future; Genetic study; Glucocorticoids; Glutamates; Goals; Grant; Health; Height; Hip region structure; Hodgkin Disease; Human; Hypertension; Impairment; Institution; Intervention; Joints; K-Series Research Career Programs; Knee; Knowledge; Left; Lesion; Link; Long-Term Survivors; Magnetic Resonance Imaging; Malignant Childhood Neoplasm; Malignant Neoplasms; Measures; Mentorship; Modeling; Modernization; Morbidity - disease rate; Mus; Nitric Oxide Synthase; Operative Surgical Procedures; Orthopedic Surgery; Outcome; Pain; Patient Outcomes Assessments; Patients; Perfusion; Physical activity; Physiologic pulse; Physiological; Physiology; Plasminogen Activator Inhibitor 1; Population; Prevention; Quality of life; Randomized; Randomized, Controlled Trials; Regimen; Regression Analysis; Replacement Arthroplasty; Reporting; Research; Research Personnel; Risk; Risk Factors; Scientist; Severities; Site; Stratification; Structure; Symptoms; Testing; Time; Toxin; Training; Training Support; Translating; Treatment-related toxicity; Validation; Variant; Vascular Diseases; Vasodilator Agents; Vasomotor; Ventricular; acute toxicity; arm; biomarker identification; blood pressure control; bone; career; career development; chemotherapy; cohort; didactic education; disability; experience; follow-up; genetic variant; health related quality of life; high risk; histological specimens; hypertension control; hypertensive; improved; leukemia; leukemia treatment; mouse model; normotensive; novel; patient stratification; pre-clinical; pressure; prevent; prospective; radiological imaging; receptor; reduce symptoms; sex; side effect; skills; tool; treatment arm; trial planning; von Willebrand Factor; young adult

Project Summary Osteonecrosis (ON) is a common and severe side-effect of modern therapy for acute lymphoblastic leukemia (ALL). It most frequently impacts older children (≥10 years old) and young adults, with 15-45% of patients in these groups developing ON symptoms during therapy. Severe ON causes pain and limited mobility, requiring orthopedic surgery including joint replacement. There are currently no interventions which reduce this risk. This award application describes a career development plan to allow me to evolve into a successful independent clinical investigator and achieve my long-term goal of being an independent investigator leading clinical trials which reduce the toxicity of ALL therapy. The short-term goal of this project is to test an intervention for its ability to decrease osteonecrosis. Our preliminary preclinical data showed that intensive antihypertensive therapy reduces ON in this setting without impairing the anti-leukemia effect of chemotherapy. We will now test this in the clinic by evaluating the ability of intensive antihypertensive control (targeted to the 50-75th percentile for age, sex, and height) to reduce ON (as measured by 9 month MRI) compared to standard antihypertensive control (targeted to the 90-95th percentile) by randomizing 160 children and young adults ages 10-18.99 years enrolled on the Total 17 ALL trial to either intensive or standard antihypertensive control (Research Aim 1). Building on our preclinical data, we will also test the ability of biomarkers of vascular dysfunction to identify patients at highest risk of developing ON (Research Aim 2). Finally, we will measure patient-reported quality of life outcomes (PROs) to determine how both the intervention and osteonecrosis impact patients’ health-related quality of life (Research Aim 3). This career development award will also prepare me to achieve my long-term goals as an independent investigator. The practical experience of leading the proposed clinical trial, combined with didactic education in clinical trial design and structured mentorship, will increase my expertise as a clinical researcher (Training Aim 1). The award will also support training and mentorship in vascular physiology to improve both the analysis of the planned trial as well as to improve future trials (Training Aim 2). Finally, I will receive training, mentorship, and practical experience in the use of PROs to better implement these tools in future trials to best understand patient complications from therapy (Training Aim 3). This proposal may identify the first intervention to reduce ON in patients with ALL. Such an intervention would have implications for patients with other malignancies or autoimmune diseases who are also at risk of developing ON due to prolonged glucocorticoid treatment. Simultaneously, the training supported by the award will prepare me for a successful career as a clinician scientist to reduce therapy toxicity in children with ALL.

项目摘要 骨坏死是现代治疗急性淋巴细胞白血病常见而严重的副作用。 (全部)。它最常影响年龄较大的儿童(≥10岁)和年轻人，15%-45%的患者 这些群体在治疗过程中根据症状发展。严重的ON会导致疼痛和行动不便，需要 包括关节置换在内的整形外科手术。目前还没有任何干预措施可以降低这种风险。 此奖项申请描述了一项职业发展计划，使我能够成长为一名成功的 独立的临床研究人员，并实现我的长期目标--成为一名独立的研究人员 降低所有疗法毒性的临床试验。这个项目的短期目标是测试一个 对其减少骨坏死的能力进行干预。我们的初步临床前数据显示，密集的 在这种情况下，抗高血压治疗减少，而不会影响化疗的抗白血病效果。 我们现在将在临床上通过评估强化降压控制的能力来测试这一点(针对 年龄、性别和身高的50-75%)与标准相比减少(通过9个月的MRI测量) 通过随机选择160名儿童和年轻人进行降压控制(目标为90-95百分位数) 10-18.99岁参加总共17项强化或标准抗高血压控制试验 (研究目标1)。在我们临床前数据的基础上，我们还将测试血管生物标记物的能力 功能障碍，以确定最高风险的患者发展(研究目标2)。最后，我们将测量 患者报告的生活质量结果(PROS)以确定干预和骨坏死 影响患者的健康相关生活质量(研究目标3)。 这一职业发展奖也将为我实现作为一名独立人士的长期目标做好准备。 调查员。领导拟议临床试验的实践经验，结合临床教学 临床试验设计和结构化指导，将增加我作为临床研究人员的专业知识(培训目标 1)。该奖项还将支持血管生理学方面的培训和指导，以改善对 计划中的试验以及改进今后的试验(培训目标2)。最后，我将接受培训，接受指导， 以及在使用专业人员方面的实际经验，以便在未来的试验中更好地实施这些工具，以便更好地理解 患者治疗并发症(培训目标3)。 这项建议可能确定第一个减少急性淋巴细胞白血病患者的干预措施。这样的干预将 对于患有其他恶性肿瘤或自身免疫性疾病的患者也有同样的风险 由于糖皮质激素治疗时间延长而继续发展。同时，该奖项支持的培训 将为我作为一名临床科学家的成功职业生涯做好准备，以减少ALL儿童的治疗毒性。