Prototype System for AML Digital Twins

项目摘要 常规化疗在治疗急性髓系白血病（AML）方面已经达到了极限， 成人最常见的白血病许多接受强化化疗的患者 随后进行异基因造血干细胞移植，最终复发。治疗 对于复发或难治性和老年患者，结果仍然特别令人沮丧，这些患者通常 不适合强化治疗有可能改善治疗的几种新疗法选择 结果已经出现，但它们受到反应不一致和缺乏方法的影响 用于识别可能受益于此类疗法的患者。 新的详细模拟称为数字双胞胎开始在许多部门实施 包括工程、制造业和医学。数字双胞胎是一个模拟 允许进行实验而不产生实际后果的实际系统或对象。一 以患者为导向的数字双胞胎将模拟生理反应或疾病， 治疗后的结果预测。 我们建议建立一个“AML数字孪生”系统（AML-DT）的原型， 该系统将由医生与他们的患者一起使用，其中患者的临床和分子 从骨髓抽吸物和外周血收集的数据将用于实例化 病人疾病的数字孪生模型。数字双胞胎将使医生和患者能够 探索个性化的基于模型的药物反应预测，使用可测量的结果， 根据AML公开分子数据产生的背景知识， 患者重要的是，AML-DT系统将通过学习 患者和他们的数字孪生模型的经验。 这项工作是与临床科学家和计算研究人员在 系统生物学研究所、赫尔辛基大学和坦佩雷大学将集中研究 应用药物敏感性分析预测维奈托克与阿扎胞苷联合用药的患者特异性药物敏感性 与正在进行的临床试验VenEx相结合，该试验包括体外患者选择， 从芬兰AML患者的骨髓穿刺液中生成分子数据。一 AML-DT系统的原型将在5年项目期的中点部署， 与临床试验的完成时间一致。在对原型进行评估之后， 将对AML-DT进行开发，以适应其他AML疗法， 患者权益倡导者和临床医生提出的建议。

Project Abstract Conventional chemotherapy has reached its limits in treating Acute Myeloid Leukemia (AML), the most common leukemia in adults. Many patients who receive intensive chemotherapy followed by allogeneic hematopoietic stem-cell transplant eventually relapse. Therapeutic results remain particularly dismal for relapsed or refractory and older patients, who are often unfit for intensive therapies. Several new therapy options with the potential to improve treatment outcomes have emerged, but they suffer from heterogeneity in responses and a lack of methods for identifying patients who might benefit from such therapies. New detailed simulations called Digital Twins are starting to be implemented in many sectors including engineering, manufacturing, and medicine. Digital Twins are a simulation of a real-world system or object that allows for experimentation without real-world consequences. A patient oriented Digital Twin would simulate physiological response or disease and allow for outcome predictions following treatment. We propose to build a prototype of the ‘AML Digital Twin’ system (AML-DT), an interactive system to be used by doctors with their patients in which the patient’s clinical and molecular data, collected from bone marrow aspirates and peripheral blood, will be used to instantiate a digital twin model of the patient’s disease. The digital twin will enable the doctor and patient to explore personalized model-based predictions of drug response, using measurable outcomes in light of background knowledge generated from publicly available molecular data from AML patients. Importantly, the AML-DT system will continuously improve by learning from the experiences of patients and their digital twin models. The work, conducted jointly with clinician-scientists and computational researchers at the Institute for Systems Biology, the University of Helsinki, and Tampere University will center on patient-specific drug sensitivity prediction of venetoclax in combination with azacitidine by integrating with an ongoing clinical trial, VenEx, that includes ex-vivo patient selection and molecular data generation from bone marrow aspirates from AML patients in Finland. A prototype of the AML-DT system will be deployed at the midpoint of the 5-year project period, coinciding with the completion of the clinical trial. Following assessment of the prototype, further developments to the AML-DT will be carried out to accommodate other AML therapies and recommendations made by patient advocates and clinicians.