Imaging and Blood Biomarkers to Predict Graft Failure after HSCT

预测 HSCT 后移植失败的影像学和血液生物标志物

• 批准号: 10022509
• 负责人: Jennifer Lin Holter Chakrabarty
• 金额: $ 55.36万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-25 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10022509
• 关键词: Address; Adult; Allogenic; Biological Markers; Blood; Bone Marrow; Bone Marrow Purging; Cells; Cessation of life; Chest; Clinical; Complication; Data; Diagnosis; Disease; Donor person; Engraftment; Enrollment; Enzymes; Failure; Financial Hardship; Growth; Hematology; Hematopoiesis; Hematopoietic; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Homing; Hospital Costs; Image; Immune system; Infusion procedures; Length; Life; Limb structure; Liver; Malignant Neoplasms; Maps; Marrow; Measurement; Measures; Methods; Outcome; PET/CT scan; Participant; Pathway interactions; Patients; Pattern; Procedures; Publishing; Recovery; Risk; Safety; Savings; Scanning; Serum; Signal Transduction; Site; Skeleton; Source; Spleen; Testing; Therapeutic Intervention; Time; Toxic effect; Transplant Recipients; Transplantation; Umbilical Cord Blood; arm; chemotherapy; circulating biomarkers; cohort; cost; experience; graft failure; high risk; imaging biomarker; improved; improved outcome; novel; novel marker; pilot trial; predictive marker; stem cells; therapy outcome; thymidine kinase 1; uptake

Allogeneic hematopoietic stem cell transplantation (HSCT) has allowed patients to be cured from previously incurable cancers or hematopoietic diseases by ablating the host immune system and infusing healthy blood stem cells from a healthy donor. Graft failure, the absence of cellular recovery after HSCT, is a significant complication of transplant. When graft failure is diagnosed late, as it frequently is, the outcome is devastating. We have identified novel imaging and blood biomarkers that can detect subclinical engraftment early after HSCT and could expedite this diagnosis and rescue through re-transplantation. In our published study, the imaging biomarker, (18)F-fluorothymidine (FLT) PET/CT, detected subclinical engraftment quantitatively in adults within 5 days of HSCT, illuminating the pathway of subclinical cellular repopulation in bone marrow. All patients engrafted and there were no toxicities associated with the procedure. Our study also showed that the serum enzyme, thymidine kinase 1 (TK1), a novel blood biomarker of HSC proliferation, increased co-incident with cellular recovery. Collectively, these data suggest that FLT imaging and TK1 blood levels may have the potential to distinguish between subclinical engraftment and graft failure. We now propose to evaluate whether these biomarkers can identify delayed engraftment or failure in the patients who are at highest risk for this complication: recipients of cord blood and haplo-identical HSCT. We hypothesize that FLT uptake will identify subclinical engraftment early after HSCT in alternative donor transplant settings and that FLT and TK1 will serve as predictive biomarkers of graft failure. We will test these in three specific aims: 1) To determine whether FLT marrow signal intensity identifies subclinical engraftment and maps distribution of early marrow settling after cord blood or haplo-identical transplantation, 2) To determine whether FLT marrow signal intensity distinguishes between engraftment and graft failure in very high-risk alternative donor HSCT recipients, and 3) To determine whether serum TK1 enzyme levels can distinguish subclinical engraftment from graft failure. Upon completion of these aims, we expect to show that these blood and imaging biomarkers can predict graft failure in patients at highest risk for this complication. If confirmed, FLT and TK1 could be used to identify primary graft failure early after HSCT, permitting expeditious rescue HSCT and significantly improved outcomes.

异基因造血干细胞移植（HSCT）使患者治愈了以前的疾病 通过消除宿主免疫系统并注入健康血液来治疗无法治愈的癌症或造血系统疾病 来自健康捐赠者的干细胞。移植失败，即 HSCT 后缺乏细胞恢复，是一个重要的因素 移植并发症。当移植失败被诊断较晚时（这种情况经常发生），结果是毁灭性的。 我们已经确定了新的成像和血液生物标志物，可以在植入后早期检测亚临床植入。 HSCT 可以加快诊断速度并通过再次移植进行抢救。在我们发表的研究中， 成像生物标志物，(18)F-氟胸苷 (FLT) PET/CT，定量检测了亚临床植入 HSCT 后 5 天内的成人，阐明了骨髓中亚临床细胞再增殖的途径。全部 患者已被移植，并且没有与手术相关的毒性。我们的研究还表明 血清酶，胸苷激酶 1 (TK1)，HSC 增殖的新型血液生物标志物，同时发生增加 随着细胞的恢复。总的来说，这些数据表明 FLT 成像和 TK1 血液水平可能具有 区分亚临床移植和移植失败的潜力。我们现在建议评估是否 这些生物标志物可以识别处于这种风险最高的患者的移植延迟或失败 并发症：脐带血和单倍体 HSCT 的接受者。我们假设 FLT 的吸收将确定 HSCT 后早期在替代供体移植环境中的亚临床植入，FLT 和 TK1 将 作为移植失败的预测生物标志物。我们将在三个具体目标中测试这些：1）确定 FLT 骨髓信号强度是否可识别亚临床植入并绘制早期骨髓的分布图 脐带血或单倍体移植后沉降，2) 确定FLT骨髓信号强度是否 区分极高风险替代供体 HSCT 受者的植入和移植失败，以及 3) 确定血清 TK1 酶水平是否可以区分亚临床移植和移植失败。 完成这些目标后，我们希望证明这些血液和成像生物标志物可以预测移植物 这种并发症风险最高的患者失败。如果得到证实，FLT 和 TK1 可用于识别 HSCT 后早期原发性移植失败，允许快速挽救 HSCT 并显着改善 结果。