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: 10482333
• 负责人: Jennifer Lin Holter Chakrabarty
• 金额: $ 56.91万
• 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/10482333
• 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; donor stem cell; experience; graft failure; high risk; imaging biomarker; improved; improved outcome; novel; novel marker; pilot trial; predictive marker; therapy outcome; thymidine kinase 1; uptake; 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; donor stem cell; experience; graft failure; high risk; imaging biomarker; improved; improved outcome; novel; novel marker; pilot trial; predictive marker; 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.

同种异体造血干细胞移植（HSCT）允许患者从先前治愈 通过消除宿主免疫系统并注入健康的血液，无法治愈的癌症或造血疾病 来自健康供体的干细胞。移植失败，HSCT后没有细胞恢复，是一个显着的 移植的并发症。当移植失败迟到时，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，可以在早期发现亚临床植入 HSCT，可以通过重新转移来加快这种诊断和救援。在我们发表的研究中 成像生物标志物（18）F-氟噻氨酰胺（FLT）PET/CT，在数量上检测到亚临床植入 成年人在HSCT后5天内照亮了骨髓中亚临床细胞重生的途径。全部 患者植入了该手术，没有毒性。我们的研究还表明 血清酶，胸苷激酶1（TK1），一种新型HSC增殖的血液生物标志物，增加了共发生 随着细胞恢复。总的来说，这些数据表明FLT成像和TK1血液水平可能具有 区分亚临床植入和移植失败的潜力。我们现在建议评估是否 这些生物标志物可以识别有最高风险的患者的延迟植入或失败 并发症：脐带血和单倍相同的HSCT的接受者。我们假设FLT吸收将确定 HSCT在替代供体移植设置中早期的亚临床植入，FLT和TK1将 用作移植物衰竭的预测生物标志物。我们将以三个特定目的进行测试：1）确定 FLT骨髓信号强度是否确定了早期骨髓的亚临床植入和地图分布 脐带血或单倍相同的移植后定居，2）确定是否flt Marrow信号强度 区分非常高风险的替代供体HSCT接受者的植入和移植失败，3） 为了确定血清TK1酶水平是否可以将亚临床植入与移植失败区分开。 这些目标完成后，我们希望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。如果确认，可以使用FLT和TK1识别 HSCT之后的初级移植失败，允许迅速营救HSCT并显着改善 结果。