Imaging and Blood Biomarkers to Predict Graft Failure after HSCT

异基因造血干细胞移植(HSCT)使患者能够从以前的 通过去除宿主免疫系统和注入健康血液来治愈癌症或血液病 来自健康捐赠者的干细胞。移植失败，即HSCT后细胞缺乏恢复，是一个重要的 移植并发症。当移植物衰竭被诊断得很晚时，就像经常发生的那样，结果是毁灭性的。 我们已经确定了新的成像和血液生物标记物，可以在术后早期发现亚临床植入物 并可通过再次移植加快诊断和抢救。在我们发表的研究中， 成像生物标志物--(18)F-氟胸腺嘧啶核苷(Flt)PET/CT定量检测卵巢癌细胞亚临床植入 HSCT后5天内的成体，阐明了亚临床细胞在骨髓中再生的途径。全 患者植入，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)，一种新的HSC增殖的血液生物标志物，增加了符合率 随着细胞的恢复。总体而言，这些数据表明Flt成像和TK1血液水平可能具有 区分亚临床植入物和移植物失败的可能性。我们现在建议评估是否 这些生物标记物可以识别有最高风险的患者的延迟植入或失败。 并发症：脐带血和半相合HSCT的接受者。我们假设，滤过性T的摄取将识别 在替代供者移植环境中，HSCT后早期亚临床植入以及Flt和TK1将 可作为移植物失败的预测生物标志物。我们将在三个具体目标上进行测试：1)确定 Flt骨髓信号强度是否能识别亚临床植入并绘制早期骨髓分布图 脐带血或半相合移植后的沉降值，2)确定Flt骨髓信号强度 区分非常高风险的替代供者HSCT受者的植入和移植失败，以及3) 目的：确定血清TK1酶水平能否区分亚临床植入物和移植物衰竭。 在完成这些目标后，我们期望显示这些血液和成像生物标记物可以预测移植物。 这一并发症风险最高的患者失败。如果得到证实，可以使用Flt和TK1来识别 HSCT后早期发生原发移植物衰竭，可迅速抢救HSCT并显著改善 结果。

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.