Imaging and Blood Biomarkers to Predict Graft Failure after HSCT

异基因造血干细胞移植（HSCT）可以使患者从以前的疾病中治愈。 无法治愈的癌症或造血系统疾病通过消融宿主免疫系统和注入健康的血液 从健康捐赠者身上提取干细胞移植失败，即HSCT后缺乏细胞恢复，是一个重要的 移植并发症。当移植失败被诊断为晚期时，正如它经常发生的那样，结果是毁灭性的。 我们已经确定了新的成像和血液生物标志物，可以检测亚临床植入后早期 HSCT可以加快这种诊断和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。所有 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（TK 1），一种新的HSC增殖的血液生物标志物， 细胞恢复。总的来说，这些数据表明，FLT成像和TK 1血液水平可能具有 有可能区分亚临床植入和移植失败。我们现在建议评估是否 这些生物标志物可以识别移植延迟或移植失败的高危患者 并发症：接受脐带血和半相合HSCT。我们假设FLT摄取将识别 在替代供体移植环境中，HSCT后早期亚临床植入，FLT和TK 1将 作为移植失败的预测性生物标志物。我们将在三个具体目标中测试这些：1）确定 FLT骨髓信号强度是否识别亚临床植入并绘制早期骨髓分布图 脐血或半相合移植后沉降，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TK 1酶水平是否可以区分亚临床植入和移植失败。 在完成这些目标后，我们希望表明这些血液和成像生物标志物可以预测移植物 在这种并发症风险最高的患者中失败。如果得到证实，FLT和TK 1可用于识别 HSCT后早期的原发性移植物衰竭，允许迅速的补救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.