Translational Research in Blood and Marrow Transplantation

项目摘要 我们的计划侧重于移植生物学从实验室到临床的翻译， 改善血液和骨髓移植（BMT）的结果。移植后高剂量 环磷酰胺（PTCy）调节GVHD是我们小组成功翻译的一个主要例子。 research. PTCy不仅允许至少75岁的患者进行安全的单倍相合（haplo）BMT， 现在的结果与匹配供体的结果相似。因此，成功利用 不匹配的捐赠者现在允许几乎任何需要BMT的人接受该程序。除了 将异基因BMT转移到非恶性适应症中，我们小组一直致力于减少复发 因为恶性肿瘤而接受同种异体骨髓移植随着非复发死亡率的降低，复发已成为迄今为止 同种异体骨髓移植的主要并发症。新出现的数据表明，一个新的非宽容和非用尽 移植的免疫系统可以增强大多数抗癌剂的活性。异基因骨髓移植后 维持疗法已经产生了令人鼓舞的结果;这也许是最好的例证， 在接受同种异体BMT和移植后FLT 3的FLT 3/ITD AML患者中观察到令人印象深刻的结果 酪氨酸激酶抑制剂，尽管这些药物在非移植环境中显示出有限的活性。的 同种异体BMT后的微小残留病（MRD）状态也可以优化抗肿瘤方法，因为 它们将以最低的肿瘤负荷以及肿瘤异质性使用。我们假设， 维持移植可能是降低异基因骨髓移植后复发率的最佳策略。然而，在这方面， 尽管我们的团队和其他人已经成功地试验了新的临床移植后维持， 但是，由于这些方法的局限性，单个项目很难用这些有前途的方法进行更大规模的试验。因此，在本发明中， 随着有前途的新疗法的快速发展，一个正式的临床试验网络， 在BMT中有效地进行多中心试验至关重要。我们的具体目标作为一个核心临床 中心将：1）通过BMT CTN参与多中心试验，2）提出一项II期多中心， 适应性随机试验筛选多种新方案治疗异基因骨髓移植后复发， AML/MDS。一个重要的目标将是使个体治疗方案与特定的疾病亚型相匹配。最终 我们的目标将是将有希望的方法转移到移植后的维护中，以防止复发。 尽管血液恶性肿瘤取得了显着进展，大多数患者现在对初始治疗有反应， 大多数人最终复发并死于该病。同种异体血液或骨髓移植仍然是 对于许多这些患者来说，这是唯一的治疗选择，但即使在治疗过程中，复发仍然是失败的最常见原因。 此设置需要新的方法来减少复发而不增加毒性。

Project Summary Our program has focused on the translation of transplantation biology from the laboratory to the clinic to improve the outcome of blood and marrow transplantation (BMT). The development high-dose post-transplant cyclophosphamide (PTCy) to modulate GVHD is a prime example of our group’s successful translational research. Not only does PTCy allow safe haploidentical (haplo) BMT in patients up to at least age 75, but results are now similar to those seen with matched donors. Accordingly, the ability to successfully utilize mismatched donors now permits virtually anyone in need of BMT to undergo the procedure. In addition to moving allogeneic BMT into non-malignant indications, our group has been concentrating on reducing relapses after allogeneic BMT for malignancy. With the reduction in non-relapse mortality, relapse has become by far the major complication of allogeneic BMT. Emerging data suggest that a new non-tolerant and non-exhausted transplanted immune system may enhance the activity of most anticancer agents. Post-allogeneic BMT maintenance therapy is already generating encouraging results; this is perhaps best exemplified by the impressive results seen in FLT3/ITD AML patients who received allogeneic BMT and post-transplant FLT3 tyrosine kinase inhibitors, despite these agents showing limited activity in the non-transplant setting. The minimal residual disease (MRD) state post-allogeneic BMT may also optimize antitumor approaches, in that they will be utilized at lowest tumor burden as well as tumor heterogeneity. Thus, we hypothesize that post- transplant maintenance may be the best strategy for decreasing relapse rates after allogeneic BMT. However, although our group and others have had successes in piloting novel clinical post-transplant maintenance strategies, it is difficult for a single program to carry out larger trials with these promising approaches. Thus, with the rapid development of promising new therapies, a formal clinical trials network that can rapidly and efficiently conduct multi-center trials in BMT is critically important. Our specific objectives as a Core Clinical Center are to: 1) Participate in multicenter trials through the BMT CTN, and 2) Propose a phase 2, multicenter, adaptively randomized trial to screen multiple novel regimens for treating relapse after allogeneic BMT for AML/MDS. An important goal will be to match individual regimens to specific disease subtypes. The ultimate goal will be to move promising approaches into post-transplant maintenance to prevent relapse. Despite remarkable progress in hematologic malignancies with most patients now responding to initial therapy, the majority eventually relapse and die of the disease. Allogeneic blood or marrow transplantation remains the only curative option for many of these patients, but relapse remains the most common cause for failure even in this setting. Novel approaches that reduce relapse without increasing toxicity are needed.