Bone Marrow Transplantation in Human Disease

总括 项目摘要 移植后应用环磷酰胺(PTCy)来调节移植物抗宿主病(GVHD)就是我们最好的例子 集团成功的翻译研究。PTCy不仅允许安全的半相合(Haplo)血液或 骨髓移植(BMT)适用于年龄至少75岁的患者，但单骨髓移植合并PTCy的结果迄今已得到证实 许多国际研究和登记册研究似乎与配对捐赠者的研究相似。我们的团队 研究还表明，PTCy还允许应用安全有效的失配非亲缘供者骨髓移植。 与PTCy相关的GVHD并发症的减少将无复发死亡率(NRM)降低到 即使在不匹配的环境下也不到10%，消除了成功进行异基因移植的主要障碍之一 (ALLO)BMT，供者可用。PTCy帮助向几乎所有需要帮助的人开放了allBMT。随着降价 到目前为止，在NRM中，复发已成为异基因骨髓移植的主要并发症。新出现的数据表明，一种新的非 耐受和不耗尽的移植免疫系统具有增强MOST活性的能力 抗癌药物、小分子药物以及免疫药物。因此，这项建议的主要目标是 研究异基因骨髓移植后的维持治疗作为减少复发的一种手段。事实上，我们的数据以及来自其他 这样的方法已经显得很有希望，或许令人印象深刻的结果是最好的例证 在Flt3/ITD AML中出现的allBMT和移植后的Flt3酪氨酸激酶抑制剂，尽管有许多 在非移植环境中表现出有限活性的药物。也有新的数据表明， 其他作为单一药物一般缺乏治疗活性的药物，如淋巴瘤的美罗华，Ph+的TKIs 白血病和氮杂西汀治疗急性髓系白血病/骨髓增生异常综合征可能显示治愈 AllBMT后设置中的活动。AllBMT后最小残留疾病状态也应优化 新的抗肿瘤方法，因为它们将被用于最低的肿瘤负担以及肿瘤的异质性。 这项新提议将建立在我们工作的基础上，证明后allBMT设置提供了一个独特的 减少异基因骨髓移植后复发的环境。此外，现在几乎可以普遍获得 在PTCy相关的良好安全性和成本概况的支持下，该程序开启了对骨髓移植的检查 用于独特的应用。这项提案的总体目标/具体目标是：1)调查 移植维持治疗以减少骨髓移植后复发，2)研究allBMT作为增强 实体肿瘤的新疗法，以及3)研究allBMT联合PTCy是否可以消除HIV。

Overall Project Summary The development 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) blood or marrow (BMT) in patients up to at least age 75, but the outcomes of haplo BMT with PTCy, confirmed by now many international as well as registry studies, appear similar to those seen with matched donors. Our group has also shown that PTCy also allows the application of safe and effective mismatched unrelated donor BMT. The reduction in GVHD complications associated with PTCy has lowered the non-relapse mortality (NRM) to less than 10% even in the mismatched setting, removing one of the major hurdles to successful allogeneic (allo) BMT, donor availability. PTCy has helped open up alloBMT to virtually anyone in need. With the reduction in NRM, relapse has become by far the major complication of alloBMT. Emerging data suggest that a new non- tolerant and non-exhausted transplanted immune system has the ability to augment the activity of most anticancer agents, small molecule as well as immunologic. Thus, the major objective of this proposal is to study maintenance therapy after alloBMT as a means to reduce relapse. In fact, our data, as well as from other groups, already appear promising with such an approach, perhaps best exemplified by the impressive results seen in FLT3/ITD AML with alloBMT and post-transplant FLT3 tyrosine kinase inhibitors despite many of these agents showing limited activity in the non-transplant setting. There are also emerging data suggesting that other agents generally lacking curative activity as single agents, such as rituximab in lymphomas, TKIs in Ph+ leukemias, and azaciditine for acute myeloid leukemia/myelodysplastic syndrom may demonstrate curative activity in the post-alloBMT setting. The minimal residual disease state post-alloBMT should also optimize novel antitumor approaches, in that they will be utilized at lowest tumor burden as well as tumor heterogeneity. This new proposal will build on our work demonstrating that the post alloBMT setting provides a unique environment for decreasing relapse after alloBMT. In addition, the now near universal availability of the procedure, enabled by the favorable safety and cost profile associated with PTCy, opens up examining BMT for unique applications. The overall goals/specific aims of this proposal are to: 1) investigate the ability of post- transplant maintenance therapy to decrease relapse after BMT, 2) study alloBMT as a platform for enhancing novel therapies for solid tumors, and 3) study whether alloBMT with PTCy can eliminate HIV.