Myeloablative T- Replete Haploidentical PBSCT for Patients Without MRD or MUD

描述（由申请人提供）：由于缺乏合适的供体，许多患者，特别是少数民族患者，无法获得异基因造血细胞移植的治疗获益。对于这些患者，脐带血可以提供造血细胞的替代来源。然而，成人通常需要同时使用两个脐带血单位（DCBT），费用相当高。在成人中，与来自常规供体的移植相比，这种移植还与延迟的免疫重建、增加的感染率和更高的治疗相关死亡率相关。最近，使用T细胞充满的骨髓移植物和移植后环磷酰胺（PTCy）的单倍体相合（部分匹配的相关供体）造血细胞移植（haplo-HCT）的使用已经显示，当与非清髓性准备方案一起使用时，在缺乏常规供体的患者中产生高的植入率和低的治疗相关死亡率（TRM）。然而，由于高复发率，这种移植在侵袭性/晚期骨髓恶性肿瘤中具有有限的功效。在一项机构试点试验中，我们评估了T-完全动员的外周血（PBSC）和具有haplo-HCT + PTC γ的清髓性制备方案的使用。尽管治疗的恶性肿瘤具有晚期和高风险的性质，但估计6个月TRM为14%，无病生存率为72%。所有患者在第+30天植入并在CD 3+和CD 33+细胞中形成完全供体嵌合体。因此，在BMT CTN内提出了一项多机构II期试验，以证实这些令人鼓舞的结果。拟议的试验将检验这一假设，即这种新的清髓性单倍HCT方法在多机构环境中使用时是安全有效的。在成功完成该II期试验后，提出了该方法与单倍HCT和清髓性DCBT之间的随机111期比较。这项111期研究的目的是直接比较这两种替代供体移植方法的安全性、毒性、有效性、成本和免疫重建。这项试验将明确确定缺乏匹配兄弟姐妹或匹配无关供体的晚期恶性肿瘤患者进行清髓性移植的最佳选择。具体而言，它测试了一种新的策略，该策略将使治疗性清髓性造血干细胞移植能够用于目前由于缺乏常规供体而无法获得治疗性清髓性造血干细胞移植的患者（特别是来自服务不足的少数民族的患者）。如果成功，它将通过为可能死于癌症的患者提供挽救生命的治疗来改变护理标准，并缩小少数民族在医疗保健方面的重大差距。

DESCRIPTION (provided by applicant): Many patients, particularly those from ethnic minorities, are unable to access the therapeutic benefit of allogeneic hematopoietic cell transplantation due to the lack of a suitable donor. For such patients, umbilical cord blood can offer an alternative source of hematopoietic cells. However, adults typically require the concurrent use of two cord blood units (DCBT) at considerable expense. In adults such transplants are also associated with delayed immune reconstitution, increased rate of infections and a higher treatment related mortality than transplants from conventional donors. Recently the use of haploidentical (partially matched related donor) hematopoietic cell transplants (haplo-HCT) using T-cell-replete marrow grafts and post- transplant cyclophosphamide (PTCy), have been shown to produce high rates of engraftment and low treatment related mortality (TRM) when used with a non-myeloablative preparative regimen, in patients who lack conventional donors. However, such transplants have limited efficacy in aggressive/advanced myeloid malignancies because of a high relapse rate. In an institutional pilot trial, we have assessed the use of T- replete mobilized peripheral blood (PBSC) and a myeloablative preparative regimen with haplo-HCT + PTCy. Despite the advanced and high-risk nature of the malignancies treated, estimated 6 month TRM was 14% and disease-free survival was 72%. All patients engrafted and developed full donor chimerism in CD3+ and CD33+ cells by day +30. A multi-institutional phase II trial is therefore proposed within the BMT CTN to confirm these encouraging results. The proposed trial will test the hypothesis that this novel approach to myeloablative haplo-HCT is safe and effective when used in a multi-institutional setting. Upon successful completion of this phase II trial, a randomized phase 111 comparison is proposed between this approach to haplo-HCT and myeloablative DCBT. The objective of this phase 111 study will be to directly compare these two approaches to alternative donor transplantation with respect to safety, toxicity, efficacy, cost and immune reconstitution. This trial would definitively determine the best option for myeloablative transplantation in patients with advanced malionancies who lack a matched-sibling or matched unrelated donor RELEVANCE (See instructions): The proposed research addresses a significant current deficiency in public health. Specifically, it tests a novel strategy that will enable curative myeloablative blood stem cell transplants in patients (particularly those from underserved minorities) who are currently unable to access them due to lack of a conventional donor. If successful, it will transform the standard-of-care by offering life-saving therapy to patients who would have died from their cancer and close a major disparity in healthcare access for ethnic minorities.