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

描述(申请人提供)：由于缺乏合适的捐赠者，许多患者，特别是来自少数族裔的患者，无法获得异基因造血细胞移植的治疗益处。对于这类患者，脐带血可以提供另一种造血细胞来源。然而，成年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，与传统捐赠者的移植相比，这种移植也与免疫重建延迟、感染率增加和与治疗相关的死亡率更高。最近，在缺乏传统供者的患者中，使用半相合(部分相合的亲属供者)造血细胞移植(haplo-hct)使用T细胞全系骨髓移植和移植后环磷酰胺(PTCy)，在非清髓性准备方案中可产生高植入率和低治疗相关死亡率(TRM)。然而，由于复发率高，这种移植对侵袭性/进展性髓系恶性肿瘤的疗效有限。在一项机构试点试验中，我们评估了T细胞动员外周血(PBSC)和清髓性准备方案的使用。尽管接受治疗的恶性肿瘤是晚期和高风险的，但估计6个月的TRM为14%，无病生存率为72%。所有患者在+30天前植入并发展为CD3+和CD33+细胞的完全供者嵌合体。因此，建议在BMT CTN内进行一项多机构第二阶段试验，以确认这些令人鼓舞的结果。这项拟议的试验将检验这一假设，即这种新的清髓性单核细胞移植方法在多机构环境下使用是安全和有效的。在这项II期试验成功完成后，我们建议进行111期随机对照试验，比较这种方法用于单核细胞移植和清髓性DCBT的疗效。这项第111阶段研究的目的将是直接比较这两种替代供体移植方法在安全性、毒性、有效性、成本和免疫重建方面的差异。这项试验将最终确定对缺乏匹配同胞或匹配的无血缘关系捐赠者相关性的晚期恶性肿瘤患者进行清髓移植的最佳选择(参见说明)：拟议的研究解决了当前公共卫生领域的一个重大缺陷。具体地说，它测试了一种新的战略，该战略将使治疗性清髓血液干细胞移植能够在由于缺乏传统捐赠者而目前无法获得的患者(特别是那些来自服务不足的少数族裔的患者)中进行。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疗法来改变护理标准，并缩小少数民族在获得医疗保健方面的一大差距。

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.