Allogeneic Hematopoietic Cell Transplantation for Myelodysplastic Syndromes

骨髓增生异常综合征（MDS）是克隆性造血系统疾病，其可通过以下方法治愈： 造血细胞移植（HCT）。然而，在患有更多疾病的患者中， 晚期疾病和方案相关毒性和移植相关并发症，特别是移植物抗- 宿主疾病（GVHD）仍然是导致非复发死亡率（NRM）问题。使用 降低强度/非清髓性预处理方案可减少急性NRM，但不能消除 移植物抗宿主病问题，特别是其慢性形式， 进展/复发。本项目的总体目标是优化MDS患者的HCT策略 从相关或不相关、HLA相同或不相同的供体移植。具体而言，在目标1中，我们将 开展一项多中心、随机前瞻性研究，比较清髓性和 非清髓性预处理，并确定任何一种方法的总生存率。在目标2中，我们 进行全身照射（TBI）剂量递增联合氟达拉滨（Flu）的试点试验， 预防未接受过治疗的高危MDS患者的疾病进展和移植物衰竭 HCT前化疗。在目的3中，我们将a）确定是否从GCSF中减少CDS细胞含量 动员的外周血单核细胞将减少移植后GVHD的发生率， HLA相同的家族成员，而不增加移植失败的风险; B）进一步完善体内 Thymoglobulin联合Flu加白消安预处理对移植患者T细胞的清除作用 有血缘关系或无血缘关系的捐赠者在目标4中，我们将确定a）是否使用流感/TBI进行条件反射 （+/-Campath（R））允许来自HLA I类错配的无关供体的HCT; B）是否用 流感/TBI和环磷酰胺在移植前后允许HCT从单倍体相合相关 捐助者。在目标5中，我们将继续长期观察接受HCT的MDS患者， 生成延迟结果的数据库。我们希望这些研究能够提供明确的数据， 在可比患者队列中，与非清髓性HCT相比， 疾病进展，扩大MDS患者HCT的适应症，并评估晚期结果， HCT。从这些研究中获得的知识应该使我们能够为更多的MDS患者提供HCT， 提高成功率和长期生存率。

Myelodysplastic syndromes (MDS) are clonal hematopoietic disorders that are potentially curable by hematopoietic cell transplantation (HCT). However, disease progression/relapse in patients with more advanced disease and regimen-related toxicity and transplant-related complications, in particular, graftversus- host disease (GVHD), remain problems that lead to non-relapse mortality (NRM). The use of reduced-intensity/nonmyeloablative conditioning regimens has reduced acute NRM but has not eliminated the problem of GVHD, particularly in its chronic form, and has been associated with disease progression/relapse. The overall objective of this Project is to optimize HCT strategies for patients with MDS transplanted from related or unrelated, HLA-identical or -nonidentical donors. Specifically, in Aim 1, we will carry out a multi-center, randomized prospective study comparing efficacy of myeloablative and nonmyeloablative conditioning, and determine overall survival with either approach. In Aim 2, we will conduct a pilot trial of total body irradiation (TBI) dose escalation in conjunction with fludarabine (Flu) to prevent disease progression and graft failure in patients with high-risk MDS who have not received chemotherapy before HCT. In Aim 3, we will a) determine whether reduction of the CDS cell content from GCSF mobilized peripheral blood mononuclear cells will reduce the incidence of GVHD after transplants from HLA-identical family members without increasing the risk of graft failure; b) further refine the use of in vivo T-cell depletion by Thymoglobulin in conjunction with Flu plus busulfan conditioning in patients transplanted from related or unrelated donors. In Aim 4, we will determine a) whether conditioning with Flu/TBI (+/-Campath(R)) allows for HCT from HLA class I mismatched unrelated donors; b) whether conditioning with Flu/TBI and cyclophosphamide before and after transplantation allows for HCT from haploidentical related donors. In Aim 5, we will continue long-term observation of patients with MDS who have undergone HCT to generate a database of late results. We expect these studies to provide definitive data with myeloablative as compared to nonmyeloablative HCT in comparable patient cohorts, reduce the incidence of GVHD and disease progression, broaden the indications of HCT for patients with MDS, and assess late results with HCT. Knowledge gained from these studies should allow us to offer HCT to more patients with MDS, and to improve the success rate and long-term survival.