Allogeneic Hematopoietic Cell Transplantation for Myelodysplastic Syndromes

骨髓增生异常综合征(MDS)是一种克隆性造血疾病，可通过以下方法治愈 造血细胞移植(HCT)。然而，在疾病进展/复发的患者中 晚期疾病和方案相关的毒性和移植相关的并发症，特别是移植物抗- 宿主病(GVHD)仍然是导致非复发性死亡(NRM)的问题。对.的使用 低强度/非清髓性预适应方案减少了急性NRM，但并未消除 GVHD问题，特别是其慢性形式，与疾病有关 进展/复发。该项目的总体目标是优化MDS患者的HCT策略 移植自有血缘关系或无血缘关系、人类白细胞抗原相合或不相合的供者。具体来说，在目标1中，我们将 开展一项多中心、随机前瞻性研究，比较清髓和清髓的疗效 非清髓性条件作用，并决定两种方法的总存活率。在目标2中，我们将 进行全身照射(TBI)剂量递增与氟达拉滨(Flu)联合的试点试验 预防高危MDS患者的疾病进展和移植物衰竭 HCT前化疗。在目标3中，我们将a)确定是否减少GCSF中CDS细胞的含量 动员的外周血单个核细胞将降低移植后移植物抗宿主病的发生率 不会增加移植失败的风险；b)进一步完善体内移植的使用 胸腺球蛋白联合流感+白丹调理对移植患者T细胞的去除作用 来自相关或不相关的捐赠者。在目标4中，我们将确定a)是否有流感/脑损伤的条件反射 (/-CamPath(R))允许来自人类白细胞抗原I类不匹配的无关供者的HCT；b)是否与 移植前后Flu/TBI和环磷酰胺允许半相合血缘关系的Hct 捐赠者。在目标5中，我们将继续对接受HCT的MDS患者进行长期观察 生成最新结果的数据库。我们期望这些研究能为清髓性AS提供确凿的数据。 与可比患者队列中的非清髓性红细胞移植相比，减少GVHD和 疾病进展，扩大MDS患者的HCT适应症，并评估近期疗效 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，并 提高成功率和长期存活率。

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.