Allogeneic Hematopoietic Cell Transplantation for Myelodysplastic Syndromes

异基因造血细胞移植治疗骨髓增生异常综合征

• 批准号: 7304858
• 负责人: H. JOACHIM DEEG
• 金额: $ 16.22万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-15 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7304858
• 关键词: MHC class I antigen; acute myelogenous leukemia; artificial immunosuppression; bone marrow disorder; busulfan; chronic myelogenous leukemia; colony stimulating factor; cyclophosphamide; fludarabine; hematopoietic stem cells; hematopoietic tissue transplantation; homologous transplantation; human subject; human therapy evaluation; immunopathology chemotherapy; longitudinal human study; method development; monoclonal antibody; patient oriented research; radiation therapy dosage; stem cell transplantation; transplant rejection; MHC class I antigen; acute myelogenous leukemia; artificial immunosuppression; bone marrow disorder; busulfan; chronic myelogenous leukemia; colony stimulating factor; cyclophosphamide; fludarabine; hematopoietic stem cells; hematopoietic tissue transplantation; homologous transplantation; human subject; human therapy evaluation; immunopathology chemotherapy; longitudinal human study; method development; monoclonal antibody; patient oriented research; radiation therapy dosage; stem cell transplantation; transplant rejection

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.

骨髓增生综合征（MDS）是克隆造血疾病，可能可以通过 造血细胞移植（HCT）。但是，更多的患者疾病进展/复发 晚期疾病和方案相关的毒性和与移植有关的并发症，特别是嫁接剂 - 宿主疾病（GVHD）仍然是导致非释放死亡率（NRM）的问题。使用 降低强度/非甲状腺阻止条件治疗方案已减少急性NRM，但尚未消除 GVHD的问题，尤其是其慢性形式，与疾病有关 进展/复发。该项目的总体目的是优化MDS患者的HCT策略 从相关或无关的，hLA的或无关的捐助者中移植。具体来说，在AIM 1中，我们将 进行多中心，随机的前瞻性研究，比较骨髓性和 非甲状腺素调节，并通过两种方法确定总体生存。在AIM 2中，我们将 与Fludarabine（流感）一起进行全身辐照（TBI）剂量升级的试验试验 预防尚未接受的高风险MD的患者的疾病进展和移植失败 HCT之前的化学疗法。在AIM 3中，我们将a）确定是否减少了GCSF的CDS细胞含量 动员的外周血单核细胞将减少从中移植后GVHD的发生率 HLA认同的家庭成员而没有增加移植失败的风险； b）进一步完善体内的使用 胸腺球蛋白与流感和busulfan条件结合的患者的T细胞耗竭 来自相关或无关的捐助者。在AIM 4中，我们将确定a）是否使用流感/TBI调理 （+/- Campath（R））允许HCT来自HLA I类不匹配的无关捐助者； b）是否与 移植前后的流感/TBI和环磷酰胺允许从单倍性相关的HCT 捐助者。在AIM 5中，我们将继续长期观察接受HCT的MDS患者 生成一个晚期结果的数据库。我们希望这些研究能够以骨髓性提供明确的数据 与可比较的患者同类中的非甲元素HCT相比，降低了GVHD的发生率和 疾病进展，扩大了MDS患者的HCT的指示，并评估了延迟结果 HCT。从这些研究中获得的知识应该使我们能够为更多的MD患者提供HCT，并 提高成功率和长期生存。