Nonmyeloablative Transplants for Nomalignant Disorders

造血干细胞移植(HSCT)是目前唯一 具有治疗潜力的慢性阻塞性肺疾病的治疗模式 骨髓增生异常综合征(MDS)。复发(晚期多发性硬化症)，方案- 相关毒性(RRT)和无复发死亡率(MRS)仍然存在 治疗失败的原因。RRT随年龄增长而增加，这是MDS的一个问题 确诊时年龄中位数为65-70岁的患者。患有疾病的患者 骨髓纤维化(MF)通常在相似的年龄范围内，并且有限 治疗选择。这个项目的长期目标是改进 骨髓增生异常综合征和多发性骨髓瘤患者行造血干细胞移植的结果。为了减少NRM， 减少新方案以改善HSCT患者的预后 MDS和MF。为了减少NRM，毒性降低的新方案 对于相关或不相关的移植将被开发。具体来说，1) “不太晚期”的MDS患者将接受有针对性的白花丹(BU)治疗 至800-900 ng/mL的血浆浓度加环磷酰胺(CY)、g-CSF 动员的外周血干细胞(PBSC)和移植后 甲氨蝶呤(MTX)和环孢素A(CSP)； 高级MDS将使用a)目标BU(800-900)进行治疗 Ng/mL)加氟达拉滨、G-CSF动员的血液干细胞(PBSC)，以及 移植后甲氨蝶呤(MTX)和环孢素A(CSP)；2)患者 如果MDS病情严重，将采用a)靶向BU(800- 900 ng/mL)加氟立止血、G-CSF动员的PBSC和MTX/CSP (患者；66岁；CD33-；.30X10/9白细胞/L)，或b)Mylotarg(抗- CD33结合的Calicheamicin)，氟达拉滨，全身200cGy. 照射、G-CSF动员的PBSC和霉酚酸酯模型 (MMF)/CSF(MF患者，&GT；65岁；CD33+； 30x10/9WBC/L；常规方案的医学禁忌症)； 3)66岁的MF患者将接受靶向BU和CY，G- CSF动员的PBSC和MMF/CSP(相关)或MTX/CSP(无关) 捐赠者)。MF患者还将接受顺序的骨髓扫描和 活检以确定MF消退的动力学；4)高危和 患有MDS或MF的老年患者将接受非清髓剂治疗 移植后方案(氟达拉滨+200cGyTBI)和MMF/CSP， 依靠移植物对宿主的效应来根除疾病。结果来自 这些研究将在设计后续议定书时予以考虑。 在这个项目下。这些治疗策略有望降低RRT。 在不增加复发的情况下，MDS和MF患者的NRM 从而进一步提高无病存活率。

Hematopoietic stem cell transplantation (HSCT) is currently the only therapeutic modality with curative potential in patients with myelodysplastic syndromes (MDS). Relapse (in advanced MS), regimen- related toxicity (RRT) and non-relapse-mortality (MRS) have remained causes of treatment failure. RRT increases with age, a concern in MDS patients with a median age at diagnosis of 65-70 years. Patients with myelofibrosis (MF) frequently are in a similar age range and have limited therapeutic options. The long-term goal of this project is to improve outcome with HSCT in patients with MDS and MF. To reduce NRM, new regimens with reduced to improve outcome with HSCT in patients with MDS and MF. To reduce NRM, new regimens with reduced toxicity for related or unrelated transplants will be developed. Specifically, 1) patients with "less advanced" MDS will receive busulfan (BU) targeted to plasma levels of 800-900 ng/mL plus cyclophosphamide (CY), g-CSF mobilized peripheral blood stem cells (PBSC), and post-grafting methotrexate (MTX) and cyclosporine (CSP); 2) patients with "advanced" MDS will be treated with either a) targeted BU (800-900 ng/mL) plus fludarabine, G-CSF mobilized blood stem cells (PBSC), and post-grafting methotrexate (MTX) and cyclosporine (CSP); 2) patients with "advanced" MDS will be treated with either a) targeted BU (800- 900 NG/mL) plus fludaribine, G-CSF mobilized PBSC, and MTX/CSP (patients <66 years old; CD33-; .30X10/9 WBC/L), or b) mylotarg (anti- CD33-conjugated calicheamicin), fludarabine, 200 cGy of total body irradiation (TBI), G-CSF mobilized PBSC and mycophenolate mofetil (MMF)/CSF (patients with MF, >65 years old; CD33+; <30x10/9WBC/L; medical contraindications to conventional regimens); 3) patients with MF, <66 years old, will receive targeted BU and CY, G- CSF mobilized PBSC, and MMF/CSP (related) or MTX/CSP (unrelated donors). MF patients will also undergo sequential marrow scanning and biopsies to determine the kinetics of regression of MF; 4) high risk and older patients with MDS or MF will be treated with a non-myeloablative regimen (fludarabine+ 200 cGy TBI) and MMF/CSP post-transplant, relying on a graft-vs-host effect for disease eradication. Results from those studies will be considered in the design of subsequent protocols under this Project. These treatment strategies are expected to reduce RRT and NRM in patients with MDS and MF without increasing the relapse rate, and thereby further improve disease-free survival.