Nonmyeloablative Transplants for Nomalignant Disorders

非清髓性移植治疗非恶性疾病

• 批准号: 6941343
• 负责人: Rainer F. Storb
• 金额: $ 9.59万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-01 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6941343
• 关键词: age difference; artificial immunosuppression; blood disorder chemotherapy; bone marrow disorder; bone marrow purging; bone marrow transplantation; busulfan; combination chemotherapy; combination therapy; cyclophosphamide; cyclosporines; dyserythropoietic anemia; hematopoietic tissue transplantation; histocompatibility typing; homologous transplantation; human subject; human therapy evaluation; methotrexate; myelofibrosis; patient oriented research; preneoplastic state; radiation immunosuppression; relapse /recurrence; stem cell transplantation; tissue /cell culture; transplant rejection

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.

造血干细胞移植（HSCT）当前是唯一的 治疗方式具有治疗潜力 骨髓增生综合征（MDS）。复发（在高级MS中），方案 - 相关毒性（RRT）和非雷神死亡率（MRS）仍然存在 治疗失败的原因。 RRT随着年龄的增长而增加，这是MD的关注 诊断为65-70岁的患者中位年龄。患者 骨髓纤维化（MF）经常处于相似的年龄范围内，并且有限 治疗选择。该项目的长期目标是改善 MDS和MF患者HSCT的结果。为了减少NRM， 患者的新方案减少以改​​善HSCT的结果 与MDS和MF。为了减少NRM，毒性降低的新方案 将开发有关相关或不相关的移植。具体来说，1） MDS的患者将受到Busulfan（BU）的针对性患者 到800-900 ng/ml的血浆水平加环磷酰胺（CY），G-CSF 动员外周血干细胞（PBSC）和治疗后 甲氨蝶呤（MTX）和环孢菌素（CSP）； 2）患者 “高级” MD将用a）目标BU（800-900 Ng/mL）加上氟达拉滨，G-CSF动员血干细胞（PBSC）和 治疗后甲氨蝶呤（MTX）和环孢菌素（CSP）； 2）患者 使用“高级” MD的MD将用a）目标BU（800-- 900 ng/ml）加上氟丁替替替啶，G-CSF动员PBSC和MTX/CSP （患者<66岁； CD33-; .30x10/9 WBC/L）或b）mylotarg（抗 - CD33偶联的Calicheamicin），Fludarabine，全体200 CGY 辐照（TBI），G-CSF动员PBSC和霉酚酸酯Mofetil （MMF）/CSF（MF患者，> 65岁； CD33+； <30x10/9wbc/l;传统方案的医学禁忌症）； 3）MF患者（<66岁）将接受靶向BU和CY，G- CSF动员PBSC和MMF/CSP（相关）或MTX/CSP（无关 捐助者）。 MF患者还将进行连续的骨髓扫描和 活检以确定MF回归动力学； 4）高风险和 MD或MF的老年患者将通过非毛刺治疗 方案（Fludarabine+ 200 CGY TBI）和MMF/CSP移植物， 依靠移植物为消除疾病的效果。结果 这些研究将在随后的协议的设计中考虑 在这个项目下。这些治疗策略有望减少RRT MDS和MF患者的NRM而不增加复发 速率，从而进一步提高无病生存率。