Nonmyeloablative haploidentical peripheral blood stem cell transplantation in congenital anemias

非清髓性单倍相合外周血干细胞移植治疗先天性贫血

• 批准号: 9572324
• 负责人: Courtney Fitzhugh
• 金额: $ 137.64万
• 依托单位: NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9572324
• 关键词: Acute; Allogenic; Alpha Cell; Biological Markers; Bone Marrow Purging; Bone Marrow Transplantation; CD3 Antigens; Cell Transplants; Chimerism; Chronic; Cirrhosis; Congenital Anemia; Cyclophosphamide; Data; Development; Disease; Dose; End stage renal failure; Engraftment; Event; Family member; Graft Rejection; Graft Survival; Granulocyte Colony-Stimulating Factor; Heart failure; Hematopoietic; Hemoglobin; Immunosuppression; Immunosuppressive Agents; Incidence; Low Dose Radiation; Lymphoid; Morbidity - disease rate; Mus; Myelogenous; Patients; Peripheral Blood Stem Cell; Peripheral Stem Cell Transplantation; Phase; Phase I/II Trial; Protocols documentation; Pulmonary Hypertension; Radiation; Regimen; Risk; Siblings; Sickle Cell Anemia; Sirolimus; T-Lymphocyte; Therapeutic; Toxic effect; Transplantation; Umbilical cord structure; Viral; Whole-Body Irradiation; alemtuzumab; base; beta Thalassemia; chronic graft versus host disease; clinical remission; cohort; conditioning; graft vs host disease; high risk; immunoregulation; improved; mortality; novel; reconstitution; sickling; success

Based on our murine data, we developed a phase 1 and 2 protocol employing alemtuzumab, 400cGy total body irradiation (TBI) and escalating doses of post-transplant cyclophosphamide (PT-Cy) ranging from 0mg/kg in cohort 1 and 50mg/kg in cohort 2 to 100mg/kg in cohort 3. A total of 21 patients with sickle cell disease and 2 patients with beta thalassemia were transplanted and had complications including cirrhosis, pulmonary hypertension, heart failure, and end-stage renal disease. The engraftment rate improved from 1/3 (33%) in the first cohort, to 5/8 (63%) in the second cohort to 10/12 (83%) in the third cohort. Percentage of donor myeloid and CD3 chimerism also improved with subsequent cohorts. Overall survival is 86.9%; there was no mortality before 100 days post-transplant. At present, 0% in the first cohort, 25% in the second cohort, and 50% in the third cohort remain free of their disease. There was no Grade 2-4 acute or chronic extensive graft-versus-host disease (GVHD). Therefore, we have shown that PT-Cy improves engraftment in patients with SCD who are at high risk for early mortality. As we have reached stopping rules for the study, we recently opened a new protocol which has added additional immunosuppression in an attempt to improve the success rate. We will also search for early biomarkers associated with graft rejection in an attempt to identify graft rejection at an early and potentially more reversible state and explore mechanisms of engraftment and tolerance induction.

根据我们的小鼠数据，我们制定了一期和二期方案，采用阿伦图珠单抗，400cGy全身照射(TBI)，移植后环磷酰胺(PT-Cy)剂量从0 mg/kg(队列1)和50 mg/kg(队列2)递增到100 mg/kg(队列3)。共有21名镰状细胞病患者和2名β地中海贫血患者接受了移植，并发症包括肝硬化、肺动脉高压、心力衰竭和终末期肾脏疾病。植入率从第一组的1/3(33%)提高到第二组的5/8(63%)到第三组的10/12(83%)。随着后续队列的进行，供者髓系和CD3嵌合体的百分比也有所改善。总存活率为86.9%；移植后100天前无死亡病例。目前，第一个队列中有0%，第二个队列中有25%，第三个队列中有50%的人没有患病。无2-4级急性或慢性广泛性移植物抗宿主病(GVHD)。因此，我们发现PT-Cy可改善早期死亡风险较高的SCD患者的植入率。随着我们达成了这项研究的终止规则，我们最近开启了一项新的方案，该方案增加了额外的免疫抑制，试图提高成功率。我们还将寻找与移植物排斥反应相关的早期生物标志物，试图在早期和可能更可逆的状态下识别移植物排斥反应，并探索植入和耐受诱导的机制。