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: 10012691
• 负责人: Courtney Fitzhugh
• 金额: $ 118.95万
• 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/10012691
• 关键词: Acute; Acute Graft Versus Host Disease; Allogenic; Anticoagulation; Bone Marrow Purging; Bone Marrow Transplantation; CD3 Antigens; Calendar; Chimerism; 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; Recording of previous events; Regimen; Risk; Siblings; Sickle Cell Anemia; Sirolimus; Steroids; Stroke; T-Lymphocyte; Therapeutic; Toxic effect; Transplantation; Umbilical cord structure; Viral; Whole-Body Irradiation; alemtuzumab; base; beta Thalassemia; chronic graft versus host disease; chronic thromboembolic pulmonary hypertension; clinical remission; cohort; conditioning; early detection biomarkers; graft vs host disease; high risk; immunoregulation; improved; mortality; novel; post-transplant; primary endpoint; reconstitution; second transplant; sickling; success; transplant centers

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 78.3%; 3 died after return of their sickle cell disease and 1 following second transplant. 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 moderate to severe chronic 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 reached stopping rules for the study, we opened a new protocol which adds additional immunosuppression in an attempt to improve the success rate while maintaining a low risk of GVHD. Since June 2017, 12 patients have been transplanted, 6 in the past year. All patients achieved high donor chimerism levels. One patient with history of stroke and chronic thromboembolic pulmonary hypertension on anticoagulation died 60 days after her second transplant. One of the 12 developed Grade 2 acute GVHD which responded well to steroids. We are planning to transplant 5 more patients by the end of this calendar year and 10 patients per year thereafter. 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. We also seek to identify whether patients are indeed tolerant of their grafts so that unnecessary immunosuppression can be discontinued.

根据我们的小鼠数据，我们制定了第 1 期和第 2 期方案，采用阿仑单抗、400cGy 全身照射 (TBI) 和移植后环磷酰胺 (PT-Cy) 的剂量递增，范围从队列 1 中的 0mg/kg 和队列 2 中的 50mg/kg 到队列 3 中的 100mg/kg。总共 21 名镰状细胞病患者和 2 名镰状细胞病患者 β地中海贫血被移植并出现并发症，包括肝硬化、肺动脉高压、心力衰竭和终末期肾病。 植入率从第一队列的 1/3 (33%) 提高到第二队列的 5/8 (63%)，再到第三队列的 10/12 (83%)。 随后的队列中供体骨髓和 CD3 嵌合体的百分比也有所提高。 总生存率为78.3%； 3 人在镰状细胞病复发后死亡，1 人在第二次移植后死亡。 移植后100天之前没有死亡。 目前，第一组中的 0%、第二组中的 25% 和第三组中的 50% 仍然没有患病。 没有发生2-4级急性或中重度慢性移植物抗宿主病（GVHD）。 因此，我们已经证明 PT-Cy 可以改善早期死亡风险高的 SCD 患者的植入。 当我们达到研究的停止规则时，我们开启了一个新的方案，增加了额外的免疫抑制，试图提高成功率，同时保持较低的 GVHD 风险。 自2017年6月以来，已有12名患者接受了移植手术，其中去年有6名患者接受了移植手术。 所有患者均达到高供体嵌合水平。 一名有中风病史且接受抗凝治疗的慢性血栓栓塞性肺动脉高压患者在第二次移植后 60 天死亡。 12 名患者中的一名出现了 2 级急性 GVHD，对类固醇反应良好。 我们计划在今年年底前再移植 5 名患者，此后每年移植 10 名患者。 我们还将寻找与移植排斥相关的早期生物标志物，试图在早期且可能更可逆的状态下识别移植排斥，并探索移植和耐受诱导的机制。 我们还试图确定患者是否确实能够耐受移植物，以便停止不必要的免疫抑制。