Nonmyeloablative haploidentical peripheral blood stem cell transplantation in congenital anemias

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%；没有与移植相关的死亡。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。由于我们已经达成了这项研究的停止规则，我们的方案目前已关闭，不能进一步增加。我们正在研究一种新的方案，该方案将增加额外的免疫抑制，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记物，试图在早期且可能更可逆的状态下识别移植物排斥反应。

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 transplant-related mortality. 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, our protocol is currently closed to further accrual. We are working on a new protocol which will add 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.