Nonmyeloablative haploidentical peripheral blood stem cell transplantation in congenital anemias

基于我们的鼠数据，我们开发了一项I期和II期方案，采用Alemtuzumab、400 cGy全身照射（TBI）和递增剂量的移植后环磷酰胺（PT-Cy），剂量范围为队列1中的0 mg/kg和队列2中的50 mg/kg至队列3中的100 mg/kg。 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，并出现了包括肝硬化、肺动脉高压、心力衰竭和终末期肾病在内的并发症。 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%）。 供体髓系和CD 3嵌合体的百分比也随着后续队列而改善。 总生存率为86.9%;移植后100天内没有死亡。 目前，第一队列中的0%、第二队列中的25%和第三队列中的50%仍然没有患病。 无2-4级急性或慢性广泛性移植物抗宿主病（GVHD）。 因此，我们已经证明PT-Cy可以改善早期死亡风险高的SCD患者的植入。 由于我们已经达到了研究的停止规则，我们最近开放了一个新的方案，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相关的早期生物标志物，试图在早期和潜在的更可逆状态下识别移植物排斥，并探索植入和耐受诱导的机制。

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.