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CD3嵌合体的百分比也随着后续队列而改善。 总生存率为78.3%; 3例在镰状细胞病复发后死亡，1例在第二次移植后死亡。 移植后100天内无死亡。 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级急性或中度至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，我们打开了一个新的方案，增加了额外的免疫抑制，试图提高成功率，同时保持GVHD的低风险。 自2017年6月以来，已有12名患者接受了移植，其中6名是在过去一年中。 所有患者均达到高供体嵌合水平。 1例有中风和慢性血栓栓塞性肺动脉高压病史的患者在第二次移植后60天死亡。 12例中有1例发生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。 我们还试图确定患者是否真的对移植物耐受，以便停止不必要的免疫抑制。

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 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.