Division of Pediatric Hematology/Oncology/Stem Cell Transplantation, Stanford University, Palo Alto, California.
Division of Blood and Marrow Transplant Program, University of Minnesota, Minneapolis, Minnesota.
Biol Blood Marrow Transplant. 2014 Apr;20(4):581-6. doi: 10.1016/j.bbmt.2013.12.564. Epub 2013 Dec 24.
Allogeneic hematopoietic stem cell transplantation for patients with a hemoglobinopathy can be curative but is limited by donor availability. Although positive results are frequently observed in those with an HLA-matched sibling donor, use of unrelated donors has been complicated by poor engraftment, excessive regimen-related toxicity, and graft-versus-host disease (GVHD). As a potential strategy to address these obstacles, a pilot study was designed that incorporated both a reduced-intensity conditioning and mesenchymal stromal cells (MSCs). Six patients were enrolled, including 4 with high-risk sickle cell disease (SCD) and 2 with transfusion-dependent thalassemia major. Conditioning consisted of fludarabine (150 mg/m(2)), melphalan (140 mg/m(2)), and alemtuzumab (60 mg for patients weighing > 30 kg and .9 mg/kg for patients weighing <30 kg). Two patients received HLA 7/8 allele matched bone marrow and 4 received 4-5/6 HLA matched umbilical cord blood as the source of HSCs. MSCs were of bone marrow origin and derived from a parent in 1 patient and from an unrelated third-party donor in the remaining 5 patients. GVHD prophylaxis consisted of cyclosporine A and mycophenolate mofetil. One patient had neutropenic graft failure, 2 had autologous hematopoietic recovery, and 3 had hematopoietic recovery with complete chimerism. The 2 SCD patients with autologous hematopoietic recovery are alive. The remaining 4 died either from opportunistic infection, GVHD, or intracranial hemorrhage. Although no infusion-related toxicity was seen, the cotransplantation of MSCs was not sufficient for reliable engraftment in patients with advanced hemoglobinopathy. Although poor engraftment has been observed in nearly all such trials to date in this patient population, there was no evidence to suggest that MSCs had any positive impact on engraftment. Because of the lack of improved engraftment and unacceptably high transplant-related mortality, the study was prematurely terminated. Further investigations into understanding the mechanisms of graft resistance and development of strategies to overcome this barrier are needed to move this field forward.
同种异体造血干细胞移植可治愈血红蛋白病患者，但受到供体可用性的限制。尽管在 HLA 匹配的同胞供体中经常观察到阳性结果，但由于植入不良、治疗相关毒性过大和移植物抗宿主病（GVHD），使用无关供体变得复杂。作为解决这些障碍的一种潜在策略，设计了一项包含低强度预处理和间充质基质细胞（MSCs）的试验。共纳入 6 例患者，其中 4 例为高危镰状细胞病（SCD），2 例为输血依赖型重型地中海贫血。预处理方案包括氟达拉滨（150mg/m2）、马法兰（140mg/m2）和阿仑单抗（体重>30kg 的患者为 60mg，体重<30kg 的患者为 0.9mg/kg）。2 例患者接受 HLA 7/8 等位基因匹配的骨髓，4 例患者接受 4-5/6 HLA 匹配的脐带血作为 HSCs 的来源。MSCs 来源于骨髓，1 例患者来自父母，其余 5 例患者来自无关的第三方供体。GVHD 预防方案包括环孢素 A 和霉酚酸酯。1 例患者发生中性粒细胞减少性植入失败，2 例患者发生自体造血恢复，3 例患者发生完全嵌合的造血恢复。2 例发生自体造血恢复的 SCD 患者仍存活。其余 4 例患者死于机会性感染、GVHD 或颅内出血。尽管未观察到输注相关毒性，但在晚期血红蛋白病患者中，MSC 的共移植不足以保证可靠的植入。尽管迄今为止在该患者人群中进行的几乎所有此类试验均观察到植入不良，但没有证据表明 MSCs 对植入有任何积极影响。由于植入改善不明显且移植相关死亡率高，该研究提前终止。需要进一步研究以了解移植物抵抗的机制，并制定克服这一障碍的策略，以推动该领域的发展。
