JAMA：新型干细胞移植促进疾病治疗

　　——一种新型血液干细胞移植技术将能帮助那些镰刀状细胞贫血症患者不再需要服用免疫抑制剂药物

生物通报道：来自美国国立卫生研究院NIH等处的研究人员报道称，他们研发出一种新技术，能帮助进行了血液干细胞移植的严重镰刀状细胞贫血症患者，令他们即使血液中携带了其他人的干细胞，也能停止使用免疫抑制剂药物（大部分干细胞移植手术患者都需要终身服用）。

这一研究成果公布在7月1日的美国著名医学杂志JAMA上。

“临床试验证明，停止服用这种药物的患者，也能安全稳定的进行部分移植疗法，”文章的第一作者，美国NIH糖尿病、消化和肾脏疾病研究院Matthew Hsieh表示。

“免疫抑制剂药物的副作用对于已经多年受到镰刀状细胞贫血影响的患者器官来说，极具危害性”，作者之一，NIH心脏，肺和血液研究所的John Tisdale说，“不必长期依赖于这种药物，并同时配合毒性相对较低偏干的干细胞移植手术，这样甚至是年龄大的患者，以及患有严重镰刀状细胞贫血症的患者都能改变他们的现状了。”

这项实验性治疗研究成果除了能令半数参与者停止服用免疫抑制剂药物后，不会产生免疫排斥或移植物抗宿主病（graft-versus-host），而且“也治疗了几乎所有患者的镰刀状细胞贫血症”。

目前，血液干细胞或骨髓移植是治疗镰刀状细胞贫血症的唯一方法，这些镰刀状细胞如果不经治疗，就会阻碍血液流动，导致疼痛、器官损伤和脑卒中。

这种新治疗方法只用替换患者的部分骨髓，比整体移植手术伤害性小（后者还需要进行高剂量化疗）。而且部分移植采用的是健康兄弟姐妹的供体干细胞。

研究人员指出，最终这30位患者中的26位，贫血症状消失了，其中15位患者不再需要服用免疫抑制剂药物进行治疗了。现在，时间已经过去了将近三年半，这15位患者全部都没有出现任何排斥反应或移植物抗宿主病。

“这是成人镰刀状细胞贫血症治疗的一项重要进步，”华盛顿大学医学院儿科助理教授Allison King表示，“这给予了那些能进行兄弟姐妹匹配的镰刀状细胞贫血症成人患者以新希望，证明他们能治愈这种疾病，获得好转。”

（生物通：张迪）

原文摘要：

Nonmyeloablative HLA-Matched Sibling Allogeneic Hematopoietic Stem Cell Transplantation for Severe Sickle Cell Phenotype

Importance Myeloablative allogeneic hematopoietic stem cell transplantation (HSCT) is curative for children with severe sickle cell disease, but toxicity may be prohibitive for adults. Nonmyeloablative transplantation has been attempted with degrees of preparative regimen intensity, but graft rejection and graft-vs-host disease remain significant.

Objective To determine the efficacy, safety, and outcome on end-organ function with this low-intensity regimen for sickle cell phenotype with or without thalassemia.

Design, Setting, and Participants From July 16, 2004, to October 25, 2013, 30 patients aged 16-65 years with severe disease enrolled in this nonmyeloablative transplant study, consisting of alemtuzumab (1 mg/kg in divided doses), total-body irradiation (300 cGy), sirolimus, and infusion of unmanipulated filgrastim mobilized peripheral blood stem cells (5.5-31.7 × 106 cells/kg) from human leukocyte antigen–matched siblings.

Main Outcomes and Measures The primary end point was treatment success at 1 year after the transplant, defined as a full donor-type hemoglobin for patients with sickle cell disease and transfusion independence for patients with thalassemia. The secondary end points were the level of donor leukocyte chimerism; incidence of acute and chronic graft-vs-host disease; and sickle cell–thalassemia disease-free survival, immunologic recovery, and changes in organ function, assessed by annual brain imaging, pulmonary function, echocardiographic image, and laboratory testing.

Results Twenty-nine patients survived a median 3.4 years (range, 1-8.6), with no nonrelapse mortality. One patient died from intracranial bleeding after relapse. As of October 25, 2013, 26 patients (87%) had long-term stable donor engraftment without acute or chronic graft-vs-host disease. The mean donor T-cell level was 48% (95% CI, 34%-62%); the myeloid chimerism levels, 86% (95% CI, 70%-100%). Fifteen engrafted patients discontinued immunosuppression medication with continued stable donor chimerism and no graft-vs-host disease. The normalized hemoglobin and resolution of hemolysis among engrafted patients were accompanied by stabilization in brain imaging, a reduction of echocardiographic estimates of pulmonary pressure, and allowed for phlebotomy to reduce hepatic iron. The mean annual hospitalization rate was 3.23 (95% CI, 1.83-4.63) the year before, 0.63 (95% CI, 0.26-1.01) the first year after, 0.19 (95% CI, 0-0.45) the second year after, and 0.11 (95% CI, 0.04-0.19) the third year after transplant. For patients taking long-term narcotics, the mean use per week was 639 mg (95% CI, 220-1058) of intravenous morphine–equivalent dose the week of their transplants and 140 mg (95% CI, 56-225) 6 months after transplant. There were 38 serious adverse events: pain and related management, infections, abdominal events, and sirolimus related toxic effects.

Conclusions and Relevance Among 30 patients with sickle cell phenotype with or without thalassemia who underwent nonmyeloablative allogeneic HSCT, the rate of stable mixed-donor chimerism was high and allowed for complete replacement with circulating donor red blood cells among engrafted participants. Further accrual and follow-up are required to assess longer-term clinical outcomes, adverse events, and transplant tolerance.