Randomized study of low versus moderate dose busulfan in transplant for severe combined immunodeficiency

项目摘要 严重联合免疫缺陷(SCID)是一组导致T细胞丧失的遗传性疾病 发展和功能。异基因造血细胞移植(HCT)是标准治疗方法， 这种疾病如果不治疗，通常会在2岁前致命。在SCID中可以成功地进行HCT 由于缺乏功能性T细胞，没有使用大剂量HCT前丁硫丹调理的患者 细胞。尽管T细胞功能得到了恢复，但许多患者的体液免疫功能在HCT后仍然较低。这 该项目旨在测试一种低剂量、个性化靶向白丹疗法的有效性和安全性。 与中等剂量接受非相合同胞治疗的SCID患者体液结局不良风险的比较 供者红细胞压积。我们将针对没有活动性感染的患者，利用广泛实施的 美国的普遍新生儿筛查。我们假设在我们提议的多机构 接受低剂量白消安治疗的随机II期试验患者将获得与 接受中等剂量(清髓性)白花丹，实现T细胞和B细胞免疫重建。 在目标1中，我们将检查试验参与者的免疫学和安全性结果。缺乏的患者 匹配的兄弟姐妹捐赠者，被确认具有适当的基因，并且没有活动性感染的人将 将在4年半内招募。在两个基因型队列(IL2RG/JAK3，RAG1/RAG2)中，32名患者将 被随机分为白消安30 mg*h/L与60 mg*h/L(32 mg*h/h)的累积曲线下面积暴露 每队列患者，患者总数)。IL2RG/JAK3患者还将接受rATG和RAG1/RAG2患者 将接受rATG、氟达拉滨和硫替巴。干细胞来源包括无关和半完全相同的相关来源 供体产品将被TCRαβ/CD19耗尽，而不进行血细胞移植后GVHD预防。初级阶段 终点是对破伤风的保护性抗体反应，破伤风是正常体液免疫功能的黄金标准 儿童，在HCT后2年。次要终点包括T细胞数量、胸腺输出量、细胞 类型特异性嵌合体、3年对活病毒疫苗的应答、存活率和红细胞压积相关的发病率 并发症。 在目标2中，我们将深入研究T和B细胞异常的纠正。中心问题是 混合/分裂嵌合体(供者来源的T细胞在B系和髓系中混合嵌合 但与正常免疫表型、功能、谱系和 在一个或多个基因型队列中的耐受性。我们假设记忆B细胞的产生，抗体- HCT后分泌细胞和纠正先前存在的B细胞受体谱系异常将是 在所有的基因型队列中都很明显，混合嵌合体环境中的纠正程度和质量 会根据每种基因异常的生物学特征而有所不同。我们假设T细胞耗尽出现在 在没有条件作用的情况下接受HCT的患者将在试验参与者中减少或缺席，原因是 与供体来源的造血干细胞植入相关的胸腺输出的改善。我们假设T细胞 根据供者的不同，耐受性将通过不同的机制(中心缺失和外周调节)发生 类型(单倍体相合与完全匹配的非亲缘供者)仍可成功诱导 混合嵌合体。

Project Summary Severe combined immunodeficiency (SCID) is a group of genetic disorders that abrogate T cell development and function. Allogeneic hematopoietic cell transplantation (HCT) is the standard treatment, for the disease, which is typically fatal by age 2 years if not treated. HCT can be performed successfully in SCID patients without the high dose pre-HCT busulfan conditioning typically used, due to the lack of functional T cells. Despite restoration of T cell function, humoral immunity remains poor in many patients post-HCT. This project seeks to test the efficacy and safety of a regimen of low dose, individualized targeted busulfan compared to moderate dose in SCID patients at risk of poor humoral outcome undergoing non-matched sibling donor HCT. We will target patients without active infection, leveraging the widespread implementation of universal newborn screening in the United States. We hypothesize that in our proposed multi-institutional randomized phase II trial patients receiving low dose busulfan will achieve similar outcomes compared to those receiving moderate dose (myeloablative) busulfan, achieving both T and B cell immune reconstitution. In Aim 1, we will examine immunological and safety outcomes in trial participants. Patients who lack matched sibling donors, confirmed to have the appropriate genotype, and who do not have active infection will be recruited over 4 1/2 years. Within each of 2 genotype cohorts (IL2RG/JAK3, RAG1/RAG2), 32 patients will be randomized to cumulative area-under-the-curve exposure of busulfan of 30 mg*h/L versus 60 mg*h/L (32 patients per cohort, 64 patients total). IL2RG/JAK3 patients will also receive rATG and RAG1/RAG2 patients will receive rATG, fludarabine, and thiotepa. Stem cell sources include unrelated and haploidentical related donor products that will be TCRαβ+/CD19+ depleted with no post-HCT GVHD prophylaxis. The primary endpoint is protective antibody response to tetanus, a gold standard of normal humoral immune function in children, by 2 years post-HCT. Secondary endpoints include reconstitution of T cell number, thymic output, cell type specific chimerism, response to live viral vaccines at 3 years, survival, and incidence of HCT related complications. In Aim 2, we will examine the correction of T and B cell abnormalities in depth. The central question is whether mixed/split chimerism (donor-derived T cells with mixed chimerism in the B and myeloid compartments) will nevertheless be associated with normal immune phenotype, function, repertoire and tolerance in one or more genotypic cohorts. We hypothesize that generation of memory B cells, antibody- secreting cells and correction of pre-existing abnormalities of the B cell receptor repertoire post-HCT will be evident in all genotype cohorts and that the degree and quality of correction in the setting of mixed chimerism will vary according to the biology of each genetic abnormality. We hypothesize that T cell exhaustion seen in patients undergoing HCT in the absence of conditioning will be diminished or absent in trial participants due to improvements in thymic output associated with engraftment of donor-derived HSC. We hypothesize that T cell tolerance will occur by different mechanisms (central deletion versus peripheral regulation) according to donor type (haploidentical versus well matched unrelated donor) yet will be induced successfully in patients with mixed chimerism.