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， 这种疾病，如果不治疗，通常在2岁时致命。在SCID中可以成功地进行HCT 由于缺乏功能性T细胞， 细胞尽管T细胞功能恢复，但许多HCT后患者的体液免疫仍然很差。这 该项目旨在测试低剂量、个体化靶向白消安方案的有效性和安全性 与中度剂量相比，在接受非匹配同胞治疗的有不良体液结局风险的SCID患者中， 供体HCT。我们将针对没有活动性感染的患者，利用广泛实施的 在美国进行新生儿筛查。我们假设，在我们提出的多机构 接受低剂量白消安的随机II期试验患者将获得与接受低剂量白消安的患者相似的结果。 接受中等剂量（清髓性）白消安，实现T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局。患者缺乏 匹配的同胞供体，确认具有适当的基因型，并且没有活动性感染， 招募时间超过4 1/2年。在2个基因型群组（IL 2 RG/JAK 3、RAG 1/RAG 2）中的每一个内，将32名患者与对照组（IL 2 RG/JAK 3、RAG 1/RAG 2）进行比较。 随机分配至30 mg*h/L与60 mg* h/L的白消安累积曲线下面积暴露组（32 每个队列的患者，总共64名患者）。IL 2 RG/JAK 3患者还将接受rATG和RAG 1/RAG 2患者 将接受rATG氟达拉滨和塞替派干细胞来源包括无关和单倍体相关 TCRαβ+/CD 19+耗尽且无HCT后GVHD预防的供体产品。主 终点是对破伤风的保护性抗体应答，破伤风是正常体液免疫功能的金标准， 儿童，HCT后2年。次要终点包括T细胞数量的重建、胸腺输出、细胞增殖和免疫应答。 型特异性嵌合体、3年时对活病毒疫苗的应答、生存率和HCT相关的发生率 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。核心问题是 混合/分裂嵌合体（供体来源的T细胞在B和髓系中具有混合嵌合体） 区室）将仍然与正常的免疫表型、功能、库和免疫应答相关。 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，抗体- 分泌细胞和校正HCT后B细胞受体库的预先存在的异常， 在所有的基因型队列中是明显的，并且在混合嵌合体环境中校正的程度和质量 会根据每种遗传异常的生物学特性而变化。我们假设，T细胞耗竭， 由于以下原因，在不存在预处理的情况下接受HCT的患者将在试验参与者中减少或缺席 与供体来源的HSC植入相关的胸腺输出的改善。我们假设T细胞 根据供体的不同，耐受性将通过不同的机制（中央缺失与外周调节）发生 型（单倍体相合与良好匹配的无关供体），但将在以下患者中成功诱导 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.