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

项目概要 严重联合免疫缺陷 (SCID) 是一组消除 T 细胞的遗传性疾病 发育和功能。同种异体造血细胞移植（HCT）是标准治疗方法， 如果不及时治疗，这种疾病通常会在 2 岁时致命。 SCID可成功进行HCT 由于缺乏功能性 T，未进行 HCT 前通常使用的高剂量白消安调理的患者 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。这个 该项目旨在测试低剂量个体化靶向白消安治疗方案的有效性和安全性 与中等剂量的 SCID 患者相比，有体液结果不良风险的非相配兄弟姐妹患者 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 美国普遍新生儿筛查。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果。缺乏的患者 匹配的兄弟姐妹捐赠者，确认具有适当的基因型，并且没有活动性感染将 被招募超过 4 1/2 年。在 2 个基因型队列（IL2RG/JAK3、RAG1/RAG2）的每一个中，有 32 名患者将 被随机分配到白消安的累积曲线下面积暴露量为 30 mg*h/L 与 60 mg*h/L (32 每组患者，总共 64 名患者）。 IL2RG/JAK3患者还将接受rATG和RAG1/RAG2患者 将接受 rATG、氟达拉滨和塞替派。干细胞来源包括不相关的和单倍体相关的 将 TCRαβ /CD19 耗尽且不进行 HCT 后 GVHD 预防的供体产品。初级 终点是对破伤风的保护性抗体反应，这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、胸腺输出、细胞的重建 类型特异性嵌合、3 年活病毒疫苗反应、存活率和 HCT 相关发生率 并发症。 在目标 2 中，我们将深入研究 T 细胞和 B 细胞异常的纠正。中心问题是 是否混合/分裂嵌合（供体来源的 T 细胞在 B 和骨髓细胞中具有混合嵌合） 尽管如此，仍将与正常的免疫表型、功能、库和 一个或多个基因型群体的耐受性。我们假设记忆 B 细胞的产生、抗体 HCT 后，分泌细胞和纠正 B 细胞受体库中先前存在的异常将是 在所有基因型队列中都很明显，并且混合嵌合状态下的校正程度和质量 会根据每种遗传异常的生物学特性而有所不同。我们假设 T 细胞耗竭见于 由于以下原因，在没有条件调节的情况下接受 HCT 的患者在试验参与者中的数量将减少或缺席： 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 根据供者的不同，耐受性将通过不同的机制（中央删除与外周调节）发生 类型（半相合与匹配良好的无关供体）但将在患有以下疾病的患者中成功诱导 混合嵌合现象。

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.