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

低剂量与中剂量白消安治疗严重联合免疫缺陷移植的随机研究

• 批准号: 10474806
• 负责人: Leslie S Kean
• 金额: $ 1.85万
• 依托单位: CHILDREN'S HOSPITAL OF LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-24 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10474806
• 关键词: 2 year old; Abnormal Cell; Acute; Adoptive Transfer; Affect; Age; Allogenic; American; Antibody Formation; Antibody Response; Antithymoglobulin; Area Under Curve; B cell reconstitution; B-Cell Antigen Receptor; B-Cell Development; B-Lymphocytes; Biological Markers; Biology; Birth; Blood; Bone Marrow Transplantation; Busulfan; CD19 gene; Cell Compartmentation; Cell Count; Cell physiology; Cells; Cellular Immunity; Chemotherapy-Oncologic Procedure; Child; Childhood; Chimerism; Data; Disease; Dose; Drug Kinetics; Engraftment; Enrollment; Funding; Future; Generations; Genetic; Genetic Diseases; Genotype; Goals; Gold; Graft Rejection; Growth; Hematopoietic stem cells; Hepatotoxicity; Host vs Graft Reaction; Hour; Humoral Immunities; IL2RG gene; Immune; Immune Tolerance; Immune system; Immunity; Immunoglobulin-Secreting Cells; Immunoglobulins; Immunologics; Immunosuppression; Incidence; Infant; Infection; Infertility; JAK3 gene; Kinetics; Life; Long-Term Effects; Lung; Mature T-Lymphocyte; Measures; Memory B-Lymphocyte; Molecular Abnormality; Monitor; Myelogenous; Myeloid Cells; National Institute of Allergy and Infectious Disease; Nature; Neonatal Screening; Non-Malignant; Opportunistic Infections; Oryctolagus cuniculus; Outcome; Output; Participant; Patients; Peripheral; Phase; Phenotype; Progenitor Cell Engraftment; Prophylactic treatment; Prospective Studies; Randomized; Recovery; Regimen; Regulation; Replacement Therapy; Retrospective Studies; Risk; Role; Safety; Second Primary Cancers; Severe Combined Immunodeficiency; Siblings; Source; Specialist; Subgroup; T cell reconstitution; T-Cell Development; T-Lymphocyte; Testing; Tetanus; Tetanus Vaccine; Thiotepa; Thymus Gland; Toxic effect; Transplantation; Transplantation Conditioning; United States; Vaccination; Viral Vaccines; base; cell type; cohort; conditioning; congenital immunodeficiency; cost; dose individualization; efficacy testing; exhaustion; fludarabine; hematopoietic cell transplantation; high risk; immune function; immune reconstitution; improved; insight; patient tolerability; phase II trial; primary endpoint; prospective; recruit; response; restoration; safety outcomes; secondary endpoint; standard care; stem cell engraftment; stem cells; virtual

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.

项目摘要 严重的联合免疫缺陷（SCID）是一组消除T细胞的遗传疾病 发展和功能。同种异体造血细胞移植（HCT）是标准治疗方法，用于 该疾病通常是在2岁时到2岁时致命的。 HCT可以在SCID中成功执行 由于缺乏功能性t 细胞。尽管恢复了T细胞功能，但HCT后许多患者的体液免疫力仍然很差。这 项目旨在测试低剂量，个性化的靶向布尔芬的效率和安全性 与中等剂量的SCID患者中等剂量相比，患有不匹配的兄弟姐妹的体液效果不佳的风险 捐助者HCT。我们将针对没有主动感染的患者，利用 美国的普遍新生儿筛查。我们假设在我们拟议的多机构中 与那些相比 接受适度的剂量（骨髓）布鲁芬，可以达到T和B细胞免疫重建。 在AIM 1中，我们将检查试验参与者中的免疫学和安全结果。缺乏的患者 匹配的兄弟姐妹捐助者，确认具有适当的基因型，并且没有主动感染的人会 被招募超过4 1/2年。在2种基因型队列中的每一个（IL2RG/JAK3，RAG1/RAG2）中，将有32名患者 被随机分配到弯曲面积不足的列出面积为30 mg*h/l对60 mg*h/l（32） 每个队列患者，总共64名患者）。 IL2RG/JAK3患者还将接受RAG1/RAG2患者 将获得Ratg，Fludarabine和Thiotepa。干细胞来源包括无关和单倍型相关的 TCRαβ+/CD19+的供体产品耗尽，没有HCT GVHD预防。主要 端点是对破伤风的保护抗体反应，破伤风是正常体液免疫功能的金标准 儿童，在HCT后2年。次要终点包括T细胞数，胸腺输出，细胞的重构 键入特定的嵌合主义，对3年时对活病毒疫苗的反应，生存和与HCT相关的事件 并发症。 在AIM 2中，我们将检查T和B细胞异常的校正深度。中心问题是 混合/分裂的嵌合（供体衍生的T细胞在B和髓样中具有混合嵌合体的T细胞 但是，隔室将与正常的免疫表型，功能，曲目和 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 - 分泌细胞和校正B细胞受体库后HCT的预先存在的异常 在所有基因型队列中的证据以及混合嵌合式的校正程度和质量 会根据每个遗传异常的生物学有所不同。我们假设在 在没有调理的情况下接受HCT的患者将在试验参与者中会减少或没有 与供体衍生的HSC植入有关的胸腺输出的改善。我们假设T细胞 供体的说法将通过不同的机制（中央删除与外围调节）进行公差 类型（单倍型与匹配良好的无关供体），但将成功诱导 混合嵌合。