Determinants of Relapse Risk After BMT for ALL

ALL BMT 后复发风险的决定因素

• 批准号: 7260150
• 负责人: STEPHAN A. GRUPP
• 金额: $ 30.42万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7260150
• 关键词: Acute; Acute Lymphocytic Leukemia; Allogenic; Animal Model; Antineoplastic Agents; Appendix; Area; Back; Biological; Biology; Blast Cell; Blood; Bone Marrow Transplantation; Cancer Therapy Evaluation Program; Categories; Cells; Child; Childhood; Childhood Leukemia; Children' s Oncology Group; Chimerism; Clinical Trials; Contracts; Correlative Study; Data; Detection; Detection of Minimal Residual Disease; Development; Discipline; Disease; Drug usage; Enrollment; Exposure to; Failure; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Human; Immune; Immunologic Monitoring; Immunosuppressive Agents; In Vitro; Left; Letters; Leukemic Cell; Lymphoblastic Leukemia; Malignant Neoplasms; Mediating; Methods; Mission; Modeling; Mono-S; Organ Transplantation; Outcome; Outcome Study; Paper; Patients; Peripheral Blood Mononuclear Cell; Personal Satisfaction; Pharmaceutical Preparations; Phase; Phase III Clinical Trials; Prevention; Prophylactic treatment; Protocols documentation; Publishing; Randomized; Rate; Recurrent disease; Refractory; Relapse; Relative (related person); Research; Research Ethics Committees; Research Infrastructure; Research Personnel; Residual Neoplasm; Residual Tumors; Residual state; Resistance; Risk; Sampling; Schedule; Siblings; Signal Transduction Inhibitor; Sirolimus; Solid; Specimen; Standards of Weights and Measures; T-Lymphocyte; Testing; Time; Transplantation; Treatment Protocols; Upper arm; Vertebral column; Work; Xenograft Model; base; data management; design; disorder control; falls; graft failure; graft vs host disease; immunogenicity; immunoprophylaxis; improved; leukemia; lymphoblast; mTOR Inhibitor; outcome forecast; pre-clinical; prevent; programs; reconstitution; response; treatment trial

DESCRIPTION (provided by applicant): Hematopoietic stem cell transplantation (HSCT) is used as the major salvage strategy for patients with relapsed or refractory acute lymphoblastic leukemia (ALL), providing long-term disease control for some patients. Unfortunately, the majority of patients fail and relapse remains the most frequent cause of failure. The studies proposed here will utilize specimens obtained from patients enrolled on Children's Oncology Group ASCT0431. ASCT0431 is a nationwide randomized phase III study comparing two regimens (standard vs. sirolimus-based) designed to control graft vs. host disease (GVHD), and testing the hypothesis that the mTOR inhibitor sirolimus will control ALL at a point of minimal residual disease and thus decrease relapse risk and improve survival. Mechanisms of post-HSCT relapse fall into two broad categories: 1) the failure of anti-leukemic therapy to control disease; and 2) the ability of MRD to escape allogeneic immunosurveillance (the GVL effect). We hypothesize that sirolimus will improve the outcome of allogeneic HSCT for ALL by eliminating or suppressing residual ALL during the period post-HSCT when GVL may be absent due to immature immune reconstitution, thus providing adequate GVHD control without decreasing the GVL effect. A method to improve HSCT outcome in this fashion would be a major advance in transplantation and antileukemia therapy. These focused and integrated biological studies will assess the relative importance of sirolimus antileukemic effect and GVL directly in children treated for relapsed ALL with defined HSCT therapies and GVHD prophylaxis, and for whom blast samples from the initial relapse are available, in the critical setting of a Phase III trial. We will accomplish two Specific Aims: 1) Assess the impact of sirolimus on patient PBMC and on the ALL blasts. 2) Assess the impact of sirolimus-based GVHD prophylaxis on the GVL effect. The work is directly relevant to the mission of the agency because it seeks to improve transplant outcome, study the mechanisms of action of this agent in the context of a phase III study, and improve cure rates for patients with relapsed ALL. Lay Summary. We have very good treatments for the most common childhood leukemia, called ALL. However, if the disease comes back (relapse), most of the children will not survive. This research will look how a new drug used in bone marrow transplant, called sirolimus, may help prevent relapse in patients and study in the cells how it may act to prevent this problem.

描述（申请人提供）：造血干细胞移植（HSCT）是复发或难治性急性淋巴细胞白血病（ALL）患者的主要挽救策略，为部分患者提供长期的疾病控制。不幸的是，大多数患者都失败了，而复发仍然是失败的最常见原因。这里提出的研究将利用从儿童肿瘤学组 ASCT0431 登记的患者获得的标本。 ASCT0431 是一项全国性随机 III 期研究，比较了两种旨在控制移植物抗宿主病 (GVHD) 的方案（标准方案与基于西罗莫司的方案），并检验了 mTOR 抑制剂西罗莫司将在微小残留病点控制 ALL 的假设从而降低复发风险并提高生存率。 HSCT后复发的机制分为两大类：1）抗白血病治疗未能控制疾病； 2) MRD 逃避同种异体免疫监视的能力（GVL 效应）。我们假设，西罗莫司将通过消除或抑制 HSCT 后由于免疫重建不成熟而导致 GVL 缺失的残留 ALL，从而改善 ALL 的同种异体 HSCT 的结果，从而在不降低 GVL 效应的情况下提供足够的 GVHD 控制。以这种方式改善 HSCT 结果的方法将是移植和抗白血病治疗的重大进步。这些重点和综合的生物学研究将评估西罗莫司抗白血病作用和 GVL 直接对接受明确的 HSCT 疗法和 GVHD 预防治疗复发 ALL 的儿童的相对重要性，并且对于这些儿童来说，在关键环境下可以获得初始复发的原始样本。 III 期试验。我们将实现两个具体目标：1) 评估西罗莫司对患者 PBMC 和 ALL 原始细胞的影响。 2) 评估基于西罗莫司的 GVHD 预防对 GVL 效果的影响。这项工作与该机构的使命直接相关，因为它旨在改善移植结果，在 III 期研究的背景下研究该药物的作用机制，并提高复发性 ALL 患者的治愈率。平铺总结。对于最常见的儿童白血病（ALL），我们有非常好的治疗方法。然而，如果疾病复发（复发），大多数儿童将无法生存。这项研究将着眼于骨髓移植中使用的一种名为西罗莫司的新药如何帮助预防患者复发，并在细胞中研究它如何发挥作用来预防这一问题。