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（由申请人提供）：造血干细胞移植（HSCT）用作复发或难治性急性急性淋巴细胞性白血病（全部）的患者的主要打捞策略，为某些患者提供长期疾病控制。不幸的是，大多数患者失败和复发仍然是最常见的失败原因。此处提出的研究将利用从入学的儿童肿瘤学组ASCT0431的患者获得的标本。 ASCT0431是一项全国性的III期随机研究，比较了旨在控制移植物与宿主疾病（GVHD）的两种方案（标准与基于西洛木木的方案），并检验了以下假设：MTOR抑制剂Sirolimus将在最小残留疾病的某个点控制所有人，从而减少复发风险并提高生存率。 HSCT后复发的机制分为两个广泛的类别：1）抗白血病治疗无法控制疾病； 2）MRD逃脱同种异体免疫监视的能力（GVL效应）。我们假设Sirolimus将通过在HSCT后消除或抑制所有人的全部情况下，在HSCT之后，由于不成熟的免疫重建造成，所有人都可以改善所有人的结果，从而在不成熟的情况下不成熟，从而提供了足够的GVHD控制而无需降低GVL效应。以这种方式改善HSCT结果的一种方法将是移植和抗血症治疗的重大进步。这些重点和综合的生物学研究将评估Sirolimus抗白血病效应和GVL的相对重要性，直接在使用定义的HSCT疗法和GVHD预防的儿童中，并在其初始复发中获得了爆炸样品，并在关键的III期试验中可用。我们将完成两个具体的目标：1）评估西罗莫司对患者PBMC的影响以及所有爆炸。 2）评估基于西罗莫司的GVHD预防对GVL效应的影响。这项工作与该机构的使命直接相关，因为它试图改善移植结果，研究该药物在III期研究的背景下的作用机理，并提高所有复发患者的治愈率。摘要摘要。我们对最常见的儿童白血病有很好的治疗，称为所有。但是，如果疾病恢复（复发），大多数儿童将无法生存。这项研究将研究如何在骨髓移植中使用的新药（称为Sirolimus）如何有助于防止患者复发并研究细胞中如何采取行动来防止此问题。