Outcomes for CLL patients treated with novel therapy

采用新疗法治疗 CLL 患者的结果

• 批准号: 10208516
• 负责人: Neil E Kay
• 金额: $ 70.55万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10208516
• 关键词: ATAC-seq; Agammaglobulinaemia tyrosine kinase; American; Architecture; Archives; Automobile Driving; Biological Assay; Blood; Blood specimen; CAR T cell therapy; Cell Compartmentation; Cell Therapy; Cell physiology; Cells; Chromatin; Chronic; Chronic Lymphocytic Leukemia; Clinical; Clinical Data; Combined Modality Therapy; Cyclophosphamide; Data; Decision Aid; Decision Making; Disease; Disease Progression; Disease remission; Drug resistance; Early treatment; Epigenetic Process; Fostering; Future; Gene Activation; Gene Expression; Generations; Genetic; Goals; Gold; Health; Immune; Immune system; Immuno-Chemotherapy; Immunotherapeutic agent; Immunotherapy; Individual; International Prognostic Index; Knowledge; Leukemic Cell; Longitudinal Studies; Medical Genetics; Methylation; Modeling; Modernization; Molecular; Mutation; Outcome; Outcome Study; PLCG2 gene; Pathway interactions; Patient-Focused Outcomes; Patients; Phase III Clinical Trials; Phenotype; Prognostic Factor; Progression-Free Survivals; Progressive Disease; Publishing; Recurrent disease; Refractory; Regulatory Pathway; Relapse; Residual Neoplasm; Residual Tumors; Residual state; Resistance; Risk; Sampling; Somatic Mutation; T-Lymphocyte; Techniques; Testing; Therapeutic; Time; Toxic effect; Tumor Burden; Tyrosine Kinase Inhibitor; Validation; Work; arm; base; cell killing; chimeric antigen receptor T cells; chronic T-cell leukemia; chronic lymphocytic leukemia cell; cohort; comparative; design; epigenomics; exhaust; fitness; fludarabine; follow-up; high dimensionality; improved; innovation; insight; molecular marker; multiple omics; novel; novel therapeutics; patient population; patient subsets; phase III trial; phase change; predict clinical outcome; pressure; prognostic model; prognostic tool; relapse patients; relapse prediction; response; restoration; risk prediction; rituximab; statistical and machine learning; targeted sequencing; targeted treatment; tool; transcriptome sequencing; transcriptomics

PROJECT SUMMARY/ABSTRACT We have recently conducted and published a game changing phase 3 clinical North American Intergroup (NAIG) trial (E1912) for chronic lymphocytic leukemia (CLL) therapy which tested a combination of Ibrutinib and Rituximab (IR) vs. the prior gold standard chemoimmunotherapy (CIT): fludarabine, cyclophosphamide, and rituximab (FCR). This trial showed that both progression free survival (PFS) and overall survival (OS) are superior with IR and subsequently was the driving factor in FDA approval for frontline use of IR in progressive previously untreated CLL in the spring of 2020. While our work revealed distinct clinical advantages to non-CIT approaches, a number of new questions have emerged with respect to how best apply this advance. The durability of the response to first-line ibrutinib-based therapy is highly variable and requires indefinite treatment exposing patients to the risk of chronic toxicity and selective pressure that may foster resistant clones. The ability to more accurately predict the durability of response could help identify patients more likely to have long term remission with ibrutinib therapy (candidates for time limited therapy) and those more likely to have a short duration of response whom may benefit from intensive combination therapy with alternative novel agents. We wish to develop a unique model(s) incorporating multiple key prognostic factors that will have a high level of confidence in predicting patient outcomes to novel therapy combination. Our initial study on patients treated on IR arm of E1912 found a subset of patients on the IR arm with evidence for emerging mutations and changes in their clonal architecture predicting relapse. The exact mechanisms for relapse need to be defined as we predict that these patients will be difficult to treat and alternative strategies needed. We found that IR therapy was uniquely able to reactivate the previously exhausted T cell killing activity directed against the leukemic CLL cells. While we have some information on the mechanism(s) for this, much remains to be learned and also the exact timing for achieving the maximal restoration of T cell function or fitness. This beneficial impact on T cell function will also be studied as it relates to generation of CAR T cells as these cells are powerful inducers of immunotherapy which is itself capable of removing residual CLL tumor burden. We hypothesize that the outcome of the studies will add significant and important information on how to best select non-chemotherapy for CLL patients and also the treatment impact on the immune system. These goals will be accomplished through the following specific aims: Aim 1: Develop an Integrated Model to Predict Clinical Outcomes for CLL Patients Treated with Novel Agents. Aim 2: Determine the Genetic, Epigenetic and Transcriptomic Changes in Ibrutinib Treated CLL. Aim 3: Characterize the Impact of Ibrutinib Treatment on T-cell Fitness to Guide Application of Immunotherapy.

项目摘要/摘要 我们最近进行并发表了一场更改游戏的3阶段临床北美组Intergroup （NAIG）试验（E1912）用于慢性淋巴细胞性白血病（CLL）疗法，该治疗测试了依鲁替尼的组合 利妥昔单抗（IR）与先前的金标准化学免疫疗法（CIT）：氟达拉滨，环磷酰胺， 和利妥昔单抗（FCR）。该试验表明，无进展生存率（PFS）和总生存期（OS）均为 IR和随后的上级是FDA批准的驱动因素，用于渐进式IR 以前在2020年春季未经处理的CLL。尽管我们的工作揭示了非CIT的明显临床优势 方法是，关于如何最好地应用此进步，已经出现了许多新问题。 对基于ibrutinib的一线治疗的反应的耐用性高度可变，需要无限期 治疗暴露于患者的慢性毒性和选择性压力的风险，可能会促进抗性 克隆。更准确地预测响应耐用性的能力可以帮助识别患者的可能性更大 通过ibrutinib疗法（用于限制时间治疗的候选者），可以长期缓解，而这些可能更有可能 响应时间较短 代理商。我们希望开发一个独特的模型，结合了多个关键预后因素 高度信心预测新型治疗组合的患者结局。 我们对在E1912 IR部门接受治疗的患者的最初研究发现了IR臂上的一部分患者，有证据 用于新兴突变及其克隆体系结构的变化，可预测复发。确切的机制 需要定义复发，因为我们预测这些患者将难以治疗和替代策略 需要。我们发现红外疗法具有独特的能力，能够重新激活先前耗尽的T细胞杀伤活性 针对白血病细胞。虽然我们有一些有关此机制的信息，但 还有待学习的尚待学习，也是实现T细胞功能最大恢复或 健康。这种对T细胞功能的有益影响也将被研究，因为它与CAR T细胞的产生有关 这些细胞是免疫疗法的强大诱导剂，它本身能够去除残留的CLL肿瘤 负担。我们假设研究的结果将为如何添加有关如何 为了最好地为CLL患者选择非化学疗法，还可以对免疫系统的治疗产生影响。这些 目标将通过以下特定目标实现： AIM 1：开发一个综合模型，以预测用新型药物治疗的CLL患者的临床结果。 AIM 2：确定依鲁替尼处理过的CLL的遗传，表观遗传和转录组变化。 AIM 3：表征Ibrutinib治疗对T细胞健身的影响以指导应用 免疫疗法。