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项改变游戏规则的第三阶段临床北美组间 (NAIG)慢性淋巴细胞白血病(CLL)治疗试验(E1912)，该试验测试了伊布鲁替尼的组合 利妥昔单抗(IR)与之前的金标准化疗免疫疗法(CIT)：氟达拉滨、环磷酰胺、 和利妥昔单抗(FCR)。这项试验表明，无进展生存期(PFS)和总生存期(OS)都是 IR的优势，随后成为FDA批准IR在进展性疾病中一线使用的驱动因素 此前未经治疗的慢性淋巴细胞性白血病于2020年春。虽然我们的工作显示了非CIT的明显临床优势 关于如何最好地应用这一进步，出现了一些新的问题。 以伊布鲁替尼为基础的一线治疗的反应的持久性是高度可变的，需要不确定的 治疗使患者面临慢性毒性和选择性压力的风险，可能会产生耐药性 克隆人。能够更准确地预测反应的持久性可以帮助识别更有可能的患者 接受伊布鲁替尼治疗的长期缓解者(限时治疗的候选对象)和更有可能缓解的患者 反应持续时间短，可能受益于与另类小说的强化联合治疗 探员们。我们希望开发一个独特的模型(S)，其中包含多种关键的预后因素，将具有 对预测患者对新的治疗组合的结果有很高的信心。 我们对接受E1912的IR臂治疗的患者进行了初步研究，发现IR臂上的患者子集有证据 新出现的突变和克隆结构中的变化预测复发。其确切的机制是 需要定义复发，因为我们预测这些患者将很难治疗，并可选择替代策略 需要的。我们发现IR疗法唯一能够重新激活之前耗尽的T细胞杀伤活性 针对白血病的CLL细胞。虽然我们有一些关于这一机制的信息(S)，但有很多 仍有待学习，以及实现T细胞功能最大恢复的确切时间或 健身。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者，免疫疗法本身就能够清除残留的CLL肿瘤 负担。我们假设，研究的结果将增加关于如何 为CLL患者选择最佳的非化疗方案以及治疗对免疫系统的影响。这些 目标将通过以下具体目标实现： 目的1：建立一个综合模型来预测接受新型药物治疗的慢性淋巴细胞白血病患者的临床结果。 目的2：确定伊布鲁替尼治疗慢性淋巴细胞性白血病的遗传学、表观遗传学和转录学改变。 目的3：了解伊布鲁替尼治疗对T细胞功能的影响，以指导临床应用 免疫疗法。