Outcomes for CLL patients treated with novel therapy

项目总结/摘要 我们最近进行并发表了一项改变游戏规则的3期临床北美国际小组 （NAIG）试验（E1912），用于慢性淋巴细胞白血病（CLL）治疗，该试验测试了伊鲁替尼与 和利妥昔单抗（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）。该试验显示，无进展生存期（PFS）和总生存期（OS）均 与IR相比具有上级疗效，随后是FDA批准IR用于进行性 在2020年春季之前未经治疗的CLL。虽然我们的工作揭示了非CIT的明显临床优势， 在采用新方法的过程中，出现了一些关于如何最好地应用这一进展的新问题。 对基于伊替尼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， 克隆更准确地预测反应持续时间的能力可以帮助识别更有可能 使用伊曲替尼治疗后长期缓解（时间限制治疗的候选者）和更有可能 缓解持续时间短，可能受益于与替代性新药物的强化联合治疗 剂.我们希望开发一个独特的模型，该模型包含多个关键的预后因素， 在预测新型治疗组合的患者结局方面具有较高的置信度。 我们对接受E1912 IR组治疗的患者进行的初步研究发现，IR组的一部分患者存在证据表明， 新出现的突变和克隆结构的变化预测复发。确切的机制， 复发需要定义为我们预测这些患者将难以治疗和替代策略 needed.我们发现，IR疗法是唯一能够重新激活先前耗尽的T细胞杀伤活性 针对白血病CLL细胞。虽然我们有一些关于这一机制的信息， 以及实现T细胞功能最大恢复的确切时间， 健身还将研究这种对T细胞功能的有益影响，因为它涉及CAR T细胞的产生， 这些细胞是免疫治疗的强有力诱导剂，其本身能够去除残留的CLL肿瘤 负担我们假设，研究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 将通过以下具体目标实现这些目标： 目的1：开发一种综合模型来预测用新型药物治疗的CLL患者的临床结局。 目的2：确定伊布替尼治疗的CLL中的遗传、表观遗传和转录组学变化。 目的3：表征伊鲁替尼治疗对T细胞适应性的影响，以指导伊鲁替尼治疗的应用。 免疫疗法

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.