Predicting Clinical Outcome After Traditional and Ibrutinib-based Therapy In Chronic Lymphocytic Leukemia

 描述(申请人提供)：虽然基于氟达拉滨的化学免疫疗法(CIT)可以诱导深度缓解和长期无进展的生存，但它不是治愈的，会导致深刻的T细胞消融，并促进耐药克隆的选择。生物学研究表明，B细胞受体介导的信号转导是CLL B细胞的关键生存途径，该途径的抑制剂，如Bruton‘s酪氨酸激酶抑制剂Ibrutinib，已显示出强大的单药活性。我们正在通过北美集团进行一项关键的3期试验，以比较基于伊布鲁替尼的治疗(非CIT)和基于氟达拉滨的CIT。在本申请中，我们利用该临床试验的平台来执行关键 评估癌症生物标记物和临床结果之间关系的研究。这些科学研究旨在：i)确定CIT和非CIT治疗中MRD评估的效用和最佳时机；ii)评估CIT和非CIT治疗患者中驱动因素突变和克隆进化的影响及其与治疗耐药性的关系；iii)比较氟达拉滨和伊布鲁替尼治疗对免疫功能的影响。这些研究旨在评估以伊布鲁替尼为基础的治疗可能不同于以氟达拉滨为基础的治疗的重要方式。我们假设，虽然MRD评估仍将是基于伊布鲁替尼的治疗的无进展和总存活率的有用替代指标，但用于对MRD进行分类的时间和阈值将不同于传统的CIT。我们还假设，在基于伊布鲁替尼的非CIT方法中，导致治疗耐药性的获得性克隆异质性和亚克隆扩展将以较低的频率发展。然而，我们也预计靶向BTK基因或BTK下游的其他基因的突变将发生在一些患者中，并与对伊布鲁替尼的耐药性有关。最后，我们预计基于伊布鲁替尼的治疗不仅比基于氟达拉滨的治疗对T细胞免疫的毒性更小，而且实际上可能会增强免疫功能。我们将通过以下具体目标使用参与E1912试验的患者的研究样本来评估这些假设：具体目标1：确定MRD是否可以用作基于伊布鲁替尼的治疗后临床结果的替代标记，并确定最佳评估时机和阈值。具体目标2：评估体细胞遗传异常对CIT和非CIT反应的影响。具体目标3：确定CIT和非CIT后的免疫功能，并评估其与临床结局的关系。

 DESCRIPTION (provided by applicant): While fludarabine-based chemoimmunotherapy (CIT) induces deep remissions and long progression free survival, it is not curative, causes profound T-cell ablation, and promotes selection of drug resistant clones. Biologic studies have demonstrated that signaling mediated by the B-cell receptor is a critical survival pathway in CLL B-cells and inhibitors of this pathway, such as the Bruton's Tyrosine Kinase inhibitor Ibrutinib, have shown robust single agent activity. We are conducting a pivotal phase 3 trial through the North American Intergroup to compare Ibrutinib-based therapy (non-CIT) to fludarabine-based CIT. In the present application we leverage the platform of this clinical trial to perform critical studies evaluating the relationship between cancer biomarkers and clinical outcomes. These scientific studies are designed to: i) define the utility and optimal timing of MRD assessment for both CIT and non-CIT based treatment ii) evaluate the impact of driver mutations and clonal evolution and their relationship to treatment resistance in CIT and non-CIT treated patients and iii) compare the effect of fludarabine and Ibrutinib-based therapy on immune function. These studies are designed to evaluate important ways in which Ibrutinib-based therapy may differ from fludarabine-based treatment. We hypothesize that, while MRD assessment will remain a useful surrogate for progression-free and overall survival for Ibrutinib-based therapy, the timing and thresholds used to classify MRD will differ from conventional CIT. We also hypothesize that acquired clonal heterogeneity and sub-clone expansion that contribute to treatment resistance will develop at lower frequency with an Ibrutinib-based non-CIT approach. However, we also anticipate that mutations in the target BTK gene or other genes downstream of BTK will occur in some patients and be associated with resistance to Ibrutinib. Finally, we expect that Ibrutinib-based therapy will not only be less toxic to T-cell immunity than fludarabine-based treatment but may actually enhance immune function. We will evaluate these hypotheses using research samples from patients participating in the E1912 trial through the following specific aims: Specific Aim 1: Determine if MRD can be used as a surrogate marker of clinical outcome after ibrutinib-based therapy and define the optimal timing and thresholds of assessment. Specific Aim 2: Assess the impact of somatic genetic abnormalities on response to CIT and non-CIT. Specific Aim 3: Characterize immune function after CIT and non-CIT and assess its relationship to clinical outcome.