Molecular Evaluation of Targeted Therapies in Lymphoid Malignancies

项目摘要/摘要 慢性淋巴细胞白血病(CLL)是成人白血病中最常见的一种，目前是无法治愈的。 三分之二被诊断为CLL的患者年龄在65岁或以上，而基于氟达拉滨的 化学免疫疗法是年轻患者的标准初始治疗，而老年患者的最佳治疗方案是 不太清楚。癌症和B组白血病的三期随机研究和回顾性分析 试验表明，在老年人群中，氟达拉滨与氯氨丁苯相比没有好处，而利妥昔单抗则有好处。 不分年龄。虽然最近的数据表明，烷化剂氯丁丁苯或 苯那莫司汀联合利妥昔单抗在这个人群中是可行的，结果仍然不是最理想的 代表了CLL患者中最大的群体。此外，新生物学的相关性和影响 标志物和最小残留疾病状态预测年轻患者的反应持续时间和生存期 在老年人中一直没有探索过。在年轻患者中发现的生物标记物的新疗法和验证 因此，在这一人群中进行研究是一个高度优先的问题。 伊布鲁替尼是一种口服生物可用的Bruton酪氨酸激酶(BTK)抑制剂，BTK是B细胞中的一种关键激酶。 通过B细胞受体(BCR)进行细胞发育和信号传递。在我们团队共同领导的Ib/II期试验中， 与这种药物相关的临床活动一直是非同寻常的，26个月的PFS为76%，对于患有 复发和难治性慢性淋巴细胞白血病，96%的老年患者以前没有治疗过的疾病。这位代理有 长期连续给药耐受性也很好。 在我们先前工作的基础上，在本申请中，我们建议进行一项研究伊布鲁替尼的第三阶段临床试验 单用或伊布鲁替尼加利妥昔单抗与标准治疗苯达莫司汀加利妥昔单抗(BR)治疗老年人的比较 未经治疗的慢性淋巴细胞性白血病患者。已建立的和新的预后标记物的相关性分析 提出的目的是试图确定与反应和结果相关的生物标志物。的具体目标 这一建议是：1：进行III期临床试验，比较a)ibrutinib，b)ibrutinib加利妥昔单抗和c) Br在有症状的CLL患者中&>65岁，以确定疗效最高的治疗方案、PFS和OS。2： 在这项第三阶段研究中进行药效学(PD)研究，以确定传统基因组 特征，选择基线BCR激活标志物，以及miR标志物在1个月内的表达变化为 预测最佳反应、临床反应时间、PFS和OS。3：评估纵向样本后 伊布鲁替尼治疗评估持续性淋巴细胞的特征，并确定 编码或非编码RNA，获取BTK或PLC的突变？2，或存在最小残差 9个月或24个月的疾病预示着伊布鲁替尼治疗后的晚期复发和PFS。它是 预计从这项试验中得出的临床和实验室结果将在多大程度上改变老年人 慢性淋巴细胞性白血病得到治疗，并对这些患者未来的临床试验设计做出了重大贡献。

Project Summary/Abstract Chronic lymphocytic leukemia (CLL) is the most prevalent form of adult leukemia and is currently incurable. Two thirds of patients diagnosed with CLL are age 65 or older, and while fludarabine-based chemoimmunotherapy is standard initial therapy for younger patients, the optimal therapy for older patients is less clear. Both a randomized phase III study and a retrospective analysis of Cancer and Leukemia Group B trials showed no benefit to fludarabine over chlorambucil in the elderly population, while rituximab offers benefit irrespective of age. While recent data suggest that administration of the alkylator agent chloramubucil or benadmustine together with rituximab is feasible in this population, outcome is still suboptimal for what represents the largest population of CLL patients. Additionally, the relevance and impact of new biologic markers and minimal residual disease status predictive of response duration and survival in younger patients has not explored in the elderly. New therapies and validation of biomarkers identified in younger patients is therefore a high priority for research in this population. Ibrutinib is an orally bioavailable inhibitor of Bruton's Tyrosine Kinase (BTK), a critical kinase involved in B cell development and signaling through the B cell receptor (BCR). In a Phase Ib/II trial co-led by our group, the clinical activity associated with this agent has been extraordinary, with a 26 month PFS of 76% for patients with relapsed and refractory CLL, and 96% for elderly patients with previously untreated disease. This agent has been well tolerated as well with extended continuous dosing. Building upon our previous work, in this application we propose a Phase III clinical trial investigating ibrutinib alone or ibrutinib plus rituximab compared with standard therapy of bendamustine plus rituximab (BR) in older patients with previously untreated CLL. Correlative analyses of established and novel prognostic markers are proposed in an attempt to identify biomarkers associated with response and outcomes. The specific aims of this proposal are: 1: To perform a phase III clinical trial comparing a) ibrutinib, b) ibrutinib plus rituximab and c) BR in symptomatic CLL patients > 65 years to determine the therapy with highest response, PFS and OS. 2: To perform pharmacodynamic (PD) studies in this phase III study to determine whether traditional genomic features, select baseline BCR activation markers, and changes in miR marker expression over 1 month are predictive for best response, time to clinical response, PFS, and OS. 3: To evaluate longitudinal samples after ibrutinib therapy to evaluate the characteristics of persistent lymphocytes and determine whether changes in coding or non-coding RNAs, acquisition of mutations in BTK or PLC¿2, or presence of minimal residual disease at 9 or 24 months will be predictive of late relapse and PFS after ibrutinib-based therapies. It is anticipated that the clinical and laboratory findings derived from this trial will be transformative in how elderly CLL are treated and contribute significantly to the design of future clinical trials for these patients.