Targeted Therapies and Mechanisms of Resistance in Chronic Lymphocytic Leukemia

描述（由申请人提供）：慢性淋巴细胞白血病（CLL）是成人白血病中最常见的形式，目前除干细胞移植外无法治愈。基于氟达拉滨的化学免疫治疗是年轻CLL患者的标准初始治疗，而老年CLL患者的最佳初始治疗尚不完善。氟达拉滨与苯丁酸氮芥的III期试验显示，老年患者的无进展生存期（PFS）或总生存期（OS）没有在年轻患者中观察到的改善。Woyach博士及其同事对一线癌症和白血病B组（CALGB）研究进行的一项回顾性分析证实了这一点，并发现对于老年患者，氟达拉滨与苯丁酸氮芥相比并不能改善PFS或OS，但在化疗中加入利妥昔单抗可以改善结局，与年龄无关。最近的数据表明，苯达莫司汀加利妥昔单抗初始治疗后，老年患者的结果良好，但需要更多的改善。 伊布替尼是布鲁顿酪氨酸激酶（BTK）的口服生物可利用抑制剂，BTK是参与B细胞发育和通过B细胞受体（BCR）进行信号传导的关键激酶。在I期和II期试验中，与他的药物相关的临床活性非常出色，复发性和难治性CLL患者的22个月PFS为76%，既往未治疗的患者为96%。这种药物也具有良好的耐受性，显著毒性的发生率低，并且非常罕见的患者因毒性而停止治疗。 在这项申请中，Woyach博士提出了一项III期临床试验，研究苯达莫司汀加利妥昔单抗与伊曲替尼加利妥昔单抗相比，以及单独使用伊曲替尼治疗65岁或65岁以上既往未经治疗的CLL患者。她还提出了建立和新的预后标志物的相关分析，试图确定与这种药物的反应和结果相关的生物标志物。最后，她提出了一系列实验室实验，其中包括对伊匹替尼耐药小鼠进行详细的基因组分析，以确定对这种药物的耐药机制。具体目标是：具体目标1：在65岁及以上未治疗的CLL患者中进行一项多中心随机III期试验，以确定1）与苯达莫司汀+利妥昔单抗的标准治疗相比，Btk抑制剂伊曲替尼单独或与利妥昔单抗联合治疗是否产生上级无进展生存期（PFS）; 2）这三种方案的总生存期（OS）和应答率; 3）进展时从标准治疗到伊鲁替尼的交叉率，以及交叉后的结果。具体目标2：在本项伊鲁替尼试验中进行相关研究，以评估 基线和动态标志物，以确定1）基线细胞遗传学标志物、Zap-70甲基化、IgVH突变状态或选择的DNA突变是否可预测结局或至缓解时间; 2）根除微小残留病是否影响基于伊匹替尼的治疗的PFS。具体目标3：通过1）使用CLL的TCL 1小鼠模型产生依鲁替尼耐药疾病; 2）进行全面的基因组和基因及miR表达分析，以确定潜在的耐药机制; 3）使用小鼠产生的数据对依鲁替尼治疗后复发的患者进行靶向评价，评价CLL对依鲁替尼的潜在耐药机制。 预计该试验将改变老年CLL患者的初始治疗，并且提出的相关和实验室研究可能会进一步深入了解CLL的生物学，并确定伊鲁替尼治疗的潜在靶点 抵抗疾病。 Jennifer Woyach博士是俄亥俄州州立大学（OSU）血液学系的初级教员，她于2012年6月完成了奖学金培训。在她的培训期间，她专注于CLL的临床和转化研究，并有10篇第一作者出版物，其中3篇影响因子超过10。她致力于成为一名独立的医生科学家，虽然她有很多机会参加临床研究作为实习生，她是在她的教师职业生涯的开始，并继续在实验室科学密集训练。作为肿瘤临床试验联盟（Alliance）白血病委员会的初级研究员，Woyach博士有机会主持一项CLL III期研究，该研究在她以前的一线CLL治疗研究中有一些基础，并且还与她的实验室工作很好地结合起来，研究了伊曲替尼治疗后体内信号传导的变化以及Btk在CLL发展和扩展中的作用。在此期间，她的职业发展计划包括临床试验设计和管理，分析技术和实验室科学的课程。职业发展也将通过每周与她的导师会议，定期出席第一/第二阶段会议在俄勒冈州立大学，并出席和在全国会议上发言。她计划在她的导师Byrd博士和约翰逊博士的实验室内进行额外的实验室培训，并在杜克大学与Sandeep Dave博士一起学习高通量基因组分析技术。通过本申请中提出的受保护的研究时间和职业发展活动，Woyach博士将培养过渡到独立教师角色所需的技能。

DESCRIPTION (provided by applicant): Chronic lymphocytic leukemia (CLL) is the most prevalent form of adult leukemia and is currently incurable outside of stem cell transplantation. Fludarabine-based chemoimmunotherapy is standard initial therapy for younger patients with CLL, while the optimal initial therapy for older adults with CLL is less well established. A phase III trial of fludarabine versus chlorambucil showed that older patients do not have the improvement in progression free survival (PFS) or overall survival (OS) that is observed in younger patients. This was confirmed by a retrospective analysis that Dr. Woyach and colleagues performed of front-line Cancer and Leukemia Group B (CALGB) studies and found that for older patients, fludarabine does not improve PFS or OS over chlorambucil, but that the addition of rituximab to chemotherapy improves outcomes regardless of age. Recent data suggests good outcomes for older patients after initial therapy with bendamustine plus rituximab, however, more improvements are needed. 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 phase I and II trials, the clinical activity associated with his agent has been extraordinary, with a 22 month PFS of 76% for patients with relapsed and refractory CLL, and 96% for patients with previously untreated disease. This agent has been well tolerated as well, with a low incidence of significant toxicity and very rare patients discontinuing therapy for toxicity. In this application, Dr. Woyach proposes a Phase III clinical trial investigating bendamustine plus rituximab versus ibrutinib plus rituximab, versus ibrutinib alone in patients age 65 or older with previously untreated CLL. She also proposes correlative analyses of established and novel prognostic markers in an attempt to identify biomarkers associated with response and outcomes with this agent. Finally, she proposes a series of laboratory experiments which involve a detailed genomic analysis of ibrutinib-resistant mice to determine mechanisms of resistance to this agent. The specific aims are: Specific Aim 1: To perform a multicenter randomized phase III trial in untreated patients with CLL age 65 and older to determine 1) Whether the Btk inhibitor ibrutinib alone or in combination with rituximab produces superior progression free survival (PFS) compared to standard therapy with bendamustine plus rituximab; 2) Overall survival (OS) and response rates with these three regimens; 3) Crossover rate from standard therapy to ibrutinib upon progression, and outcome after crossover. Specific Aim 2: To perform correlative studies in this ibrutinib trial to evaluate baseline and dynamic markers to determine 1) Whether baseline cytogenetic markers, Zap-70 methylation, IgVH mutational status, or select DNA mutations predict outcomes or time to response; 2) Whether eradication of minimal residual disease affects PFS with ibrutinib-based therapies. Specific Aim 3: To evaluate potential resistance mechanisms to ibrutinib in CLL by 1) Using the TCL1 mouse model of CLL to generate ibrutinib resistant disease; 2) Performing comprehensive genome and gene and miR expression analysis to determine potential resistance mechanisms; and 3) Using data generated from mice for targeted evaluation of patients who relapse after ibrutinib. It is expected that this trial will transform the initial thrapy of older patients with CLL, and that the correlative and laboratory studies proposed may offer further insight into the biology of CLL and identify potential targets for the therapy of ibrutinib resistant disease. Dr. Jennifer Woyach is a junior faculty member in the Division of Hematology at The Ohio State University (OSU) who completed her fellowship training in June 2012. During her training, she was focused on clinical and translational research in CLL, and has 10 first author publications, including 3 with an impact factor above 10. She is committed to becoming an independent physician scientist, and while she has had a number of opportunities to participate in clinical research as a trainee, she is at the beginning of her faculty career, and also continues to train intensely in laboratory science. As the Junior Investigator for the Leukemia Committee of the Alliance for Clinical Trials in Oncology (Alliance), Dr. Woyach has been given the opportunity to chair a Phase III study in CLL which has some foundations in her previous research into front-line CLL therapy, and also integrates nicely with her laboratory work studying in vivo signaling changes after ibrutinib therapy and the role of Btk in the development and expansion of CLL. Her career development plan during the duration of this award includes coursework in clinical trial design and management, analysis techniques, and laboratory science. Career development will also occur through weekly meetings with her mentors, regular attendance at phase I/II meetings at OSU, and attendance and presentations at national meetings. She plans to pursue additional laboratory training within the laboratory of her mentors Drs. Byrd and Johnson, as well as learning techniques of high-throughput genomic analysis with Dr. Sandeep Dave at Duke University. Through the protected research time and career development activities proposed in this application, Dr. Woyach will develop the skills necessary to transition to an independent faculty role.