Targeted Therapies and Mechanisms of Resistance in Chronic Lymphocytic Leukemia

描述(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，目前在干细胞移植之外是无法治愈的。以氟达拉滨为基础的化学免疫疗法是年轻CLL患者的标准初始治疗，而对于老年人CLL的最佳初始治疗还不是很成熟。氟达拉滨与氯氨丁苯的III期试验表明，老年患者在无进展生存期(PFS)或总生存期(OS)方面没有年轻患者观察到的改善。Woyach博士和他的同事对一线癌症和白血病B组(CALGB)进行的回顾分析证实了这一点，他们发现对于老年患者，氟达拉滨没有改善PFS或OS，而不同年龄的患者在化疗中加入利妥昔单抗可以改善预后。最近的数据表明，在使用苯达莫司汀和利妥昔单抗进行初步治疗后，老年患者的疗效良好，然而，还需要更多的改进。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是一种参与B细胞发育和通过B细胞受体(BCR)传递信号的关键激酶。在I期和II期试验中，与他的药物相关的临床活动一直是非同寻常的，复发和难治性CLL患者22个月的PFS为76%，而以前未治疗的疾病患者的PFS为96%。这种药物的耐受性也很好，显著毒性的发生率很低，很少有患者因毒性而停止治疗。在这项申请中，沃亚奇博士提出了一项第三阶段临床试验，研究苯达莫司汀联合利妥昔单抗与伊布鲁替尼联合利妥昔单抗治疗65岁或以上未经治疗的慢性淋巴细胞性白血病患者的疗效。她还建议对已建立的和新的预后标记物进行相关分析，试图确定与该药物的反应和结果相关的生物标记物。最后，她提出了一系列实验室实验，其中包括对伊布鲁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：1)对65岁及以上未经治疗的慢性淋巴细胞性白血病患者进行一项多中心随机III期试验，以确定1)BTK抑制剂ibrutinib单独或联合应用利妥昔单抗是否能产生比苯达莫司汀加利妥昔单抗的标准疗法更好的无进展生存率(PFS)；2)这三种方案的总生存率(OS)和缓解率；3)进展时标准治疗与ibrutinib的交叉比率，以及交叉后的结果。具体目标2：在伊布鲁替尼试验中进行相关研究，以评估 基础和动态标记物用于确定1)基线细胞遗传学标记物、ZAP-70甲基化、IgVH突变状态或选定的DNA突变是否可以预测结果或反应时间；2)微小残留病的根除是否会影响以伊布鲁替尼为基础的治疗方案的PFS。具体目标3：通过以下方式评估CLL对ibrutinib的潜在耐药机制：1)使用CLL的TCL1小鼠模型产生ibrutinib耐药疾病；2)进行全面的基因组和基因以及miR表达分析，以确定潜在的耐药机制；以及3)使用从小鼠产生的数据对使用ibrutinib的复发患者进行有针对性的评估。预计这项试验将改变老年慢性淋巴细胞性白血病患者最初的症状，所提出的相关和实验室研究可能为进一步深入了解慢性淋巴细胞性白血病的生物学机制和确定伊布鲁替尼治疗的潜在靶点提供帮助。 抵抗力强的疾病。詹妮弗·沃亚克博士是俄亥俄州立大学(OSU)血液科的初级教员，于2012年6月完成了她的团契培训。在培训期间，她专注于CLL的临床和翻译研究，有10篇第一作者论文，其中3篇影响因子超过10。她致力于成为一名独立的内科科学家，虽然她作为实习生有过多次参与临床研究的机会，但她的教职生涯才刚刚开始，还在继续进行高强度的实验室科学培训。作为肿瘤学临床试验联盟(Alliance)白血病委员会的初级研究员，Woyach博士有机会主持CLL的第三阶段研究，该研究有她以前对一线CLL治疗的研究的一些基础，也与她的实验室工作很好地结合在一起，研究ibrutinib治疗后体内信号的变化以及BTK在CLL的开发和扩展中的作用。她在获奖期间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方面的课程。职业发展还将通过与她的导师每周举行一次会议、定期出席俄勒冈州州立大学的第一阶段/第二阶段会议以及出席和介绍国家会议来实现。她计划在她的导师伯德博士和约翰逊博士的实验室里进行更多的实验室培训，并与杜克大学的桑迪普·戴夫博士一起学习高通量基因组分析的技术。通过本申请中提出的受保护的研究时间和职业发展活动，沃亚赫博士将发展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.