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）是最常见的成人白血病，目前除干细胞移植外无法治愈。以氟达拉滨为基础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确定。一项氟达拉滨与氯苯bucil的III期试验显示，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博士及其同事进行的一线癌症和白血病B组（CALGB）研究的回顾性分析证实了这一点，并发现对于老年患者，氟达拉滨并没有比氯霉素改善PFS或OS，但在化疗中加入利妥昔单抗可以改善预后，而与年龄无关。最近的数据表明，在苯达莫司汀加利妥昔单抗的初始治疗后，老年患者的预后良好，然而，还需要更多的改善。Ibrutinib是一种口服的布鲁顿酪氨酸激酶（BTK）抑制剂，布鲁顿酪氨酸激酶是通过B细胞受体（BCR）参与B细胞发育和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，复发和难治性CLL患者的22个月PFS为76%，以前未治疗的疾病患者的PFS为96%。该药的耐受性也很好，显著毒性的发生率很低，很少有患者因毒性而停止治疗。在该申请中，Woyach博士提出了一项III期临床试验，研究苯达莫司汀+利妥昔单抗与伊鲁替尼+利妥昔单抗相比，在65岁或以上未经治疗的CLL患者中单独使用伊鲁替尼。她还建议对已建立的和新的预后标志物进行相关分析，试图确定与该药物的反应和结果相关的生物标志物。最后，她提出了一系列实验室实验，包括对伊鲁替尼耐药小鼠进行详细的基因组分析，以确定对该药物的耐药机制。具体目标是：1)在65岁及以上未经治疗的CLL患者中进行一项多中心随机III期试验，以确定1)与苯达莫司汀加利妥昔单抗的标准治疗相比，Btk抑制剂依鲁替尼单独使用或与利妥昔单抗联合使用是否能产生更好的无进展生存期（PFS）；2)三种方案的总生存期（OS）和有效率；3)进展时从标准治疗到依鲁替尼的交叉率和交叉后的结果。具体目标2：在伊鲁替尼试验中进行相关研究以评估

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.