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.