While fludarabine-based chemoimmunotherapy (CIT) induces deep remissions and long progression free survival, it is not curative, causes profound T-cell ablation, and promotes selection of drug resistant clones. Biologic studies have demonstrated that signaling mediated by the B-cell receptor is a critical survival pathway in CLL B-cells and inhibitors of this pathway, such as the Bruton's Tyrosine Kinase inhibitor Ibrutinib, have shown robust single agent activity. We are conducting a pivotal phase 3 trial through the North American Intergroup to compare Ibrutinib-based therapy (non-CIT) to fludarabine-based CIT. In the present application we leverage the platform of this clinical trial to perform critical studies evaluating the relationship between cancer biomarkers and clinical outcomes. These scientific studies are designed to: i) define the utility and optimal timing of MRD assessment for both CIT and non-CIT based treatment ii) evaluate the impact of driver mutations and clonal evolution and their relationship to treatment resistance in CIT and non-CIT treated patients and iii) compare the effect of fludarabine and Ibrutinib-based therapy on immune function. These studies are designed to evaluate important ways in which Ibrutinib-based therapy may differ from fludarabine-based treatment. We hypothesize that, while MRD assessment will remain a useful surrogate for progression-free and overall survival for Ibrutinib-based therapy, the timing and thresholds used to classify MRD will differ from conventional CIT. We also hypothesize that acquired clonal heterogeneity and sub-clone expansion that contribute to treatment resistance will develop at lower frequency with an Ibrutinib-based non-CIT approach. However, we also anticipate that mutations in the target BTK gene or other genes downstream of BTK will occur in some patients and be associated with resistance to Ibrutinib. Finally, we expect that Ibrutinib-based therapy will not only be less toxic to T-cell immunity than fludarabine-based treatment but may actually enhance immune function. We will evaluate these hypotheses using research samples from patients participating in the E1912 trial through the following specific aims: Specific Aim 1: Determine if MRD can be used as a surrogate marker of clinical outcome after ibrutinib-based therapy and define the optimal timing and thresholds of assessment. Specific Aim 2: Assess the impact of somatic genetic abnormalities on response to CIT and non-CIT. Specific Aim 3: Characterize immune function after CIT and non-CIT and assess its relationship to clinical outcome. PUBLIC HEALTH RELEVANCE: While effective, standard fludarabine-based chemoimmunotherapy (CIT) approaches for treatment of CLL are not curative and result in substantial toxicity. The Bruton's Tyrosine Kinase (BTK) inhibitor Ibrutinib has profound single agent activity in patients with CLL and appears to be well-tolerated. We are conducting a pivotal phase 3 trial through the North American Intergroup to compare Ibrutinib-based therapy (non-CIT) to standard fludarabine-based CIT. This trial has the potential to dramatically change the initial treatment approach for patients with CLL. The present application leverages the platform of this clinical trial to perform critical studies evaluating the relationship between cancer biomarkers and clinical outcomes. These scientific studies are designed to: i) define the utility and optimal timing of minimal residual disease (MRD) assessment for both CIT and non-CIT based treatment, ii) evaluate the relationship between genetic characteristics and treatment resistance in both CIT and non-CIT treated patients and iii) compare the effect of fludarabine and Ibrutinib-based therapy on immune function. These studies evaluate important ways that Ibrutinib-based therapy may differ from fludarabine-based CIT. Importantly this data will provide critical insights into biomarkers that will improve the clinical application of both CIT and non-CI based treatment approaches for patients with CLL and in this fashion improve the health of patients with this disease.