PROJECT SUMMARY Chronic lymphocytic leukemia (CLL) is the most prevalent adult leukemia in the United States and until recently was treated with chemoimmunotherapy at the time of disease related symptoms. Our team has been a major contributor to the introduction of the Bruton’s tyrosine kinase inhibitor ibrutinib and humbled by the results with this agent. Along with this work our recently completed R01 grant for which we seek renewal generated over 30 publications related to mechanism of action, resistance, and toxicities observed with ibrutinib. Additionally, we identified at least 5 new medications that either are in phase 1 clinical trials for resistant diease or will begin within the next year. The initial results of ibrutinib therapy in frontline CLL are promising with 92% of patients being progression free at 5 years and also having immune recovery that diminishes the frequency of infectious morbidity. However, the great majority of patients still have a small component of minimal residual disease (MRD) that requires continuous treatment resulting in long-term morbidity that impacts survivorship. When ibrutinib is discontinuation after extended treatment, it has been observed that some patients rapidly progress whereas other patients can have durable remissions off therapy. This suggests heterogeneity in the residual MRD tumor populations among CLL patients on extended BTKi. Aim 1 therefore focuses on utilizing novel techniques developed by the team to assess the clonal genomic, epigenetic, and biochemical changes in tumor cells from baseline to an extended time on treatment in responding patients treated with ibrutinib for 3 years. Additionally, we seek to understand differential immune statuses of patients with detectable compared to undetectable residual leukemia. Such studies will better guide combination studies in ibrutinib responsive patients to eliminate these residual cells and allow treatment discontinuation. Aim 2 will support a recently initiated phase 1b clinical trial with VAY-736 administered to patients who have been on ibrutinib for 1 year or more. VAY-736 is a BAFF- receptor directed antibody that blocks both BAFF signaling and also has enhanced antibody dependent cytotoxicity. We have demonstrated a novel BAFF-BCL3 signaling pathway that is active in CLL patients on ibrutinib and which may contribute later to resistance. Our pre-clinical and translational data support that VAY- 736 is synergistic with ibrutinib in the TCL1 mouse model of CLL, that it blocks BAFF signaling in CLL cells, and that NK cell function improves with ibrutinib therapy. This trial with ibrutinib followed by VAY-736 will be the first to give delayed antibody therapy when ibrutinib mediated immune recovery has occurred. If successful, this trial will provide justification to pursue future strategies allowing discontinuation of ibrutinib. Ultimately, our goal is to develop combination therapies, such as the one herein with ibrutinib and VAY-736 which...