Background: The Bruton’s Tyrosine Kinase (BTK) inhibitor ibrutinib (I) is very effective in chronic lymphocytic leukemia (CLL), with progression free survival of 76% at 26 months (mo) for patients (pts) with relapsed disease (Byrd J et al, NEJM 2013). We evaluated pts treated with I to explore features associated with progressive disease (PD) and subsequent outcomes. Methods: 267 pts from The Ohio State University Comprehensive Cancer Center participating in 3 previously reported Institutional Review Board approved trials of I were included; 196 pts received single agent I and 71 received I plus ofatumumab. A subset of pts with PD had Ion Torrent deep sequencing (DS) performed on peripheral blood at baseline and relapse. Results: With a median follow-up of 16 mo (<1 mo-42 mo), 201 pts remain on I, and 66 have discontinued due to PD (24), infection (22), toxicity (8), transplant (4), or other (8). PD includes Richter’s transformation (RT; n=16) or progressive CLL(n=8). RT tended to occur early, with 10 pts transforming prior to 12 mo of I. CLL progression tended to occur later, with 1 pt relapsing prior to 12 mo of I. 9 RT pts have died, with 6 deaths occurring within 1 mo without further therapy. Of pts with CLL PD, only 3 of 8 have died at day 25, 142, and 180 after going off study. 3 patients have survived >1 year after PD. 6 pts with CLL PD received further therapy <2 mo post PD, most in ≤ 2 weeks. DS on 4 pts with RT revealed 2 with mutations in BTK and 2 without mutations in BTK or PLCγ2. DS on 6 pts with CLL PD revealed BTK or PLCγ2 mutations in all. 1 pt had both BTK C481S and 3 mutations of PLCγ2, 2 had BTK C481S (1 previously reported; Chang B et al, ASCO 2013), 1 had BTK C481F, and 1 had PLCγ2 R665W (previously reported). An additional 2 pts who have relapsed outside of these studies both have BTK C481S. Conclusions: This single institution experience with I confirms it to be a well tolerated and effective therapy. Patients with PD require therapy quickly due to rapid disease progression. These DS confirm initial reports associating mutations in BTK and PLCγ2 with PD, and require further study in larger populations.